bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACROSIN deficiency causes total fertilization failure in humans by preventing the sperm from penetrating the zona pellucida
Authors: Hua Rong , Xue Rufeng , Liu Yiyuan , Li Yuqian , Sha Xuan , Li Kuokuo , Gao Yang , Shen Qunshan , Lv Mingrong , Xu Yuping , Zhang Zhiguo , He Xiaojin , Cao Yunxia , Wu Huan 
Published: April 2023

Abstract

STUDY QUESTION
Does a homozygous nonsense mutation in ACR lead to total fertilization failure (TFF) resulting in male infertility in humans?

SUMMARY ANSWER
A novel homozygous nonsense mutation of ACR (c.167G&gt;A, p.Trp56X) was identified in two infertile brothers and shown to cause human TFF.

WHAT IS KNOWN ALREADY
ACROSIN, encoded by ACR, is a major acrosomal enzyme expressed only in the acrosome of the sperm head. Inhibition of acrosin prevents sperm penetration of the zona pellucida (ZP) in several species, including humans. Acr-knockout in hamsters causes male infertility with completely blocked fertilization. Of note, there are no reports of ACR mutations associated with TFF in humans.

STUDY DESIGN, SIZE, DURATION
Whole-exome sequencing (WES) was used for the identification of pathogenic genes for male factor TFF in eight involved couples.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Data from eight infertile couples who had experienced TFF during their IVF or ICSI attempts were collected. Functional assays were used to verify the pathogenicity of the potential genetic factors identified by WES. Subzonal insemination (SUZI) and IVF assays were performed to determine the exact pathogenesis of TFF caused by deficiencies in ACROSIN.

MAIN RESULTS AND THE ROLE OF CHANCE
A novel homozygous nonsense mutation in ACR, c.167G&gt;A, p.Trp56X, was identified in two additional primary infertile brothers whose parents were first cousins. This rare mutation caused ACROSIN deficiency and acrosomal ultrastructural defects in the affected sperm. Spermatozoa lacking ACROSIN were unable to penetrate the ZP, rather than hampering sperm binding, disrupting gamete fusion, or preventing oocyte activation. These findings were supported by the fertilization success of SUZI and ICSI attempts, as well as the normal expression of ACTL7A and PLCζ in the mutant sperm, suggesting that ICSI without remedial assisted oocyte activation is an optimal treatment for ARCOSIN-deficient TFF.

LIMITATIONS, REASONS FOR CAUTION
The absence of another independent pedigree to support our argument is a limitation of this study.

WIDER IMPLICATIONS OF THE FINDINGS
The findings expand our understanding of the genes involved in human TFF, providing information for appropriate genetic counseling and fertility guidance for these patients.

STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the National Natural Science Foundation of China (grant no. 82201803, 81901541, 82271639, and 32000584), University Synergy Innovation Program of Anhui Province (GXXT-2019-044), and the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences (grant no. 2019PT310002). The authors declare no conflicts of interest.

TRIAL REGISTRATION NUMBER
N/A.
Experimental investigations on the thermal characteristics of a multi-functional air-conditioner
Authors: Qiu Fuqiang , Du Juanli , Xu Taoping 
Published: April 2023

AbstractThis paper presents a novel schematic diagram of a multi-functional air-conditioner (NMFAC) with four operating modes to enhance energy efficiency and increase equipment utilization. A prototype was designed to test the performances according to Chinese condition standards. The results indicated that the NMFAC could run reliably all year round. In summer and winter, the space cooling and heating capacity were in normal ranges, with an average space cooling performance (COPsc) and heating performance (COPsh) of 2.73 and 3.58, respectively. In the water-heating only mode in season and out of season, the mean water heating performance (COPwh) varied from 2.97 to 4.2 under typical conditions as hot water was heated from 15 °C to 55 °C. In condensing heat recovery mode, the average COPwh and COPsc were 4.54 and 4.30, respectively, and the overall performance (COPcw) was up to 8.84.
Terminal Illness and Compassionate Release
Authors: Mulgrew Róisín 
Published: April 2023

Abstract
International prisoners can apply for early release. However, terminally ill prisoners seeking release in the international criminal justice system face significant legal and practical obstacles. This is particularly the case for prisoners convicted by the International Criminal Court (ICC): there is currently no framework for granting compassionate release prior to serving the statutory required amount of a sentence. To build a foundation for recommendations for the creation of a system of compassionate release at the ICC, this article critically examines the systems used to grant early release to terminally ill persons in international (International Residual Mechanism for Criminal Tribunals) and national criminal law, with a particular focus on how these systems operate for prisoners that have served less than the typical eligibility requirement for release. This article sets out a normative basis for creating a novel and distinct form of release at the ICC: a compassionate system based, not on penological justifications, but on the impossibility of continued detention on human rights grounds. It concludes with recommendations for essential substantial and procedural elements for this system and means of incorporating it into the current legal framework.
Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis
Authors: Ekman Diana , Sennblad Bengt , Knight Ann , Karlsson Åsa , Rantapää-Dahlqvist Solbritt , Berglin Ewa , Stegmayr Bernd , Baslund Bo , Palm Øyvind , Haukeland Hilde , Gunnarsson Iva , Bruchfeld Annette , Segelmark Mårten , Ohlsson Sophie , Mohammad Aladdin J , Svärd Anna , Pullerits Rille , Herlitz Hans , Söderbergh Annika , Omdal Roald , Jonsson Roland , Rönnblom Lars , Eriksson Per , Lindblad-Toh Kerstin , Dahlqvist Johanna 
Published: April 2023

Abstract

Objective
To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.

Methods
A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.

Results
rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10−4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.

Conclusions
Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.
Associations Between Clinical Insight and History of Severe Violence in Patients With Psychosis
Authors: Fischer-Vieler Thomas , Ringen Petter Andreas , Kvig Erling , Bell Christina , Hjell Gabriela , Tesli Natalia , Rokicki Jaroslav , Melle Ingrid , Andreassen Ole Andreas , Friestad Christine , Haukvik Unn Kristin 
Published: April 2023

AbstractBackground and HypothesisViolence is more prevalent in patients with psychotic disorders compared to the general population. Hence, adequate violence risk assessment is of high clinical importance. Impaired insight is suggested as a risk factor for violence in psychosis, but studies have yielded conflicting results. We hypothesized that impaired insight was associated with a history of severe violence in patients with psychotic disorders.Study DesignClinical insight was assessed both using the Birchwood Insight Scale (BIS) and the Positive and Negative Symptom Scale (PANSS) item G12 (lack of judgment and insight). The degree of impaired clinical insight was compared between psychosis patients with (N = 51) and without (N = 178) a history of severe violence. Multiple linear regression analyses were performed to investigate the effects of putative confounders.Study ResultsWe found that a history of severe violence was significantly associated with lower insight in one of the three BIS components (the relabeling of symptoms) (P = .03, R2 = 0.02) and the PANSS item G12 (P = .03, R2 = 0.02) also after controlling for putative confounders.ConclusionsThe results suggest there is an association between impaired insight and severe violence in psychosis patients. We propose that examination of insight by validated instruments comprising different components may add useful information to clinical violence risk assessment in psychosis patients.
Early detection of glomerular dysfunction and renal tubulopathy in children with sickle cell disease in India
Authors: Karapurkar Sonia , Ghildiyal Radha , Shah Nikita , Keshwani Rachna , Sharma Sujata 
Published: April 2023

AbstractBackgroundSickle cell disease causes microvascular occlusion in different vascular beds. In kidneys, it leads to occult glomerular dysfunction causing asymptomatic microalbuminuria, proximal tubulopathy causing hyposthenuria and increased free water loss and distal tubulopathy causing poor urine acidification. We studied the prevalence of various types of renal dysfunction, the ability of different tests to detect it at an early stage and the correlation of these parameters in children receiving hydroxyurea (HU).ProcedureFifty-six children (sample size calculated using SAS9.2 package) attending paediatric clinical services in a tertiary care hospital between 2 and 12 years of age diagnosed by high-performance liquid chromatography (HPLC) were enrolled. Their demographic and laboratory data including renal and urine parameters were collected. Parameters like fractional excretion of sodium (FeNa), trans tubular potassium gradient (TtKg) and free water clearance (TcH2O) were derived by calculations. Data were analysed using IBM SPSS Version 21.0 and Microsoft Office Excel 2007.ResultsWe found a significant number of children to have microalbuminuria (17.8%), hyposthenuria (30.4%) and impaired renal tubular potassium excretion (TtKg) (81.3%). A significant correlation was found between the dose of HU with urine osmolality (p &lt; 0.0005) and free water clearance (p = 0.002), while all parameters showed a significant correlation with compliance with HU. Derangement in urine microalbumin and TcH2O correlated significantly with low mean haemoglobin levels (&lt;9 g/dl).ConclusionRenal dysfunction is common in children with SCD and can be detected early using simple urine parameters and can be prevented with an early and appropriate dosage of HU with good compliance.
Distinct mesenchymal cell states mediate prostate cancer progression
Authors: Pakula Hubert , Omar Mohamed , Carelli Ryan , Pederzoli Filippo , Fanelli Giuseppe Nicolò , Pannellini Tania , Van Emmenis Lucie , Rodrigues Silvia , Fidalgo-Ribeiro Caroline , Nuzzo Pier V. , Brady Nicholas J. , Jere Madhavi , Unkenholz Caitlin , Alexanderani Mohammad K. , Khani Francesca , de Almeida Francisca Nunes , Abate-Shen Cory , Greenblatt Matthew B , Rickman David S. , Barbieri Christopher E. , Robinson Brian D. , Marchionni Luigi , Loda Massimo 
Published: April 2023

SummaryAlterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for common and GEMM-specific transcriptional programs. We show that stromal responses are conserved in mouse models and human prostate cancers with the same genomic alterations. We noted striking similarities between the transcriptional profiles of the stroma of murine models of advanced disease and those of of human prostate cancer bone metastases. These profiles were then used to build a robust gene signature that can predict metastatic progression in prostate cancer patients with localized disease and is also associated with progression-free survival independent of Gleason score. Taken together, this offers new evidence that stromal microenvironment mediates prostate cancer progression, further identifying tissue-based biomarkers and potential therapeutic targets of aggressive and metastatic disease.
Uniformity of performance during the collection of maximum voluntary contraction tasks for the muscles of the forearm
Authors: Rezende Mercedes Aramayo Gomes , Akinnola Oluwalogbon O , Kedgley Angela E 
Published: April 2023

AbstractElectromyographic (EMG) signals are used to gain insight into muscle activation patterns and thus neuromuscular control. To allow for comparisons between studies and participants, the EMG signal is generally normalised, with the signal obtained during a task that is designed to elicit maximum voluntary contraction (MVC) frequently used as the basis. Recommendations for how to collect MVCs have been made; however, previous studies have not been able to determine if the EMG variation noted within a population was due to different muscle activation patterns, or the tasks being performed differently, or other variables such as skin impedance, or the stochastic nature of electromyography.EMG signals were recorded during hand-wrist tasks selected to elicit MVCs in the muscles of the forearm – pull up, push down, radial pull, ulnar pull, pull, pronation, finger flexion, finger extension, and grip – as well as two activities of daily living – pouring a glass of water from a jug and turning a key in a lock. A load cell mounted to a statically mounted handle was used to record contemporaneously the forces and moments exerted by participants in pull up, push down, radial pull, ulnar pull, pull, pronation, finger flexion, and finger extension tasks.Ninety percent of tasks yielded the expected load cell outputs for the directed tasks and thus were considered as having been performed correctly. The tasks performed incorrectly were not the same for all participants, nor were they all performed by the same participants. Of note was that there were instances when a task was performed incorrectly but still an expected MVC was achieved. The EMG signals showed similar variation to that seen in previous studies. However, the applied forces and moments did not appear to explain the variation seen in the tasks that elicited MVCs.The results of this study indicate that different muscle activation patterns may be used to exert the same force by the hand. Thus, it may not be possible for a given task to elicit MVC in the same muscle in all people. However, by using several activities, MVCs for the forearm muscles may be obtained for most of the population. Beyond designing EMG protocols, the results of this study suggest that people have unique muscle activation patterns and raise questions as to whether this is a result of physiology or conditioning.
Divergent proinflammatory immune responses associated with the differential susceptibility of cattle breeds to Tuberculosis
Authors: Kumar Rishi , Gandham Sripratyusha , Rana Avi , Maity Hemant Kumar , Sarkar Uttam , Dey Bappaditya 
Published: April 2023

AbstractTuberculosis (TB) in the bovine is one of the most predominant chronic debilitating infectious diseases primarily caused byMycobacterium bovis. Besides, the incidence of TB in humans due toM. bovis, and that in bovines due toM. tuberculosis-indicates cattle as a major reservoir of zoonotic TB. While India accounts for the highest global burden of both TB and multidrug-resistant TB in humans, systematic evaluation of bovine TB (bTB) prevalence in India is largely lacking. Recent reports emphasized markedly greater bTB prevalence in exotic and crossbred cattle compared to indigenous cattle breeds that represent more than one-third of the total cattle population in India, which is the largest globally. This study aimed at elucidating the immune responses underlying the differential bTB incidence in prominent indigenous (Sahiwal), and crossbred (Sahiwal x Holstein Friesian) cattle reared in India. Employing the standard Single Intradermal Tuberculin Test (SITT), and mycobacterial gene-targeting single as well as multiplex-PCR-based screening revealed higher incidences of bovine tuberculin reactors as well asMycobacterium tuberculosisComplex specific PCR positivity amongst the crossbred cattle. Further,ex vivomycobacterial infection in cultures of bovine peripheral blood mononuclear cells (PBMC) from SITT, and myco-PCR negative healthy cattle exhibited significantly higher intracellular growth ofM. bovisBCG, andM. tuberculosisH37Ra in the crossbred cattle PBMCs compared to native cattle. In addition, native cattle PBMCs induced higher pro-inflammatory cytokines and signaling pathways, such as interferon-gamma (IFN-γ), interleukin-17 (IL-17), and tank binding kinase-1 (TBK-1) upon exposure to live mycobacterial infection in comparison to PBMCs from crossbred cattle that exhibited higher expression of IL-1β transcripts. Together, these findings highlight that differences in the innate immune responses of these cattle breeds might be contributing to the differential susceptibility to TB infection, and the resultant disparity in bTB incidence amongst indigenous, and crossbred cattle.
MtDNA d-loop variation in Prespa dwarf cattle (Bos taurus) from Albania
Authors: Schlumbaum Angela , Granado Jose , Hans-Peter Gruenenfelder , Schibler Joerg 
Published: April 2023

AbstractAlbanian Prespa dwarf cattle belong to the Busha group of cattle with short horns, uniform coat color and low withers heights. Their breeding population is very small and the population is recognized as endangered. Here we report mtDNA d-loop diversity (475bp) from 10 unrelated Albanian Prespa individuals from Liqenas, one male and nine females. Diversity measures are high and members of the taurine haplogroups T3, common in Europe, and one female with T1, common in Africa and rare on the Balkans, were detected. This supports a complex female genetic history in the past.
Microphase Separation Produces Interfacial Environment within Diblock Biomolecular Condensates
Authors: Latham Andrew P. , Zhu Longchen , Sharon Dina A. , Ye Songtao , Willard Adam P. , Zhang Xin , Zhang Bin 
Published: April 2023

AbstractThe phase separation of intrinsically disordered proteins is emerging as an important mechanism for cellular organization. However, efforts to connect protein sequences to the physical properties of condensates, i.e., the molecular grammar, are hampered by a lack of effective approaches for probing high-resolution structural details. Using a combination of multiscale simulations and fluorescence lifetime imaging microscopy experiments, we systematically explored a series of systems consisting of diblock elastin-like polypeptides (ELP). The simulations succeeded in reproducing the variation of condensate stability upon amino acid substitution and revealed different microenvironments within a single condensate, which we verified with environmentally sensitive fluorophores. The interspersion of hydrophilic and hydrophobic residues and a lack of secondary structure formation result in an interfacial environment, which explains both the strong correlation between ELP condensate stability and interfacial hydrophobicity scales, as well as the prevalence of protein-water hydrogen bonds. Our study uncovers new mechanisms for condensate stability and organization that may be broadly applicable.
HLA topography enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients
Authors: Killian John T. , Glenn King R. , Lucander Aaron C.K. , Kizziah James L. , Fucile Christopher F. , Diaz-Avalos Ruben , Qiu Shihong , Silva-Sanchez Aaron , Mousseau Betty J. , Macon Kevin J. , Callahan Amanda R. , Yang Guang , Emon Hossain M. , Akther Jobaida , Good Daryl B. , Kelso Susan , Houp Julie A. , Rosenblum Frida , Porrett Paige M. , Ong Song C. , Kumar Vineeta , Saphire Erica Ollmann , Kearney John F. , Randall Troy D. , Rosenberg Alexander F. , Green Todd J. , Lund Frances E. 
Published: April 2023

SUMMARYDonor-specific antibody (DSA) responses against human leukocyte antigen (HLA) proteins mismatched between kidney transplant donors and recipients cause allograft loss. The rules governing the immunogenicity of non-self donor HLA are poorly understood. Using single-cell, molecular, structural, and proteomic techniques, we profiled the HLA-specific B cell response in the kidney and blood of a transplant recipient with antibody-mediated rejection (AMR). We observed an immunodominant B cell antibody response focused on topographically exposed, solvent-accessible mismatched HLA residues along the peptide-binding groove – a subregion comprising only 20% of the HLA molecule. We further demonstrated that, even within a diverse cohort of transplant recipients, the B cell alloresponse consistently converges on this same immunodominant subregion on the crown of the HLA molecule. Based on these findings, we propose that B cell immunodominance in transplant rejection relies on antigenic topography, and we suggest that this link could be exploited for organ matching and therapeutics.