Unnamed: 0
int64 0
10k
| title
stringlengths 3
547
| abstract
stringlengths 10
122k
⌀ |
|---|---|---|
3,800 |
Deep learning-based behavioral analysis reaches human accuracy and is capable of outperforming commercial solutions
|
To study brain function, preclinical research heavily relies on animal monitoring and the subsequent analyses of behavior. Commercial platforms have enabled semi high-throughput behavioral analyses by automating animal tracking, yet they poorly recognize ethologically relevant behaviors and lack the flexibility to be employed in variable testing environments. Critical advances based on deep-learning and machine vision over the last couple of years now enable markerless tracking of individual body parts of freely moving rodents with high precision. Here, we compare the performance of commercially available platforms (EthoVision XT14, Noldus; TSE Multi-Conditioning System, TSE Systems) to cross-verified human annotation. We provide a set of videos—carefully annotated by several human raters—of three widely used behavioral tests (open field test, elevated plus maze, forced swim test). Using these data, we then deployed the pose estimation software DeepLabCut to extract skeletal mouse representations. Using simple post-analyses, we were able to track animals based on their skeletal representation in a range of classic behavioral tests at similar or greater accuracy than commercial behavioral tracking systems. We then developed supervised machine learning classifiers that integrate the skeletal representation with the manual annotations. This new combined approach allows us to score ethologically relevant behaviors with similar accuracy to humans, the current gold standard, while outperforming commercial solutions. Finally, we show that the resulting machine learning approach eliminates variation both within and between human annotators. In summary, our approach helps to improve the quality and accuracy of behavioral data, while outperforming commercial systems at a fraction of the cost.
|
3,801 |
Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers
|
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
|
3,802 |
A novel bacterial thiosulfate oxidation pathway provides a new clue about the formation of zero-valent sulfur in deep sea
|
Zero-valent sulfur (ZVS) has been shown to be a major sulfur intermediate in the deep-sea cold seep of the South China Sea based on our previous work, however, the microbial contribution to the formation of ZVS in cold seep has remained unclear. Here, we describe a novel thiosulfate oxidation pathway discovered in the deep-sea cold seep bacterium Erythrobacter flavus 21–3, which provides a new clue about the formation of ZVS. Electronic microscopy, energy-dispersive, and Raman spectra were used to confirm that E. flavus 21–3 effectively converts thiosulfate to ZVS. We next used a combined proteomic and genetic method to identify thiosulfate dehydrogenase (TsdA) and thiosulfohydrolase (SoxB) playing key roles in the conversion of thiosulfate to ZVS. Stoichiometric results of different sulfur intermediates further clarify the function of TsdA in converting thiosulfate to tetrathionate ((−)O(3)S–S–S–SO(3)(−)), SoxB in liberating sulfone from tetrathionate to form ZVS and sulfur dioxygenases (SdoA/SdoB) in oxidizing ZVS to sulfite under some conditions. Notably, homologs of TsdA, SoxB, and SdoA/SdoB widely exist across the bacteria including in Erythrobacter species derived from different environments. This strongly indicates that this novel thiosulfate oxidation pathway might be frequently used by microbes and plays an important role in the biogeochemical sulfur cycle in nature.
|
3,803 |
Erratum: Diurnal variation of urinary sodium-to-potassium ratio in free-living Japanese individuals
| null |
3,804 |
Erratum: miR-194-5p/BCLAF1 deregulation in AML tumorigenesis
| null |
3,805 |
The effect of sample size on polygenic hazard models for prostate cancer
|
We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR(98/50) (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69–1.77] to 2.41 [2.40–2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR(98/50) of the Discovery-SNP model increased from 1.05 [0.93–1.18] to 2.19 [2.16–2.23]. HR(98/50) of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70–1.85] and 1.73 [1.71–1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
|
3,806 |
A randomised, prospective study of ‘off-the-shelf’ use of toric intraocular lenses for cataract patients with pre-existing corneal astigmatism in the NHS
|
BACKGROUND/OBJECTIVES: To compare visual and refractive outcomes of monofocal intraocular lenses (IOLs) with limbal relaxing incisions (LRI) with ‘off-the-shelf’ use of toric IOLs (TIOLs), with a fixed 2-dioptre cylinder (DC) correction, for cataract patients with pre-existing corneal astigmatism in a public-sector setting. SUBJECTS/METHODS: Seventy-seven patients (77 eyes, first treated eye) with visually significant cataract and pre-operative corneal astigmatism ≥2.00 DC were randomised to receive either ‘off-the-shelf’ TIOLs, with a fixed 2.00 DC cylinder correction (39 eyes), or monofocal IOLs (38 eyes) with LRIs. The concept of fixing the cylindrical correction was to minimise costs, allow a full TIOL bank to be available and eliminate the need for individual TIOL ordering. Outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA) and refraction. Astigmatic changes were evaluated using the Alpins vector method. RESULTS: Mean UDVA improved from logMAR 0.88 (SD 0.56)[~20/150] pre-operatively to 0.18 (SD 0.19)[~20/30] post-operatively in TIOL group, versus 0.82 (SD 0.55)[~20/130] to 0.27 (SD 0.15)[~20/40] in monofocal/LRI group (P = 0.02; 95% CI: −0.17, −0.01). Mean CDVA improved from logMAR 0.40 (SD 0.26)[~20/50] to 0.01 (SD 0.12)[~20/20] in TIOL group, and 0.41 (SD 0.38)[~20/40] to 0.06 (SD 0.12)[~20/25] in LRI group (P = 0.07; 95% CI: −0.11, 0.01). Average post-operative refractive cylinder in TIOL group was 1.35 DC (SD 0.84 DC) and in LRI group 1.91 DC (SD 1.07 DC) (P = 0.01; 95% CI: −1, −0.12). Mean difference vector magnitude was 1.92 DC (SD 1.08 DC) in LRI group and 1.37 DC (SD 0.84 DC) in TIOL group (P = 0.02; 95% CI: 0.11, 0.99). CONCLUSIONS: TIOLs with a fixed 2.00 DC correction during cataract surgery may improve UDVA, reduce post-operative cylinder and result in a more reliable astigmatic correction compared with monofocal IOLs with LRIs.
|
3,807 |
Author Correction: Origin and evolution of the octoploid strawberry genome
| null |
3,808 |
Tear analysis as the next routine body fluid test
| null |
3,809 |
Correction: Corrigendum: Sources of discordance among germ-line variant classifications in ClinVar
| null |
3,810 |
Earlier parasite arrival reduces the repeatability of host adaptive radiation
|
Although parasites are known to have various effects on their hosts, we know little about their role in the assembly of diversifying host populations. Using an experimental bacterium (Pseudomonas fluorescens SBW25)-bacteriophage (ϕ2) system, we show that earlier parasite arrival significantly reduced the repeatability of host diversification. Earlier parasite arrival amplified the priority effects associated with the stochastic emergence of novel SBW25 phenotypes, translating into greater historical contingency in SBW25 diversification. Our results highlight the important role of parasite-host interactions in driving host adaptive radiation.
|
3,811 |
Correction: Cultivation and characterization of Candidatus Nitrosocosmicus exaquare, an ammonia-oxidizing archaeon from a municipal wastewater treatment system
| null |
3,812 |
Correction: Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis
| null |
3,813 |
Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration
|
Peripheral nerve injury (PNI), one of the most common concerns following trauma, can result in a significant loss of sensory or motor function. Restoration of the injured nerves requires a complex cellular and molecular response to rebuild the functional axons so that they can accurately connect with their original targets. However, there is no optimized therapy for complete recovery after PNI. Supplementation with exogenous growth factors (GFs) is an emerging and versatile therapeutic strategy for promoting nerve regeneration and functional recovery. GFs activate the downstream targets of various signaling cascades through binding with their corresponding receptors to exert their multiple effects on neurorestoration and tissue regeneration. However, the simple administration of GFs is insufficient for reconstructing PNI due to their short half‑life and rapid deactivation in body fluids. To overcome these shortcomings, several nerve conduits derived from biological tissue or synthetic materials have been developed. Their good biocompatibility and biofunctionality made them a suitable vehicle for the delivery of multiple GFs to support peripheral nerve regeneration. After repairing nerve defects, the controlled release of GFs from the conduit structures is able to continuously improve axonal regeneration and functional outcome. Thus, therapies with growth factor (GF) delivery systems have received increasing attention in recent years. Here, we mainly review the therapeutic capacity of GFs and their incorporation into nerve guides for repairing PNI. In addition, the possible receptors and signaling mechanisms of the GF family exerting their biological effects are also emphasized.
|
3,814 |
Correction: Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by downregulating GluN2B
| null |
3,815 |
Correction: The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1–6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7–34 pathogenic variant
| null |
3,816 |
Potential utilization of terrestrially derived dissolved organic matter by aquatic microbial communities in saline lakes
|
Lakes receive large amounts of terrestrially derived dissolved organic matter (tDOM). However, little is known about how aquatic microbial communities interact with tDOM in lakes. Here, by performing microcosm experiments we investigated how microbial community responded to tDOM influx in six Tibetan lakes of different salinities (ranging from 1 to 358 g/l). In response to tDOM addition, microbial biomass increased while dissolved organic carbon (DOC) decreased. The amount of DOC decrease did not show any significant correlation with salinity. However, salinity influenced tDOM transformation, i.e., microbial communities from higher salinity lakes exhibited a stronger ability to utilize tDOM of high carbon numbers than those from lower salinity. Abundant taxa and copiotrophs were actively involved in tDOM transformation, suggesting their vital roles in lacustrine carbon cycle. Network analysis indicated that 66 operational taxonomic units (OTUs, affiliated with Alphaproteobacteria, Actinobacteria, Bacteroidia, Bacilli, Gammaproteobacteria, Halobacteria, Planctomycetacia, Rhodothermia, and Verrucomicrobiae) were associated with degradation of CHO compounds, while four bacterial OTUs (affiliated with Actinobacteria, Alphaproteobacteria, Bacteroidia and Gammaproteobacteria) were highly associated with the degradation of CHOS compounds. Network analysis further revealed that tDOM transformation may be a synergestic process, involving cooperation among multiple species. In summary, our study provides new insights into a microbial role in transforming tDOM in saline lakes and has important implications for understanding the carbon cycle in aquatic environments.
|
3,817 |
Innate lymphoid cells: Potent early mediators of the host immune response during sepsis
| null |
3,818 |
Erratum to: Health-exploring complexity: an interdisciplinary systems approach HEC2016: 28 August–2 September 2016, Munich, Germany
| null |
3,819 |
Prevalence and risk factors of childhood blepharoptosis in Koreans: the Korea National Health and Nutrition Examination Survey
|
PURPOSE: Childhood blepharoptosis may cause cosmetic and functional problems in children, but there is a paucity of studies about its epidemiology. This study aimed to investigate the prevalence of childhood blepharoptosis and associated risk factors in a representative Korean population. METHODS: This cross-sectional nation-wide study analysed the data set acquired from the Korea National Health and Nutrition Examination Survey 2008–2012. A total of 8218 children aged 3–18 years were included. The prevalence of childhood blepharoptosis, defined as a margin reflex distance (MRD) of < 2 mm in either eye, was estimated, and the risk factors were identified using multivariate logistic regression analysis. RESULTS: The mean age of participants was 11.3 ± 0.1 years, and 52.8 ± 0.6% were boys. The overall prevalence of childhood blepharoptosis in Korea was 8.0% (95% CI, 6.9–9.1%). Boys exhibited a higher prevalence of blepharoptosis than girls at most of ages. Levator function increased with age in the normal general population. The proportion of subjects exhibiting MRD1 ≥ 4.0 mm also increased significantly with age (p < 0.001). Male gender, higher body mass index, and urban residency were significantly associated with childhood blepharoptosis. CONCLUSIONS: The prevalence of childhood blepharoptosis is higher in urban obese boys. The increase of levator function with age should be considered in evaluations of childhood ptosis.
|
3,820 |
Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model?
|
Noonan syndrome (NS) is an autosomal-dominant disorder with variable expressivity and locus heterogeneity. Despite several RAS pathway genes were implicated in NS, 20–30% of patients remain without molecular diagnosis, suggesting the involvement of further genes or multiple mechanisms. Eight patients out of 60, negative for conventional NS mutation analysis, with heterogeneous NS phenotype were investigated by means of target resequencing of 26 RAS/MAPK pathway genes. A trio was further characterized by means of whole-exome sequencing. Protein modeling and in silico prediction of protein stability allowed to identify possible pathogenic RAS pathway variants in four NS patients. A new c.355T>C variant in LZTR1 was found in patient 43. Two patients co-inherited variants in LRP1 and LZTR1 (patient 53), or LRP1 and SOS1 genes (patient 67). The forth patient (56) carried a compound heterozygote of RASAL3 gene variants and also an A2ML1 variant. While these subclinical variants are singularly present in healthy parents, they co-segregate in patients, suggesting their addictive effect and supporting a digenic inheritance, as alternative model to a more common monogenic transmission. The ERK1/2 and SAPK/JNK activation state, assessed on immortalized lymphocytes from patients 53 and 67 showed highest phosphorylation levels compared to their asymptomatic parents. These findings together with the lack of their co-occurrence in the 1000Genomes database strengthen the hypothesis of digenic inheritance in a subset of NS patients. This study suggests caution in the exclusion of subclinical variants that might play a pathogenic role providing new insights for alternative hereditary mechanisms.
|
3,821 |
Foraging postures are a potential communicative signal in female bonobos
|
Body postures are essential in animal behavioural repertoires and their communicative role has been assessed in a wide array of taxa and contexts. Some body postures function as amplifiers, a class of signals that increase the detection likelihood of other signals. While foraging on the ground, bonobos (Pan paniscus) can adopt different crouching postures exposing more or less of their genital area. To our knowledge, their potential functional role in the sociosexual life of bonobos has not been assessed yet. Here we show, by analysing more than 2,400 foraging events in 21 captive bonobos, that mature females adopt a rear-exposing posture (forelimb-crouch) and do so significantly more often when their anogenital region is swollen than during the non-swollen phase. In contrast, mature males almost completely avoid this posture. Moreover, this strong difference results from a diverging ontogeny between males and females since immature males and females adopt the forelimb-crouch at similar frequencies. Our findings suggest that the forelimb-crouch posture may play a communicative role of amplification by enhancing the visibility of female sexual swellings, a conspicuous signal that is very attractive for both males and females. Given the high social relevance of this sexual signal, our study emphasizes that postural signalling in primates probably deserves more attention, even outside of reproductive contexts.
|
3,822 |
Using an integrative machine learning approach utilising homology modelling to clinically interpret genetic variants: CACNA1F as an exemplar
|
Advances in DNA sequencing technologies have revolutionised rare disease diagnostics and have led to a dramatic increase in the volume of available genomic data. A key challenge that needs to be overcome to realise the full potential of these technologies is that of precisely predicting the effect of genetic variants on molecular and organismal phenotypes. Notably, despite recent progress, there is still a lack of robust in silico tools that accurately assign clinical significance to variants. Genetic alterations in the CACNA1F gene are the commonest cause of X-linked incomplete Congenital Stationary Night Blindness (iCSNB), a condition associated with non-progressive visual impairment. We combined genetic and homology modelling data to produce CACNA1F-vp, an in silico model that differentiates disease-implicated from benign missense CACNA1F changes. CACNA1F-vp predicts variant effects on the structure of the CACNA1F encoded protein (a calcium channel) using parameters based upon changes in amino acid properties; these include size, charge, hydrophobicity, and position. The model produces an overall score for each variant that can be used to predict its pathogenicity. CACNA1F-vp outperformed four other tools in identifying disease-implicated variants (area under receiver operating characteristic and precision recall curves = 0.84; Matthews correlation coefficient = 0.52) using a tenfold cross-validation technique. We consider this protein-specific model to be a robust stand-alone diagnostic classifier that could be replicated in other proteins and could enable precise and timely diagnosis.
|
3,823 |
Erratum: Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials
| null |
3,824 |
Response to ‘Comment on: ‘A new era for giant cell arteritis’’
| null |
3,825 |
Access to intraoperative tumour margin control: a survey of the British Oculoplastic Surgery Society
|
BACKGROUND: Periocular malignancy is common and in most cases will undergo excision with pre-determined margins and subsequent histological examination. Intraoperative margin control (IOMC) modalities such as fast frozen section (FFS), fast paraffin (FP) and Mohs micrographic surgery (MMS) are being increasingly widely used, though there is a lack of information regarding utility. The aim of this study was to survey members of the British Oculoplastic Surgery Society (BOPSS) to determine attitudes and access to different modalities of IOMC. METHODS: A 12-question online survey was disseminated via an e-mail to full members of the BOPSS. The survey was hosted using Qualtrics software via the University of Sussex. RESULTS: The overall response rate was 64 of 165 (38.8%). MMS was readily available in a neighbouring trust to 23 of 64 respondents (35.9%). Seven respondents (10.9%) reported no regional access to MMS. Twenty-nine members had readily available access to FFS (45.3%) and 37 of 64 to FP (57.8%) in their own institution. There is variation in what tumour types would be considered appropriate for IOMC, though most thought clinically ill-defined (morphoeic) basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) should undergo one form of IOMC (90.6% and 81.3%, respectively). CONCLUSION: This study highlights variation in availability and utilisation of IOMC amongst oculoplastic surgeons and in different regions of the UK. While the exact place of IOMC in periocular tumour excision is debated, there is a consistent view that it should be available for some tumours. Greater consistency in provision may improve patient outcomes.
|
3,826 |
BANK1 interacts with TRAF6 and MyD88 in innate immune signaling in B cells
|
Evidence supports a possible role of BANK1 in innate immune signaling in B cells. In the present study, we investigated the interaction of BANK1 with two key mediators in interferon and inflammatory cytokine production, TRAF6 and MyD88. We revealed by coimmunoprecipitation (CoIP) analyses the binding of BANK1 with TRAF6 and MyD88, which were mediated by the BANK1 Toll/interleukin-1 receptor (TIR) domain. In addition, the natural BANK1–40C variant showed increased binding to MyD88. Next, we demonstrated in mouse splenic B cells that BANK1 colocalized with Toll-like receptor (TLR) 7 and TLR9 and that after stimulation with TLR7 and TLR9 agonists, the number of double-positive BANK1–TLR7, –TLR9, –TRAF6, and –MyD88 cells increased. Furthermore, we identified five TRAF6-binding motifs (BMs) in BANK1 and confirmed by point mutations and decoy peptide experiments that the C-terminal domain of BANK1-full-length (-FL) and the N-terminal domain of BANK1–Delta2 (-D2) are necessary for this binding. Functionally, we determined that the absence of the TIR domain in BANK1–D2 is important for its lysine (K)63-linked polyubiquitination and its ability to produce interleukin (IL)-8. Overall, our study describes a specific function of BANK1 in MyD88–TRAF6 innate immune signaling in B cells, clarifies functional differences between the two BANK1 isoforms and explains for the first time a functional link between autoimmune phenotypes including SLE and the naturally occurring BANK1–40C variant.
|
3,827 |
Response to ‘Comment on: ‘You have got dry macular degeneration, end of story’: a qualitative study into the experience of living with non-neovascular age-related macular degeneration’
| null |
3,828 |
Correction to: 2020 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference
| null |
3,829 |
Correction to: Trends in erectile dysfunction research from 2008 to 2018: a bibliometric analysis
| null |
3,830 |
The tsAPOBEC3 proteins restrict HBV replication and may limit the establishment of persistent infection in tree shrews
| null |
3,831 |
Correction: Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells
| null |
3,832 |
Nesfatin-1 puts the brakes on reward-based feeding
| null |
3,833 |
Correction: The Relative Contribution of Metabolic and Structural Abnormalities to Diastolic Dysfunction in Obesity
| null |
3,834 |
Correction: USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation
| null |
3,835 |
The Royal College of Ophthalmologists’ National Ophthalmology Database study of cataract surgery: Report 7, immediate sequential bilateral cataract surgery in the UK: Current practice and patient selection
|
BACKGROUND: Cataract extraction is the most frequently performed surgical intervention in the world and demand is rising due to an ageing demography. One option to address this challenge is to offer selected patients immediate sequential bilateral cataract surgery (ISBCS). This study aims to investigate patient and operative characteristics for ISBCS and delayed bilateral cataract surgery (DSCS) in the UK. METHODS: Data were analysed from the Royal College of Ophthalmologists’ National Ophthalmology Database Audit (NOD) of cataract surgery. Eligible patients were those undergoing bilateral cataract extraction from centres with a record of at least one ISBCS operation between 01/04/2010 and 31/08/2018. Variable frequency comparison was undertaken with chi-square tests. RESULTS: During the study period, 1073 patients had ISBCS and 248,341 DSCS from 73 centres. A higher proportion of ISBCS patients were unable to lie flat (11.3% vs. 1.8%; p < 0.001), unable to cooperate (9.7% vs. 2.7%; p < 0.001); underwent general anaesthesia (58.7% vs. 6.6% (p < 0.001)); had brunescent/white/mature cataracts (odds ratio (OR) 5.118); no fundal view/vitreous opacities (OR 8.381); had worse pre-operative acuity 0.60 LogMAR ISBCS vs. 0.50 (first) and 0.40 (second eye) DSCS and were younger (mean ages, 71.5 vs. 75.6 years; p < 0.001). Posterior capsular rupture (PCR) rates adjusted for case complexity were comparable (0.98% ISBCS and 0.78% DSCS). CONCLUSIONS: ISBCS was performed on younger patients, with difficulty cooperating and lying flat, worse pre-operative vision, higher rates of known PCR risk factors and more frequent use of general anaesthesia than DSCS in centres recorded on NOD.
|
3,836 |
Erratum: Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment
| null |
3,837 |
Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis
| null |
3,838 |
Correction to: Abstracts: 31(st) European Congress of Pathology
| null |
3,839 |
Erratum: Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats
| null |
3,840 |
Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome
|
PTEN hamartoma tumour syndrome is a diverse multi-system disorder predisposing to the development of hamartomatous growths, increasing risk of breast, thyroid, renal cancer, and possibly increasing risk of endometrial cancer, colorectal cancer and melanoma. There is no international consensus on cancer surveillance in PHTS and all current guidelines are based on expert opinion. A comprehensive literature review was undertaken and guidelines were developed by clinicians with expertise from clinical genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and general surgery, together with affected individuals and their representatives. Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. The proposed cancer surveillance recommendations for PHTS require a coordinated multidisciplinary approach and significant patient commitment. The evidence base for cancer surveillance in this guideline are limited, emphasising the need for prospective evaluation of the effectiveness of surveillance in the PHTS population.
|
3,841 |
A novel case and review of paediatric Horner syndrome
| null |
3,842 |
Correction to: Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis
| null |
3,843 |
Erratum: A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence
| null |
3,844 |
Publisher Correction: Image Data Resource: a bioimage data integration and publication platform
| null |
3,845 |
Erratum to: JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects
| null |
3,846 |
Correction: TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants
| null |
3,847 |
Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study
|
Proton magnetic resonance spectroscopy ((1)H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain (1)H-MRS, in early schizophrenia. Three dimensional (1)H-MRS was acquired in young schizophrenia subjects (N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N-acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV’s > 0.05). However, creatine was higher in antipsychotic-treated vs HC’s in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.
|
3,848 |
Author Correction: Telemedicine — maintaining quality during times of transition
| null |
3,849 |
Alternative Checkpoints as Targets for Immunotherapy
|
PURPOSE OF REVIEW: Immunotherapy has shown an unprecedented response in treatment of tumors. However, challenges such as lack of cytotoxic lymphocytes to mount an immune response or development of resistance to therapy can limit efficacy. Here, we discuss alternative checkpoints that can be targeted to improve cytotoxic lymphocyte function while harnessing other components of the immune system. RECENT FINDINGS: Blockade of alternative checkpoints has improved anti-tumor immunity in mouse models and is being tested clinically with encouraging findings. In addition to modulating T cell function directly, alternative checkpoints can also regulate activity of myeloid cells and regulatory T cells to affect anti-tumor response. SUMMARY: Combination of immune checkpoint inhibitors can improve treatment of tumors by activating multiple arms of the immune system.
|
3,850 |
Optical coherence tomography angiography (OCTA) applications in ocular oncology
|
Optical coherence tomography angiography (OCTA) is a revolutionary method in the visualization of the vascular system in different retinal and choroidal layers. During the last 4 years since the commercial availability of different OCTA devices, attempts have been made to utilize this technology in various aspects of ocular oncology from the differentiation of benign and malignant lesions to assisting in evaluation of post-treatment complications, such as radiation retinopathy. However, current OCTA technology is restricted by various artefacts and inherent limitations, some of which are more pronounced in the presence of elevated tumoural lesions. Imminent advancements in OCTA systems and image acquisition processes promise a great potential for application of OCTA in ocular oncology.
|
3,851 |
Erratum: Prediction of human population responses to toxic compounds by a collaborative competition
| null |
3,852 |
Correction to: Abstracts: 31st European Congress of Pathology
| null |
3,853 |
Correction: Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori
| null |
3,854 |
Publisher Correction: The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group
| null |
3,855 |
Observation of topical tacrolimus on high-risk penetrating keratoplasty patients: a randomized clinical trial study
|
BACKGROUND/OBJECTIVES: To evaluate the clinical efficacy of topical tacrolimus 0.1% and cyclosporine 1% on high-risk penetrating keratoplasty (PKP) patients. SUBJECTS/METHODS: A series of 49 high-risk PKP patients (49 eyes), 20 males, 29 females from the age of 4 months to 74 years of age with the mean of 32.5 from 2012 to 2017 were recruited in this study. The patients were randomly divided into two groups by receiving either topical tacrolimus 0.1% or cyclosporine 1% respectively. Twenty five patients were treated with topical tacrolimus 0.1% and 24 patients with topical cyclosporine 1%. The traditional baseline management on these two groups were Tobramycin and Dexamethasone eye drops in the first 3 weeks and then tapered off. Clinical procedures and postoperative follow-up were documented. RESULTS: After 6–54 months follow-up, with the average of 24 months, 11 of 24 high-risk patients (11 eyes) had graft rejection, the rejection rate was 45.8% in topical cyclosporine 1% group. The rejections occurred from 35 days to 20 months after PKP. Three patients had irreversible rejection. On topical tacrolimus 0.1% group, the rejection occurred in four patients (four eyes) with rejection rate of 16%, and no irreversible rejection was observed. The graft rejection episodes were documented between 23 days and 24 months. As compared with the topical cyclosporine 1%, topical tacrolimus 0.1%, a key immunosuppressant, significantly decreased corneal graft rejection rate (p = 0.02). CONCLUSIONS: Topical tacrolimus 01% on high-risk PKP patients significantly prevented corneal graft rejection, and it had less adverse effects and was very safe to high-risk patients as to topical cyclosporine 1%. Further case controlled randomized clinical trial studies are needed to establish the best management option for these high-risk patients.
|
3,856 |
Variants of innate CD8(+) T cells are associated with Grip2 and Klf15 genes
| null |
3,857 |
Retraction Note: Resveratrol rescues hyperglycemia-induced endothelial dysfunction via activation of Akt
| null |
3,858 |
Erratum: A high-salt diet enhances leukocyte adhesion in association with kidney injury in young Dahl salt-sensitive rats
| null |
3,859 |
Evaluation of medical and surgical decompression in patients with dysthyroid optic neuropathy
|
PURPOSE: To evaluate the effectiveness of steroid-pulse therapy and three-wall orbital decompression in patients with dysthyroid optic neuropathy (DON). METHODS: Twenty-five patients (46 eyes) with a diagnosis of DON between 2008 and 2015 were included in the study. The first group (7 patients, 16 eyes) consisted of patients with a steroid-pulse treatment only and the second group (18 patients, 30 eyes) included patients with medical and surgical decompression. RESULTS: Twenty patients were female; five patients were male. After the diagnosis of DON, all patients were treated with steroid-pulse treatment (intravenous 500 mg prednisolon twice/week for 4 weeks, 250 mg twice/week for 2 weeks) as a first-line treatment (medical decompression). In 30 eyes (18 patients) out of 46 eyes, (25 patients) an orbital decompression was needed to preserve the optic nerve function. In those therapy-resistant cases (surgical decompression group), the orbital decompression led to statistically significant improvements in best-corrected visual acuity (BCVA), protan and tritan value of the color vision (p = 0.007, p < 0.0001, p = 0.019, respectively, comparison of first visit to last visit). CONCLUSION: According to our data, the mild cases of DON with better initial visual acuity (in our case series mean: 0.3 logMAR) seem to respond well to steroid treatment. However, therapy-resistant cases with an impaired initial BCVA (in our case series, mean: 0.6 logMAR) seem to need the surgery to preserve the optic nerve function. In conclusion, this retrospective study confirms the effectiveness of surgical decompression in therapy-resistant cases of DON.
|
3,860 |
Inflammasome genetics and complex diseases: a comprehensive review
|
The inflammasome is a cytoplasmic multiprotein complex responsible for the activation of inflammatory caspases (caspase-1, -4, and -5) in response to pathogen- and/or damage-associated molecular patterns or to homeostasis-altering molecular pathways, and for the consequent release of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Taking in account the complexity of inflammasome activation and that several regulatory steps are involved in maintaining its physiologic role in homeostasis and innate immune response, it does not surprise that several genetic variants in inflammasome components have been associated with common pathologies in the general population, such as autoimmune disorders, cardiovascular diseases, obesity and associated metabolic syndrome, neurodegenerative diseases, and cancer. Moreover, the susceptibility to infectious agents and/or to develop severe complications during infections also has been related to inflammasome genetics. In this work, we revised genetic association studies about polymorphisms of main inflammasome genes in sterile as well as infectious diseases, trying to depict the genetic contribution of inflammasome in disease pathogenesis.
|
3,861 |
Warning wristbands for patients with intra-ocular gas
| null |
3,862 |
Correction: High-risk additional chromosomal abnormalities at low blast counts herald death by CML
| null |
3,863 |
Correction: Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies
| null |
3,864 |
Erratum: Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer
| null |
3,865 |
Erratum zu: Epidemiologie des Ebolafiebers und anderer, in Deutschland seltener hochkontagiöser, lebensbedrohlicher Erkrankungen
| null |
3,866 |
Erratum to: Is this critically ill patient immunocompromised?
| null |
3,867 |
Correction to: Abstracts: 31(st) European Congress of Pathology
| null |
3,868 |
Correction to: Schistosomiasis—from immunopathology to vaccines
| null |
3,869 |
Correction to: Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)
| null |
3,870 |
Elevated fatty acid amide hydrolase in the prefrontal cortex of borderline personality disorder: a [(11)C]CURB positron emission tomography study
|
Amygdala-prefrontal cortex (PFC) functional impairments have been linked to emotion dysregulation and aggression in borderline personality disorder (BPD). Fatty acid amide hydrolase (FAAH), the major catabolic enzyme for the endocannabinoid anandamide, has been proposed as a key regulator of the amygdala-PFC circuit that subserves emotion regulation. We tested the hypothesis that FAAH levels measured with [(11)C]CURB positron emission tomography in amygdala and PFC would be elevated in BPD and would relate to hostility and aggression. Twenty BPD patients and 20 healthy controls underwent FAAH genotyping (rs324420) and scanning with [(11)C]CURB. BPD patients were medication-free and were not experiencing a current major depressive episode. Regional differences in [(11)C]CURB binding were assessed using multivariate analysis of covariance with PFC and amygdala [(11)C]CURB binding as dependent variables, diagnosis as a fixed factor, and sex and genotype as covariates. [(11)C]CURB binding was marginally elevated across the PFC and amygdala in BPD (p = 0.08). In a priori selected PFC, but not amygdala, [(11)C]CURB binding was significantly higher in BPD (11.0%, p = 0.035 versus 10.6%, p = 0.29). PFC and amygdala [(11)C]CURB binding was positively correlated with measures of hostility in BPD (r > 0.4; p < 0.04). This study is the first to provide preliminary evidence of elevated PFC FAAH binding in any psychiatric condition. Findings are consistent with the model that lower endocannabinoid tone could perturb PFC circuitry that regulates emotion and aggression. Replication of these findings could encourage testing of FAAH inhibitors as innovative treatments for BPD.
|
3,871 |
Erratum to: The Intensive Care Global Study on Severe Acute Respiratory Infection (IC‑GLOSSARI): a multicenter, multinational, 14-day inception cohort study
| null |
3,872 |
The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L
|
Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including cancer. In mammals, mitophagy is mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN(+/+) cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN(+/+), but not CRBN(−/−) cell. Thus, our data uncover a novel role of CC-885 in the regulation of mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.
|
3,873 |
Publisher Correction: Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)
| null |
3,874 |
Correction: A molecular portrait of epithelial–mesenchymal plasticity in prostate cancer associated with clinical outcome
| null |
3,875 |
Ritanserin blocks Ca(V)1.2 channels in rat artery smooth muscles: electrophysiological, functional, and computational studies
|
Ca(V)1.2 channel blockers or 5-HT(2) receptor antagonists constitute effective therapy for Raynaud’s syndrome. A functional link between the inhibition of 5-HT(2) receptors and Ca(V)1.2 channel blockade in arterial smooth muscles has been hypothesized. Therefore, the effects of ritanserin, a nonselective 5-HT(2) receptor antagonist, on vascular Ca(V)1.2 channels were investigated through electrophysiological, functional, and computational studies. Ritanserin blocked Ca(V)1.2 channel currents (I(Ca1.2)) in a concentration-dependent manner (K(r) = 3.61 µM); I(Ca1.2) inhibition was antagonized by Bay K 8644 and partially reverted upon washout. Conversely, the ritanserin analog ketanserin (100 µM) inhibited I(Ca1.2) by ~50%. Ritanserin concentration-dependently shifted the voltage dependence of the steady-state inactivation curve to more negative potentials (K(i) = 1.58 µM) without affecting the slope of inactivation and the activation curve, and decreased I(Ca1.2) progressively during repetitive (1 Hz) step depolarizations (use-dependent block). The addition of ritanserin caused the contraction of single myocytes not yet dialyzed with the conventional method. Furthermore, in depolarized rings, ritanserin, and to a lesser extent, ketanserin, caused a concentration-dependent relaxation, which was antagonized by Bay K 8644. Ritanserin and ketanserin were docked at a region of the Ca(V)1.2 α(1C) subunit nearby that of Bay K 8644; however, only ritanserin and Bay K 8644 formed a hydrogen bond with key residue Tyr-1489. In conclusion, ritanserin caused in vitro vasodilation, accomplished through the blockade of Ca(V)1.2 channels, which was achieved preferentially in the inactivated and/or resting state of the channel. This novel activity encourages the development of ritanserin derivatives for their potential use in the treatment of Raynaud’s syndrome.
|
3,876 |
Lowered endogenous mu-opioid receptor availability in subclinical depression and anxiety
|
Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain’s MOR availability was measured with positron emission tomography (PET) using an agonist radioligand [(11)C]carfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.
|
3,877 |
Brolucizumab and immunogenicity
| null |
3,878 |
Erratum to: Protein Phosphatase 2A as a Drug Target in the Treatment of Cancer and Alzheimer’s Disease
| null |
3,879 |
Correction: Estimating the burden and economic impact of pediatric genetic disease
| null |
3,880 |
Erratum to: Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies
| null |
3,881 |
Differential DNA methylation in allergen-specific immunotherapy of asthma
| null |
3,882 |
Correction: Sequencing as a first-line methodology for cystic fibrosis carrier screening
| null |
3,883 |
Correction: Active PLK1-driven metastasis is amplified by TGF-β signaling that forms a positive feedback loop in non-small cell lung cancer
| null |
3,884 |
Erratum: Strains, functions and dynamics in the expanded Human Microbiome Project
| null |
3,885 |
What do we do and how do we do it? Assessing genetic counselling in the modern era
| null |
3,886 |
Publisher Correction: Precision and accuracy of single-molecule FRET measurements—a multi-laboratory benchmark study
| null |
3,887 |
Correction to: The landscape of epilepsy-related GATOR1 variants
| null |
3,888 |
Assessing the stability of biobank donor preferences regarding sample use: evidence supporting the value of dynamic consent
|
Dynamic consent has been proposed as a strategy for addressing the limitations of traditional, broad consent for biobank participation. Although the argument for dynamic consent has been made on theoretical grounds, empirical studies evaluating the potential utility of dynamic consent are needed to enhance deliberations about the merits of dynamic consent. Few studies have assessed such considerations as whether donor preferences may change over time or if participants would use a dynamic consent mechanism to modify preferences when they change. We administered a 66-item survey to participants in a large DNA biobank. The survey sought to gauge the stability of donor preferences specified at the time of biobank enrollment, specifically the stability of donors’ preference regarding posthumous availability of biospecimens to next-of-kin. We received 1164 completed surveys for a response rate of 72%. Forty percent of respondents indicated a preference regarding sample availability on the survey (T2) that was inconsistent with the preference they had expressed when they enrolled in the biobank (T1). Most (94%) individuals with inconsistent preferences regarding sample availability had initially restricted sample availability at T1 but were comfortable with broader availability when asked at the time of the survey (T2). Our findings demonstrate that preferences regarding sample use expressed at the time of enrollment in a DNA biobank may not be reliable indicators of donor preferences over time. These findings lend empirical support to the case for a dynamic consent model in which biobank participants are approached over time to clarify their views regarding sample use.
|
3,889 |
Management of information within Portuguese families with Huntington disease: a transgenerational process for putting the puzzle together
|
Huntington disease (HD) is a rare progressive neurological disease, with no cure, inherited in an autosomal dominant fashion, significantly impacting family relations, health and well-being. So far, no studies have reported how Portuguese families deal with information about HD, from a transgenerational perspective. This qualitative study aims to fill in that gap, and focuses on how families acquire knowledge about HD and management of information within the family and in their social relationships. The study adopted semi-structured interviews with 10 participants from HD families. Interviews were transcribed and analysed thematically. Findings suggested that management of information in the family started with the search for a diagnosis in an affected family member. Diagnosis led to a process of “making sense of HD in the family”, which activated a transgenerational process to understand HD in the family context, marked by improved awareness and different ways family members manage it (closedness and openness). These results should be relevant for health-care professionals, bringing further insight into the process of acquiring knowledge about HD, and highlighting the relevance of continued efforts for enhanced pre- and post-test counselling and ongoing support to the HD families.
|
3,890 |
Opioid antagonists are associated with a reduction in the symptoms of schizophrenia: a meta-analysis of controlled trials
|
Current treatments for the symptoms of schizophrenia are only effective for positive symptoms in some individuals, and have considerable side effects that impact compliance. Thus, there is a need to investigate the efficacy of other compounds in treating both positive and negative symptoms. We conducted a meta-analysis of English language placebo-controlled clinical trials of naloxone, naltrexone, nalmefene, and buprenorphine in patients with schizophrenia to determine whether opioid antagonists have therapeutic efficacy on positive, negative, total, or general symptoms. We searched online databases Ovid Medline and PsychINFO, PubMed, EMBASE, Scopus, Cochrane library/CENTRAL, Web of Science, and Google Scholar from 1970 through February 2019. Following PRISMA guidelines, Hedges g was calculated for each study. Primary study outcomes were the within-subject change on any symptom assessment scale for positive, negative, total, or general symptoms of schizophrenia between active drug and placebo conditions. Thirty studies were included with 434 total patients. We found a significant effect of all drugs on all scales combined with both a standard random effects model: (g = 0.26; P = 0.02; k = 22; CI = 0.03–0.49) and a more inclusive bootstrap model: (g = 0.26; P = 0.0002; k = 30; CI = 0.11–0.51) and a significant effect on total scales with the bootstrap model (g = 0.25288; P = 0.015; k = 19; CI = 0.04–0.35). We also observed a significant effect of all drugs on all positive scales combined with both the random effects (g = 0.33; P = 0.015; k = 17; CI = 0.07–0.60) and bootstrap models (g = 0.32; P < 0.0001; k = 21; CI = 0.13–1.38). This evidence provides support for further testing in randomized clinical trials of a new class of non-D2-receptor drugs, based on opioid mechanisms, for the treatment of positive and negative symptoms of schizophrenia.
|
3,891 |
Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1–BP2) deletion in the UK Biobank
|
Deletion of a non-imprinted 500kb genomic region at chromosome 15q11.2, between breakpoints 1 and 2 of the Prader–Willi/Angelman locus (BP1–BP2 deletion), has been associated in previous studies with phenotypes including congenital cardiovascular malformations (CVM). Previous studies investigating association between BP1–BP2 deletion and CVM have tended to recruit cases with rarer and more severe CVM phenotypes; the impact of CVM on relatively unselected population cohorts, anticipated to contain chiefly less severe but commoner CHD phenotypes, is relatively unexplored. More precisely defining the impact of BP1–BP2 deletion on CVM risk could be useful to guide genetic counselling, since the deletion is frequently identified in the neurodevelopmental clinic. Using the UK Biobank (UKB) cohort of ~500,000 individuals, we identified individuals with CVM and investigated the association with deletions at the BP1–BP2 locus. In addition, we assessed the association of BP1–BP2 deletions with neuropsychiatric diagnoses, cognitive function and academic achievement. Cases of CVM had an increased prevalence of the deletion compared with controls (0.64%; OR = 1.73 [95% CI 1.08–2.75]; p = 0.03), as did those with neuropsychiatric diagnoses (0.68%; OR = 1.84 [95% CI 1.23–2.75]; p = 0.004). We conclude that BP1–BP2 deletion moderately increases the risk of the generally milder, but commoner, CVM phenotypes seen in this unselected population, in addition to its previously demonstrated association in case/control studies ascertained for CVM.
|
3,892 |
Δ(9)-Tetrahydrocannabinol (THC) impairs visual working memory performance: a randomized crossover trial
|
With the increasing prevalence of legal cannabis use and availability, there is an urgent need to identify cognitive impairments related to its use. It is widely believed that cannabis, or its main psychoactive component Δ(9)-tetrahydrocannabinol (THC), impairs working memory, i.e., the ability to temporarily hold information in mind. However, our review of the literature yielded surprisingly little empirical support for an effect of THC or cannabis on working memory. We thus conducted a study with three main goals: (1) quantify the effect of THC on visual working memory in a well-powered sample, (2) test the potential role of cognitive effects (mind wandering and metacognition) in disrupting working memory, and (3) demonstrate how insufficient sample size and task duration reduce the likelihood of detecting a drug effect. We conducted two double-blind, randomized crossover experiments in which healthy adults (N = 23, 23) performed a reliable and validated visual working memory task (the “Discrete Whole Report task”, 90 trials) after administration of THC (7.5 and/or 15 mg oral) or placebo. We also assessed self-reported “mind wandering” (Exp 1) and metacognitive accuracy about ongoing task performance (Exp 2). THC impaired working memory performance (d = 0.65), increased mind wandering (Exp 1), and decreased metacognitive accuracy about task performance (Exp 2). Thus, our findings indicate that THC does impair visual working memory, and that this impairment may be related to both increased mind wandering and decreased monitoring of task performance. Finally, we used a down-sampling procedure to illustrate the effects of task length and sample size on power to detect the acute effect of THC on working memory.
|
3,893 |
Cheaters shape the evolution of phenotypic heterogeneity in Bacillus subtilis biofilms
|
Biofilms are closely packed cells held and shielded by extracellular matrix composed of structural proteins and exopolysaccharides (EPS). As matrix components are costly to produce and shared within the population, EPS-deficient cells can act as cheaters by gaining benefits from the cooperative nature of EPS producers. Remarkably, genetically programmed EPS producers can also exhibit phenotypic heterogeneity at single-cell level. Previous studies have shown that spatial structure of biofilms limits the spread of cheaters, but the long-term influence of cheating on biofilm evolution is not well understood. Here, we examine the influence of EPS nonproducers on evolution of matrix production within the populations of EPS producers in a model biofilm-forming bacterium, Bacillus subtilis. We discovered that general adaptation to biofilm lifestyle leads to an increase in phenotypical heterogeneity of eps expression. However, prolonged exposure to EPS-deficient cheaters may result in different adaptive strategy, where eps expression increases uniformly within the population. We propose a molecular mechanism behind such adaptive strategy and demonstrate how it can benefit the EPS producers in the presence of cheaters. This study provides additional insights on how biofilms adapt and respond to stress caused by exploitation in long-term scenario.
|
3,894 |
Correction: Corrigendum: Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea
| null |
3,895 |
Comment on: ‘A new era for giant cell arteritis’
| null |
3,896 |
Author Correction: Nitrogen-fixing populations of Planctomycetes and Proteobacteria are abundant in surface ocean metagenomes
| null |
3,897 |
Publisher Correction: Delphine Parrott, a pioneer of T cell biology
| null |
3,898 |
Neurodegeneration in Alzheimer’s disease and glaucoma: overlaps and missing links
|
The eye is said to be the window into the brain. Alzheimer’s disease (AD) and glaucoma both being diseases of the elderly, have several epidemiological and histological overlaps in pathogenesis. Both these diseases are neurodegenerative conditions. Over the years, a consensus has developed that both may be two ends of a singular spectrum of diseases. Epidemiological studies have shown that more Alzheimer’s patients may be suffering from glaucoma than general healthy population. Retinal ganglion cell damage is a characteristic of both diseases, along with discovery of amyloid-β and tau protein deposition in the retina and aqueous humor of eye. The latter two proteins are known to be pathognomonic of AD. Other pathways such as the insulin receptor pathway also seem to be affected in both diseases similarly. In spite of these overlaps, there are few missing links which still need more evidence, namely, intraocular pressure mechanisms, cerebrospinal fluid pressure and trans-lamina cribrosa pressure gradients, vascular autoregulation factors, etc. Several factors point towards a common pathogenesis at some level for both diseases and prospective studies are necessary to study the natural course of both diseases.
|
3,899 |
AAV-mediated FOXG1 gene editing in human Rett primary cells
|
Variations in the Forkhead Box G1 (FOXG1) gene cause FOXG1 syndrome spectrum, including the congenital variant of Rett syndrome, characterized by early onset of regression, Rett-like and jerky movements, and cortical visual impairment. Due to the largely unknown pathophysiological mechanisms downstream the impairment of this transcriptional regulator, a specific treatment is not yet available. Since both haploinsufficiency and hyper-expression of FOXG1 cause diseases in humans, we reasoned that adding a gene under nonnative regulatory sequences would be a risky strategy as opposed to a genome editing approach where the mutated gene is reversed into wild-type. Here, we demonstrate that an adeno-associated viruses (AAVs)-coupled CRISPR/Cas9 system is able to target and correct FOXG1 variants in patient-derived fibroblasts, induced Pluripotent Stem Cells (iPSCs) and iPSC-derived neurons. Variant-specific single-guide RNAs (sgRNAs) and donor DNAs have been selected and cloned together with a mCherry/EGFP reporter system. Specific sgRNA recognition sequences were inserted upstream and downstream Cas9 CDS to allow self-cleavage and inactivation. We demonstrated that AAV serotypes vary in transduction efficiency depending on the target cell type, the best being AAV9 in fibroblasts and iPSC-derived neurons, and AAV2 in iPSCs. Next-generation sequencing (NGS) of mCherry(+)/EGFP(+) transfected cells demonstrated that the mutated alleles were repaired with high efficiency (20–35% reversion) and precision both in terms of allelic discrimination and off-target activity. The genome editing strategy tested in this study has proven to precisely repair FOXG1 and delivery through an AAV9-based system represents a step forward toward the development of a therapy for Rett syndrome.
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.