bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of glucocorticoid and antibiotic exposure as risk factors for diabetes mellitus in selected dog breeds attending UK primary‐care clinics
Authors: Heeley Angela M. , Brodbelt Dave C. , O'Neill Dan G. , Church David B. , Davison Lucy J.
Published: April 2023

Background

Diabetes mellitus (DM) is an important endocrine disorder in dogs. This study explored prior exposure to glucocorticoids or antibiotic treatment as risk factors for developing DM in dogs attending primary‐care VetCompass clinics in the UK.

Methods

A breed frequency matched case–control study nested in a cohort of dogs (n= 480,469) aged 3 years or over was used to explore associations between glucocorticoid and antibiotic exposure and the odds of developing DM.

Results

A total of 565 cases and 2179 controls were included. Dogs with DM had over four times the odds of exposure to glucocorticoids within 6 weeks prior to diagnosis (odds ratio [OR] 4.07, 95% confidence interval [CI] 2.41–6.89,p< 0.001) compared to controls within 6 weeks prior to a randomly selected quasi‐date of diagnosis. Dogs that had only one unique documented antibiotic course had a decreased odds of developing DM (OR 0.65, 95% CI 0.46–0.91,p= 0.012) compared to dogs that had no documented courses of antibiotics.

Limitations

This study only included selected breeds, so the results may not be generalisable to all dog breeds.

Conclusions

Exposure to glucocorticoids is associated with a substantial increase in the risk of developing DM for the dog breeds included in this analysis.
Multicentric malignant round cell tumour in a cria: Clinical presentation, pathologic findings and differential diagnoses
Authors: Cocchi Monia , Foiani Greta , Melchiotti Erica , Feliziani Francesco , De Zan Gabrita
Published: April 2023

A 2‐month‐old cria that died following a short episode of constipation and diarrhoea was presented for a postmortem examination. The main macroscopic findings were widely disseminated, multinodular, whitish lesions involving liver and kidney and severe and diffuse haemorrhagic jejunitis. Histopathologically, the nodules are characterised by sheets of neoplastic round cells. An immunohistochemical panel including lymphoid, histiocytic/myeloid and pan‐neuroendocrine markers was performed. Taking into account the epidemiology of malignant round cell tumours in camelids, the neoplastic cell morphology as well as the negativity to all the tested markers, null cell lymphoma is considered as the most likely differential diagnosis. As recently highlighted by the literature, these findings confirm lymphoma as a potential systemic and aggressive neoplasm in young alpacas.
Long‐term management of multifocal, facially oriented squamous cell carcinoma in an American Yorkshire pig with intralesional bleomycin electrochemotherapy, CO2 laser surgery and cryosurgery
Authors: Gould Aubrey , Stockler Jenna W. , Lindley Stephanie E. S. , Yin Ji‐Hang , White Amelia G.
Published: April 2023

A 4‐year‐old American Yorkshire barrow (Sus scrofa domesticus) presented for masses on the left ventral palpebra and convex pinnae bilaterally. Multiple incisional biopsies were consistent with cutaneous squamous cell carcinoma. The pig was hospitalised for three sessions of electrochemotherapy, with intralesional bleomycin chemotherapy conducted over 1 month. No significant complications from the chemotherapy occurred. Long‐term follow‐up for newly developing lesions on the pinnae and periocular skin included treatment with CO2 laser and cryosurgery with success. Although squamous cell carcinoma is a common finding in food animals, methods other than humane euthanasia for long‐term management of this disease in pigs is poorly documented. Pigs are increasingly becoming popular pet animals, and veterinarians need to consider new modalities and treatment approaches for management of cutaneous neoplasms. This case report describes a comprehensive clinical workup, treatment and long‐term management of squamous cell carcinoma in a domesticated, pet American Yorkshire barrow not intended for food consumption.
Reliability modelling and evaluating of wind turbine considering imperfect repair
Authors: Fan Panpan , Yuan Yiping , Gao Jianxiong , Zhang Yuchao
Published: April 2023

To model and evaluate the reliability of wind turbine (WT) under imperfect repair, an improved Log-linear Proportional Intensity Model (LPIM)-based method was proposed. Initially, using the three-parameter bounded intensity process (3-BIP) as the benchmark failure intensity function of LPIM, an imperfect repair effect-aware WT reliability description model was developed. Among them, the 3-BIP was used to describe the evolution process of the failure intensity in the stable operation stage with running time, while the LPIM reflected the repair effect. Second, the estimation problem for model parameters was transformed into a minimum solution problem for a nonlinear objective function, which was then solved using the Particle Swarm Optimization algorithm. The confidence interval of model parameters was finally estimated using the inverse Fisher information matrix method. Key reliability indices interval estimation based on the Delta method and point estimation was derived. The proposed method was applied to a wind farm’s WT failure truncation time. The proposed method has a higher goodness of fit based on verification and comparison. As a result, it can bring the evaluated reliability closer to engineering practice.
Approximation algorithms for scheduling single batch machine with incompatible deteriorating jobs
Authors: Cheng Bayi , Yuan Haimei , Zhou Mi , Qi Tan
Published: April 2023

Motivated by the soaking process under separate heating mode in iron and steel enterprises, we study the parallel batch machine scheduling problem with incompatible deteriorating jobs. The objective is to minimize makespan. A soaking furnace can be seen as a parallel batch processing machine. In order to avoid the thermal stress caused by excessive temperature difference, initial temperature is needed for the ingot before processing. With the increasing of waiting time, the ingot temperature decreases and the soaking time increases. This property is called deterioration. Setup time is needed between incompatible jobs. We show that if jobs have the same sizes, an optimal solution can be found withinO(nlogn) time. If jobs have identical processing times, the problem is proved to be NP-hard in the strong sense. We propose an approximate algorithm whose absolute and asymptotic worst-case ratios are less than 2 and 11/9, respectively. When the jobs have arbitrary sizes and arbitrary processing times, the model is also NP-hard in the strong sense. An approximate algorithm with an absolute and asymptotic worst-case ratio less than 2 is proposed. The time complexity isO(nlogn).
Effect of minor allele frequency and density of single nucleotide polymorphism marker arrays on imputation performance and prediction ability using the single-step genomic Best Linear Unbiased Prediction in a simulated beef cattle population
Authors: Rodríguez Juan Diego , Peripolli Elisa , Londoño-Gil Marisol , Espigolan Rafael , Lôbo Raysildo Barbosa , López-Correa Rodrigo , Aguilar Ignacio , Baldi Fernando
Published: April 2023

Context In beef cattle populations, there is little evidence regarding the minimum number of genetic markers needed to obtain reliable genomic prediction and imputed genotypes. Aims This study aimed to evaluate the impact of single nucleotide polymorphism (SNP) marker density and minor allele frequency (MAF), on genomic predictions and imputation performance for high and low heritability traits using the single-step genomic Best Linear Unbiased Prediction methodology (ssGBLUP) in a simulated beef cattle population. Methods The simulated genomic and phenotypic data were obtained through QMsim software. 735 293 SNPs markers and 7000 quantitative trait loci (QTL) were randomly simulated. The mutation rate (10−5), QTL effects distribution (gamma distribution with shape parameter = 0.4) and minor allele frequency (MAF ≥ 0.02) of markers were used for quality control. A total of 335k SNPs (high density, HD) and 1000 QTLs were finally considered. Densities of 33 500 (35k), 16 750 (16k), 4186 (4k) and 2093 (2k) SNPs were customised through windows of 10, 20, 80 and 160 SNPs by chromosome, respectively. Three marker selection criteria were used within windows: (1) informative markers with MAF values close to 0.5 (HI); (2) less informative markers with the lowest MAF values (LI); (3) markers evenly distributed (ED). We evaluated the prediction of the high-density array and of 12 scenarios of customised SNP arrays, further the imputation performance of them. The genomic predictions and imputed genotypes were obtained with Blupf90 and FImpute software, respectively, and statistics parameters were applied to evaluate the accuracy of genotypes imputed. The Pearson’s correlation, the coefficient of regression, and the difference between genomic predictions and true breeding values were used to evaluate the prediction ability (PA), inflation (b), and bias (d), respectively. Key results Densities above 16k SNPs using HI and ED criteria displayed lower b, higher PA and higher imputation accuracy. Consequently, similar values of PA, b and d were observed with the use of imputed genotypes. The LI criterion with densities higher than 35k SNPs, showed higher PA and similar predictions using imputed genotypes, however lower b and quality of imputed genotypes were observed. Conclusion The results obtained showed that at least 5% of HI or ED SNPs available in the HD array are necessary to obtain reliable genomic predictions and imputed genotypes. Implications The development of low-density customised arrays based on criteria of MAF and even distribution of SNPs, might be a cost-effective and feasible approach to implement genomic selection in beef cattle.
Boolean network sketches: a unifying framework for logical model inference
Authors: Beneš Nikola , Brim Luboš , Huvar Ondřej , Pastva Samuel , Šafránek David
Published: April 2023

Motivation

The problem of model inference is of fundamental importance to systems biology. Logical models (e.g. Boolean networks; BNs) represent a computationally attractive approach capable of handling large biological networks. The models are typically inferred from experimental data. However, even with a substantial amount of experimental data supported by some prior knowledge, existing inference methods often focus on a small sample of admissible candidate models only.

Results

We propose Boolean network sketches as a new formal instrument for the inference of Boolean networks. A sketch integrates (typically partial) knowledge about the network’s topology and the update logic (obtained through, e.g. a biological knowledge base or a literature search), as well as further assumptions about the properties of the network’s transitions (e.g. the form of its attractor landscape), and additional restrictions on the model dynamics given by the measured experimental data. Our new BNs inference algorithm starts with an ‘initial’ sketch, which is extended by adding restrictions representing experimental data to a ‘data-informed’ sketch and subsequently computes all BNs consistent with the data-informed sketch. Our algorithm is based on a symbolic representation and coloured model-checking. Our approach is unique in its ability to cover a broad spectrum of knowledge and efficiently produce a compact representation of all inferred BNs. We evaluate the method on a non-trivial collection of real-world and simulated data.

Availability and implementation

All software and data are freely available as a reproducible artefact at https://doi.org/10.5281/zenodo.7688740.
Transepithelial Barrier Dysfunction Drives Microbiota Dysbiosis to Initiate Epithelial Clock-driven Inflammation
Authors: Pai Yu-Chen , Li Yi-Hsuan , Turner Jerrold R , Yu Linda Chia-Hui
Published: April 2023

Background

Factors that contribute to inflammatory bowel disease [IBD] pathogenesis include genetic polymorphisms, barrier loss, and microbial dysbiosis. A major knowledge gap exists in the origins of the colitogenic microbiome and its relationship with barrier impairment. Epithelial myosin light chain kinase [MLCK] is a critical regulator of the paracellular barrier, but the effects of MLCK activation on the intraepithelial bacteria [IEB] and dysbiosis are incompletely understood. We hypothesise that MLCK-dependent bacterial endocytosis promotes pathobiont conversion and shapes a colitogenic microbiome.

Methods

To explore this, transgenic [Tg] mice with barrier loss induced by intestinal epithelium-specific expression of a constitutively active MLCK were compared with wild-type [WT] mice.

Results

When progeny of homozygous MLCK-Tg mice were separated after weaning by genotype [Tg/Tg, Tg/WT, WT/WT], increased IEB numbers associated with dysbiosis and more severe colitis were present in Tg/Tg and Tg/WT mice, relative to WT/WT mice. Cohousing with MLCK-Tg mice induced dysbiosis, increased IEB abundance, and exacerbated colitis in WT mice. Conversely, MLCK-Tg mice colonised with WT microbiota at birth displayed increased Escherichia abundance and greater colitis severity by 6 weeks of age. Microarray analysis revealed circadian rhythm disruption in WT mice co-housed with MLCK-Tg mice relative to WT mice housed only with WT mice. This circadian disruption required Rac1/STAT3-dependent microbial invasion but not MLCK activity, and resulted in increased proinflammatory cytokines and glucocorticoid downregulation.

Conclusions

The data demonstrate that barrier dysfunction induces dysbiosis and expansion of invasive microbes that lead to circadian disruption and mucosal inflammation. These results suggest that barrier-protective or bacterium-targeted precision medicine approaches may be of benefit to IBD patients.
Aging on the Job? The Association Between Occupational Characteristics and Accelerated Biological Aging
Authors: Andrasfay Theresa , Kim Jung Ki , Ailshire Jennifer A , Crimmins Eileen
Published: April 2023

Objectives

There is a common belief that demanding jobs can make workers age faster, but there is little empirical evidence linking occupational characteristics to accelerated biological aging. We examine how occupational categorizations and self-reported working conditions are associated with expanded biological age, which incorporates 22 biomarkers and captures physiologic dysregulation throughout several bodily systems.

Methods

Data are from 1,133 participants in the Health and Retirement Study who were aged 51–60 and working for pay in the 2010 or 2012 wave and who participated in the 2016 Venous Blood Study. We estimate associations between occupational category (professional/managerial, sales/clerical, service, and manual) and self-reported working conditions (psychosocial demands, job control, heavy lifting, and working 55 or more hours per week) and expanded biological age.

Results

Compared to same-age individuals working in professional or managerial positions, those working in service jobs appear 1.65 years older biologically even after adjusting for social and economic characteristics, self-reported working conditions, health insurance, and lifestyle-related risk factors. Low job control is associated with 1.40 years, heavy lifting with 2.08 years, and long working hours with 1.87 years of accelerated biological aging.

Discussion

Adverse occupational characteristics held at midlife, particularly service work, low job control, heavy lifting, and long work hours, are associated with accelerated biological aging. These findings suggest that work may be important for the overall aging process beyond its associations with specific diseases or risk factors.
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

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>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>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

This 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

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

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

Background and Hypothesis

Violence 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 Design

Clinical 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 Results

We 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.

Conclusions

The 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

Background

Sickle 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).

Procedure

Fifty-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.

Results

We 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 < 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 (<9 g/dl).

Conclusion

Renal 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

Alterations 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

Electromyographic (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

Tuberculosis (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

Albanian 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

The 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

Donor-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.
Dissecting the Ca2+dependence ofMycobacterium tuberculosisDesA1 function
Authors: Savanagouder Mamata , Mukku Ravi Prasad , Kiran Uday , Yeruva Chaitanya Veena , Nagarajan Nandhini , Sharma Yogendra , Raghunand Tirumalai R.
Published: April 2023

Mycobacterium tuberculosis (M. tb)has a complex cell wall, largely composed of mycolic acids and long-chain fatty acids that play a crucial role in maintaining its integrity and permeability. This complex lipid structure has a role in abrogating the process of phagosome-lysosome fusion and infection establishment. TheM. tbdesaturase A1 (DesA1) catalyzes the introduction of position-specific double bonds, a key step in the biosynthesis of a diverse range of mycolic acids. We have previously demonstrated thatM. tbDesA1 is a Ca2+-binding protein, belonging to the extended βγ-crystallin superfamily. Using a combination of biophysical and genetic approaches, we investigated the structural and functional significance of Ca2+binding on DesA1 activity. A protein unfolding assay of the protein in the presence and absence of Ca2+shows that Ca2+binding imparts structural stability to DesA1. To identify the role of Ca2+, we introduced mutations at key residues in the identified Ca2+-binding motif of DesA1 and generated F303A, E304Q, and F303A-E304Q variants of DesA1. We identified F303 as a hot point which disables the protein for Ca2+binding. Two other mutations E304Q and F303A-E304Q showed reduced Ca2+binding. Complementation of a conditionally complementeddesA1deletion mutant strain ofMycobacterium smegmatiswith these mutants, either failed to complement its growth phenotype or led to a compromise in complementation. In addition, the F303A and F303A-E304Q complements exhibit increased sensitivity to isoniazid, a first-line anti-tubercular drug, pointing to a cell wall permeability defect in these strains. Our findings highlight the critical importance of Ca2+in the functioning of DesA1 and its implicit role in the maintenance of mycobacterial cellular integrity.
Inflammation and bacteriophages affect DNA inversion states and functionality of the gut microbiota
Authors: Carasso Shaqed , Zaatry Rawan , Hajjo Haitham , Kadosh-Kariti Dana , Ben-Assa Nadav , Naddaf Rawi , Mandelbaum Noa , Pressman Sigal , Chowers Yehuda , Gefen Tal , Jeffrey Kate L. , Jofre Juan , Coyne Michael J. , Comstock Laurie E. , Sharon Itai , Geva-Zatorsky Naama
Published: April 2023

Reversible genomic DNA-inversions control expression of numerous bacterial molecules in the human gut, but how this relates to disease remains uncertain. By analyzing metagenomic samples from six human Inflammatory Bowel Disease cohorts combined with mice experimentation, we identified multiple invertible regions where a particular orientation was correlated with disease. These include the promoter of the anti-inflammatory polysaccharide-A (PSA) ofBacteroides fragilis, which is mostly oriented ‘OFF’ during inflammation but is present in the ‘ON’ orientation when inflammation is resolved. We further detected increased abundances ofB. fragilis-associated bacteriophages in patients with the PSA ‘OFF’ orientation, and a significant reduction in the frequency of the ‘ON’ orientation, in the presence of theB. fragilis-associated bacteriophage, thereby altering the bacterial induced immune modulation. Altogether, we reveal dynamic and reversible bacterial phase-variations driven both by bacteriophages and the host inflammatory state, signifying bacterial functional plasticity during inflammation and opening future research avenues.
Arterial stiffness and subclinical atherosclerosis in the coronary arteries at different stages of dysglycaemia
Authors: Cederqvist John , Rådholm Karin , Muhammad Iram Faqir , Engström Gunnar , Engvall Jan , Östgren Carl Johan
Published: April 2023

Aim

Our aim was to investigate in a large population‐based cohort study whether increased arterial stiffness and subclinical atherosclerosis in the coronary arteries differ at different stages of dysglycaemia.

Methods

Data were obtained from SCAPIS, a population‐based cohort of participants 50–64 years. The study population of 9379 participants was categorised according to glycaemic status: normoglycaemic, pre‐diabetes (fasting glucose: 6.1–6.9 mmol/L and/or HbA1c 6%–6.4%) and diabetes. Pulse wave velocity (PWV) was measured by the SphygmoCor XCEL system and arterial stiffness was defined by PWV ≥10 m/s. Coronary artery calcium score (CACS) was assessed by coronary computed tomography and coronary artery calcification was defined by CACS ≥100.

Results

We identified 1964 (21%) participants with dysglycaemia, out of which 742 (7.9%) had diabetes mellitus. PWV ≥10 m/s was present in 808 (11%), 191 (16%), 200 (27%) and CACS ≥100 in 801 (11%), 190 (16%), 191 (28%) participants with normoglycaemia, pre‐diabetes and diabetes, respectively, all, p < 0.001. The overlap between PWV ≥10 m/s and CACS ≥100 within each glycaemic category was 188 (2.5%), 44 (3.6%) and 77 (10) respectively. There was an association between glycaemic status and increased PWV in the fully adjusted models, but not for glycaemic status and CACS ≥100, where there was no difference for pre‐diabetes compared to normoglycaemia, OR 1.2 (95% CI 0.98–1.4). In the total study population, there was an association between HbA1c and PWV after adjustment, p < 0.001.

Conclusions

Our results show that increased arterial stiffness and subclinical coronary artery atherosclerosis are present in the early stages of dysglycaemia, but the overlap between markers of major subclinical vascular damage was small in all glycaemic categories. This could be explained by different pathways in the pathogenesis of arterial stiffness or atherosclerosis in the coronary arteries.
Pregnancy‐related venous thromboembolism in Wuhan, China 2010–2022: A case–control study
Authors: Sha Menghan , Chen Suhua
Published: April 2023

Objective

To explore the time trends and risk factors for pregnancy‐related venous thromboembolism (VTE) in the Chinese population.

Methods

A case–control study was conducted with 120 652 pregnancies between Jan 2010 and June 2022 in Wuhan, China. Medical records from pregnant patients with VTE and patients without VTE were reviewed and analyzed.

Results

There were 197 cases of VTE diagnosed during pregnancy or postpartum, with an overall incidence of 1.63 per 1000 pregnancies, and the incidence rate trend of VTE was increasing year by year and then declining. The incidence of deep venous thrombosis (DVT) was 1.24 per 1000 pregnancies (76.1%). Consistent with previous studies, most VTE occurred in the puerperium (1.05 per 1000 pregnancies, 64.5%). Significant risk factors included immobility, previous VTE, systemic infection, BMI over 30, and hypertensive disorders of pregnancy.

Conclusion

Pregnancy‐related VTE is not uncommon in China which is consistent with current foreign reports, and the change in incidence trend may be related to greater physicians' understanding of VTE and effective preventive measures after the publication of Chinese guidelines.
Osteoarthritis, part of life or a curable disease? A bird's‐eye view
Authors: Englund Martin
Published: April 2023

Osteoarthritis (OA) is a chronic joint disease caused by disruption of joint homeostasis by a variety of systemic and biomechanical factors. The disease is characterized by degradation of cartilage and other joint tissues, and low‐grade inflammation which may result in pain, reduced function, and disability. The disease appears to have ancient origins, with findings of OA recognized in fossilized bones from birdlike dinosaurs living some 130 million years ago. Today, the burden of OA in the world's population is steadily increasing due to aging and often rising rates of obesity. Structural findings, indicative of the disease, are also frequent in asymptomatic persons, which make the distinction between disease and normal aging sometimes challenging. OA is frequently associated with comorbidity in the form of obesity, cardiovascular disease, and depressive symptoms. The current management and treatments largely rely on contextual factors, and the actual effects of the intended therapeutic element of today's interventions are minor. The different mechanistic pathways (endotypes) and clinical characteristics (phenotypes) of OA make the development of disease‐modifying treatments challenging. Current development of drug candidates, aimed to restore joint homeostasis, is mainly targeting either inhibition of catabolic factors or stimulation of anabolic factors. However, there is yet no breakthrough in stage III clinical trials. Earlier diagnosis, better knowledge of endotypes—for example, by new insights into soluble biomarkers, and compositional imaging—and more careful selection of patients into clinical trials are possible tools to aid development of future therapies.
Anterior provisional fixed partial dentures: A finite element analysis
Authors: Almeganni Nouf , Abulaban Rotana , Naguib Ghada , Tharwat Mohamed , Nassar Hani M.
Published: April 2023

Purpose

The aim of this study was to analyze the stress distribution of fiber‐reinforced composite provisional fixed partial denture utilizing a finite element analysis model.

Material and methods

Three anterior teeth were collected: upper right central, left central, and right lateral incisors. A fiber‐reinforced composite strip was applied to the palatal surfaces of the teeth. Micro‐computed tomographic scans were acquired of the models in order to generate three‐dimensional geometrical replicas. Finite element analysis was used to assess the stress distribution of fiber‐reinforced composite provisional fixed partial denture using different pontic types under static applied forces that were 100, 30, and 0 N.

Results

The maximum stress values were found on the unprepared natural pontic. Stress values ranged from 92.2 to 909.8, 116.4 to 646.7, and 93.8 to 393.5 MPa for composite, naturally prepared, and natural unprepared pontic, respectively.

Conclusions

Using unprepared natural tooth pontic in anterior provisional fixed partial denture to replace missing central incisors is considered superior to other types in terms of stress distribution.