bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Homozygous Protein-Truncating Mutation in ACTL7A Causes Male Infertility Characterized by Fertilization Failure
Authors: Chen Yao , Chen Biao-Bang , Sang Qing , Wang Lei , Zhao Jun-Li , Sun Xiao-Xi 
Published: July 2022

Objective:
This study aimed to screen for novel mutations in ACTL7A and expand the spectrum of known mutations responsible for recurrent fertilization failure.

Methods:
Whole-exome sequencing was performed on samples from couples who experienced recurrent assisted reproductive technology failure and visited the General Hospital of Ningxia Medical University. Western blotting and quantitative RT-PCR were used to investigate the effects of the mutation on HEK293T cells.

Results:
Samples from 12 couples with total fertilization failure or poor fertilization (fertilization rate < 20%) were subjected to whole-exome sequencing, and a novel homozygous protein-truncating mutation (c. 1101dupC, p. S368Qfs*5) in ACTL7A was identified in a patient with recurrent poor fertilization. The mutant resulted in a truncated protein as well as decreased protein expression level in HEK293T cells.

Conclusion:
Our findings expand the mutational and phenotypic spectrum of ACTL7A, thus providing a potential diagnostic marker for fertilization failure due to male factors.
The Repeatable Battery for the Assessment of Neuropsychological Status, While Useful for Measuring Cognitive Changes in Manifest Huntington Disease, May Show Limited Utility in Premanifest Disease
Authors: Mustafa Andrea I. , Corey-Bloom Jody , Beltran-Najera Ilex , Snell Chase , Castleton Jordan , Smith Haileigh , Gilbert Paul E. 
Published: July 2022

Background:
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized neuropsychological test that assesses several areas of cognitive function. Recent studies, although sparse, have examined the use of the RBANS to detect cognitive deficits in individuals with manifest Huntington disease (HD); however, no studies have investigated its utility to detect cognitive deficits in individuals with premanifest HD (PreHD), where cognitive symptoms are thought to be more subtle.

Objective:
To assess cognitive deficits in individuals with HD, particularly in individuals with PreHD, using an easily administered, brief but comprehensive, neuropsychological test.

Method:
We administered the RBANS to 31 individuals with HD, 29 individuals with PreHD, and 22 healthy controls (HC) at an academic HD clinical research center and collected RBANS Total, Index, and subtest scores for group comparisons.

Results:
The HD group had significantly lower RBANS Total, Index, and subtest scores than the HC. The PreHD group had significantly lower RBANS Total scores and Coding subtest scores than the HC, but no other significant group differences were identified.

Conclusion:
Our results substantiate previous findings of significant impairment on the RBANS in individuals with HD. In addition, we are the first to demonstrate that, although the RBANS can identify deficits in psychomotor speed and information processing in individuals with PreHD, it does not appear to have the ability to detect impairment in any additional cognitive domains in individuals with PreHD.
Distinguishing Between Genuine and Feigned Dementia Using Event-related Potentials
Authors: Price August M. , Palumbo Rocco , Marin Anna , Uppal Prayerna , Suh Cheongmin , Budson Andrew E. , Turk Katherine W. 
Published: July 2022

Background:
Individuals with probable Alzheimer disease (AD) may perform below cutoffs on traditional, memory-based performance validity tests. Previous studies have found success using event-related potentials (ERPs) to detect feigned neurocognitive impairment in younger populations.

Objective:
To evaluate the utility of an auditory oddball task in conjunction with the P3b peak amplitude to distinguish probable AD from simulated dementia.

Method:
Twenty individuals with probable AD and 20 older healthy controls (HC) underwent an ERP auditory oddball protocol and the Test of Memory Malingering (TOMM). The HC were asked to perform honestly for one condition and to simulate dementia for the other. The individuals with probable AD were asked to perform honestly. The P3b peak amplitude and button press accuracy were collected from each participant and were analyzed to determine their effectiveness in detecting performance validity.

Results:
The P3b peak amplitude remained stable regardless of behavioral condition in the HC group. When combined with the TOMM Trial 2 score, the P3b peak amplitude further improved the ability to correctly differentiate individuals with probable AD from HC simulating dementia with 100% sensitivity and 90% specificity.

Conclusion:
The P3b peak amplitude was found to be an effective physiologic measure of cognitive impairment in individuals with probable AD compared with HC simulating dementia. When combined with the TOMM Trial 2 score, the P3b peak amplitude served as a promising performance validity measure for differentiating individuals with probable AD from HC simulating dementia.
Endogenous modulation of pain relief: evidence for dopaminergic but not opioidergic involvement
Authors: Desch Simon , Schweinhardt Petra , Seymour Ben , Flor Herta , Becker Susanne 
Published: July 2022

AbstractRelief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here we studied pain modulation during a probabilistic relief-seeking task (a ‘wheel of fortune’ gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa, but not naltrexone, enhanced each of these information-specific aspects of relief modulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior.
Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape
Authors: Golkaram Mahdi , Kuo Fengshen , Gupta Sounak , Carlo Maria I. , Salmans Michael L. , Vijayaraghavan Raakhee , Tang Cerise , Makarov Vlad , Rappold Phillip , Blum Kyle A. , Zhao Chen , Mehio Rami , Zhang Shile , Godsey Jim , Pawlowski Traci , DiNatale Renzo G. , Morris Luc GT , Durack Jeremy , Russo Paul , Kotecha Ritesh R. , Coleman Jonathan , Chen Ying-Bei , Reuter Victor E , Motzer Robert J , Voss Martin H. , Liu Li , Reznik Ed , Chan Timothy A. , Ari Hakimi A. 
Published: July 2022

AbstractBackgroundIntratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance.MethodsHere, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI treated patients. Deep multi-regional whole exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy.ResultsAngiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts.ConclusionsThese results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC.Trial registrationWe completed a single-arm pilot study at Memorial Sloan Kettering Cancer Center (MSKCC; ClinicalTrials.gov identifier NCT02595918) to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.
Human Microbiome Mixture Analysis using Weighted Quantile Sum Regression
Authors: Eggers Shoshannah , Bixby Moira , Renzetti Stefano , Curtin Paul , Gennings Chris 
Published: July 2022

ABSTRACTStudies of the health effects of the microbiome often measure overall associations by using diversity metrics, and individual taxa associations in separate analyses, but do not consider the correlated relationships between taxa in the microbiome. In this study, we applied random subset weighted quantile sum regression with repeated holdouts (WQSRSRH), a mixture method successfully applied to ‘omic data to account for relationships between many predictors, to processed amplicon sequencing data from the Human Microbiome Project. We simulated a binary variable associated with 20 operational taxonomic units (OTUs). WQSRSRH was used to test for the association between the microbiome and the simulated variable, adjusted for sex, and sensitivity and specificity were calculated. The WQSRSRH method was also compared to other standard methods for microbiome analysis. The method was further illustrated using real data from the Growth and Obesity Cohort in Chile to assess the association between the gut microbiome and body mass index. In the analysis with simulated data, WQSRSRH predicted the correct directionality of association between the microbiome and the simulated variable, with an average sensitivity and specificity of 75% and 70%, respectively, in identifying the 20 associated OTUs. WQSRSRH performed better than all other comparison methods. In the illustration analysis of the gut microbiome and obesity, the WQSRSRH analysis identified an inverse association between body mass index and the gut microbe mixture, identifying Bacteroides, Clostridium, and Ruminococcus, among others, as important genera in the negative association. The application of WQSRSRH to the microbiome allows for analysis of the mixture effect of all the taxa in the microbiome, while simultaneously identifying the most important to the mixture, and allowing for covariate adjustment. It outperformed other methods when using simulated data, and in analysis with real data found results consistent with other study findings.
A comprehensive analysis of gut and skin microbiota in canine atopic dermatitis in Shiba Inu dogs
Authors: Thomsen Mirja , Künstner Axel , Wohlers Inken , Olbrich Michael , Lenfers Tim , Osumi Takafumi , Shimazaki Yotaro , Nishifuji Koji , Ibrahim Saleh M , Watson Adrian , Busch Hauke , Hirose Misa 
Published: July 2022

AbstractBackgroundLike its human counterpart, canine atopic dermatitis (cAD) is a chronic relapsing condition; thus, most cAD-affected dogs will require lifelong treatment to maintain an acceptable quality of life. A potential intervention is modulation of the composition of gut microbiota, and in fact, probiotic treatment has been proposed and tried in human atopic dermatitis (AD) patients. Since dogs are currently receiving intensive medical care, this will be the same option for dogs, while evidence of gut dysbiosis in cAD is still missing, although skin microbial profiling in cAD has been conducted in several studies. Therefore, we conducted a comprehensive analysis of both gut and skin microbiota in cAD in one specific cAD-predisposed breed, Shiba Inu. Additionally, we evaluated the impact of commonly used medical management on cAD (Janus kinase; JAK inhibitor, oclacitinib) on the gut and skin microbiota. Furthermore, we genotyped the Shiba Inu dogs according to the mitochondrial DNA haplogroup and assessed its association with the composition of the gut microbiota.ResultsStaphylococcus was the most predominant bacterial genus observed in the skin; Escherichia/Shigella and Clostridium sensu stricto were highly abundant in the gut of cAD-affected dogs. In the gut microbiota, Fusobacteria and Megamonas were highly abundant in healthy dogs but significantly reduced in cAD-affected dogs. The abundance of these bacterial taxa was positively correlated with the effect of the treatment and state of the disease. Oclacitinib treatment on cAD-affected dogs shifted the composition of microbiota towards that in healthy dogs, and the latter brought it much closer to healthy microbiota, particularly in the gut. Additionally, even within the same dog breed, the mtDNA haplogroup varied, and there was an association between the mtDNA haplogroup and gut microbial composition.ConclusionsDysbiosis of both the skin and the gut was observed in cAD in Shiba Inu dogs. Our findings provide a basis for the potential treatment of cAD by manipulating the gut microbiota as well as the skin microbiota.
FEZ1 participates in human embryonic brain development by modulating neuronal progenitor subpopulation specification and migration
Authors: Qu Yinghua , An Omer , Yang Henry , Toh Yi-Chin , En John Chua Jia 
Published: July 2022

AbstractAbnormal neuronal networks arising from perturbations during early brain development contribute to neurodevelopmental disorders. Mutations and deletions of human Fasciculation and Elongation Protein Zeta 1 (FEZ1) are found in schizophrenia and Jacobsen syndrome patients. However, its roles in human brain development and manifestation of clinical pathological symptoms remain unknown. Here, using human cerebral organoids (hCOs), we observed that FEZ1 expression is turned on early during brain development and is detectable in both neuroprogenitor subtypes and immature neurons. Deletion of FEZ1 disrupts expression of genes involved in neuronal and synaptic development. Using single-cell RNA sequencing, we further uncovered an abnormal expansion of homeodomain-only protein homeobox (HOPX)− outer radial glia (oRG) in FEZ1-null hCOs, occurring at the expense of HOPX+ oRG. HOPX− oRGs show higher cell mobility as compared to HOPX+ oRGs, which is accompanied by the ectopic localization of the neuroprogenitors to the outer layer of FEZ1-null hCOs. Moreover, abnormal encroachment of TBR2+ intermediate progenitors into CTIP2+ deep layer neurons indicated that cortical layer formation is disrupted in FEZ1-null hCOs. Collectively, our findings highlight the involvement of FEZ1 in early cortical brain development and how it contributes to neurodevelopmental disorders.
Holographic stimulation of opposing amygdala ensembles bidirectionally modulates valence-specific behavior
Authors: Piantadosi Sean C , Zhou Zhe Charles , Pizzano Carina , Pedersen Christian E , Nguyen Tammy K , Thai Sarah , Stuber Garret D , Bruchas Michael R 
Published: July 2022

SummaryThe basolateral amygdala (BLA) is an evolutionarily conserved brain region, well known for valence processing. Despite this central role, the relationship between activity of BLA neuronal ensembles in response to appetitive and aversive stimuli and the subsequent expression of valence-specific behavior has remained elusive. Here we leverage 2-photon calcium imaging combined with single cell holographic photostimulation through an endoscopic lens implanted in the deep brain to demonstrate a direct causal role for discrete ensembles of BLA neurons in the control of oppositely valenced behavior. We report that targeted photostimulation of individual groups of appetitive or aversive BLA neurons shifts behavioral responses toward those behaviors which recruited a specific consumption or avoidance ensemble. Here we identify that neuronal encoding of valence in the BLA is graded and relies on the relative proportion of individual BLA neurons recruited in a stable appetitive or aversive ensemble.
NOTCH3 active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model
Authors: Oliveira Daniel V. , Coupland Kirsten G. , Jin Shaobo , Del Gaudio Francesca , Wang Sailan , Fox Rhys , Rutten Julie W. , Sandin Johan , Lundkvist Johan , Lesnik Oberstein Saskia A. J. , Lendahl Urban , Karlström Helena 
Published: July 2022

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease and no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild type EGF1-5 repeats for a total of four months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior or the number and integrity of vascular smooth muscle cells in the retina, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of CADASIL-like NOTCH3 accumulation in mice supporting further development towards clinical application for the benefit of CADASIL patients.
The olivary input to the cerebellum dissociates sensory events from movement plans
Authors: Pi Jay S. , Fakharian Mohammad Amin , Hage Paul , Sedaghat-Nejad Ehsan , Muller Salomon Z. , Shadmehr Reza 
Published: July 2022

AbstractThe inferior olive is thought to act as an instructor that mentors the Purkinje cells (P-cells) of the cerebellum. As a result, if during a behavior two groups of P-cells received different kinds of information from their olivary inputs, then each group might contribute to different aspects of that behavior. Here, we designed a saccade task in marmosets that dissociated sensory and motor events and then recorded the complex and simple spikes of hundreds of P-cells. We found that the olivary input to one group of P-cells robustly reported the direction of the random visual target, whereas the input to another group principally reported the spatial properties of the forthcoming movement. When a saccade encountered a sensory prediction error, but the subject chose not to make a corrective movement, the error was reported to the first group of P-cells, not the second group. In the first group the simple spikes were suppressed during fixation, then produced a burst before saccade onset that acted primarily as an agonist which accelerated the movement. In the second group the simple spikes were not suppressed during fixation and did not provide an agonist assistance. Rather, the simple spikes acted as an antagonist that decelerated the movement. Therefore, the olive differentiated the P-cells based on whether they would receive primarily sensory or motor information, and this dissociated their contributions to both control of movements and holding still.Significance statementThe inferior olive provides more than just error information to the P-cells: it also informs them regarding the spatial properties of forthcoming movements. However, these two kinds of information are sent to two different groups of cells. The P-cells whose olivary input directionally report a visual event have a simple spike response that accelerates the saccade toward that same direction. The P-cells whose olivary input directionally predicts a forthcoming movement have a simple spike response that decelerates the saccade in that same direction.
Thermodynamic analysis of the GASrighttransmembrane motif supports energetic model of dimerization
Authors: Vázquez Gladys Díaz , Cui Qiang , Senes Alessandro 
Published: July 2022

AbstractThe GASrightmotif, best known as the fold of the glycophorin A transmembrane dimer, is one of the most common dimerization motifs in membrane proteins, characterized by its hallmark GxxxG-like sequence motifs (GxxxG, AxxxG, GxxxS, and similar). Structurally, GASrightdisplays a right-handed crossing angle and short inter-helical distance. Contact between the helical backbones favors the formation of networks of weak hydrogen bonds between Cα–H carbon donors and carbonyl acceptors on opposing helices (Cα–H∙∙∙O=C). To understand the factors that modulate the stability of GASright, we previously presented a computational and experimental structure-based analysis of 26 predicted dimers. We found that the contributions of van der Waals packing and Cα–H hydrogen bonding to stability, as inferred from the structural models, correlated well with relative dimerization propensities estimated experimentally with thein vivoassay TOXCAT. Here we test this model with a quantitative thermodynamic analysis. We used FRET to determine the free energy of dimerization of a representative subset of 7 of the 26 original TOXCAT dimers using FRET. To overcome the technical issue arising from limited sampling of the dimerization isotherm, we introduced a globally fitting strategy across a set of constructs comprising a wide range of stabilities. This strategy yielded precise thermodynamic data that show strikingly good agreement between the original propensities and ΔG° of association in detergent, suggesting that TOXCAT is a thermodynamically driven process. From the correlation between TOXCAT and thermodynamic stability, the predicted free energy for all the 26 GASrightdimers was calculated. These energies correlate with thein silicoΔE scores of dimerization that were computed on basis of their predicted structure. These findings corroborate our original model with quantitative thermodynamic evidence, strengthening the hypothesis that van der Waals and Cα–H hydrogen bond interactions are the key modulators of GASrightstability.Secondary AbstractWe present a thermodynamic analysis of the dimerization of the GASrightmotif, a common dimerization motif in membrane proteins. Previously, we found that the stability of GASrightis modulated by van der Waals packing and weak hydrogen bonds between Cα–H carbon donors and carbonyl acceptors on opposing helices. The experimental dimerization propensities were obtained with anin vivoassay. Here we assess this model quantitatively by measuring the free energy of dimerization of a subset of the original dimers. The thermodynamic data show strikingly good agreement between the original propensities and their ΔG° of association, confirming the model and strengthening the hypothesis that van der Waals and Cα–H hydrogen bond interactions are the key modulators of GASrightstability.