bluuebunny/crossref_metadata_2025 huggingface dataset:
Homozygous mutation in SLO3 leads to severe asthenoteratozoospermia due to acrosome hypoplasia and mitochondrial sheath malformations
Authors: Lv Mingrong , Liu Chunyu , Ma Chunjie , Yu Hui , Shao Zhongmei , Gao Yang , Liu Yiyuan , Wu Huan , Tang Dongdong , Tan Qing , Zhang Junqiang , Li Kuokuo , Xu Chuan , Geng Hao , Zhang Jingjing , Li Hang , Mao Xiaohong , Ge Lei , Fu Feifei , Zhong Kaixin , Xu Yuping , Tao Fangbiao , Zhou Ping , Wei Zhaolian , He Xiaojin , Zhang Feng , Cao Yunxia
Published: January 2022

Background

Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated.

Methods

We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy.

Results

We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition.

Conclusions

SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K+ channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families.
Use of research evidence varied in efforts to expand specific pharmacist autonomous prescriptive authority: an evaluation and recommendations to increase research utilization
Authors: Kumar Akshara , Ray Amber Bivins , Blanchard Carrie
Published: January 2022

Background

An expanding body of literature shows that pharmacists’ interventions improve health outcomes and are cost-saving. However, diverse state regulations of pharmacists’ scope of practice create a discrepancy between what pharmacists are trained to do and what they legally can do. This study investigated how stakeholders utilized research evidence when developing expanded scope of practice policies in their respective states.

Methods

Using autonomous pharmacist prescriptive authority as a surrogate for general pharmacist scope of practice, a general policy document analysis was performed to understand the scope of practice landscape for pharmacists across the United States. Next, semi-structured interviews with policy-makers and pharmacy advocates were conducted to explore how the identified states in the policy document analysis utilized evidence during the policy-making process. Investigators analysed findings from the transcribed interviews through application of the SPIRIT Action Framework. Resulting codes were summarized across themes, and recommendations to researchers about increasing utilization of research evidence were crafted.

Results

Sixteen states with 27 autonomous pharmacist prescriptive authority policies were identified. Public health need and safety considerations motivated evidence engagement, while key considerations dictating utilization of research included perceptions of research, access to resources and experts, and the successful implementation of similar policy. Research evidence helped to advocate for and set terms for pharmacist prescribing. Barriers to research utilization include stakeholder opposition to pharmacist prescribing, inability to interpret research, and a lack of relevant evidence. Recommendations for researchers include investigating specific metrics to evaluate scope of practice policy, developing relationships between policy-makers and researchers, and leveraging pharmacy practice stakeholders.

Conclusions

Overall, alignment of researcher goals and legislative priorities, coupled with timely communication, may help to increase research evidence engagement in pharmacist scope of practice policy. By addressing these factors regarding research engagement identified in this study, researchers can increase evidence-based scope of practice, which can help to improve patient outcomes, contain costs, and provide pharmacists with the legal infrastructure to practise at the top of their license.
Health technology assessment-informed pricing negotiation in China: higher negotiated price for more effective targeted anticancer medicines?
Authors: Huang Cong , Ung Carolina Oi Lam , Wushouer Haishaerjiang , Bai Lin , Huang Tao , Li Xinyi , Guan Xiaodong , Shi Luwen
Published: January 2022

Background

In China, health technology assessment (HTA) has recently been adopted in pricing negotiation for medicine listing in the National Reimbursement Drug List. At present, how HTA is applied to inform the decision-making process remains underreported. In order to explore how the adoption of HTA was translated into listing and price negotiation results in light of the confidential nature of the negotiating process, this study aimed to compare the negotiated price and the clinical benefit of selected targeted anticancer medicines (TAMs) involved in the 2019 negotiation.

Main text

Among 16 TAMs successfully negotiated, only four TAMs representing four indication groups had appropriate reference medicines for comparison and were, therefore, included in the analysis. The price and clinical benefit of the four TAMs were compared against one or two reference medicines with the same initial indications. The sales prices for nine TAMs before and after the negotiation were extracted from the centralized medication procurement system. Clinical benefits were evaluated based on evidence from published articles and clinical guidelines. The results suggested that, despite the application of HTA, both rational and irrational decisions had been made about the reimbursement of TAMs in the 2019 negotiation, warranting further investigation.

Conclusion

While the development and adoption of HTA has seen significant progress in China, actions are needed to ensure that the adoption of HTA is effectively applied in decisions on the reimbursement of medicines.
CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma
Authors: Yan Xiaorong , Kang Dezhi , Lin Yuanxiang , Qi Songtao , Jiang Changzhen
Published: January 2022

Background

Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. However, the roles of HAT and HDAC in the calcification and osteoblastic differentiation of ACP are not known.

Methods

In this study, primary cells were isolated from ACP tissues, and calcification was induced with bone morphogenetic protein 2 (Bmp2). HDAC3 expression was assessed in 12 tissue samples by Western blotting and immunohistochemistry. ACP calcification was assessed by Alizarin red staining. A luciferase reporter assay was performed to examine the interaction between miR-181b and the 3’-untranslated region of the polycomb chromobox 4 (CBX4) gene.

Results

Our results showed that the expression of HDAC3 was increased in the calcified ACP samples, but inhibition of HDAC3 promoted ACP cell calcification and osteoblastic differentiation. Mechanistically, HDAC3 nuclear translocation was suppressed by Bmp2, leading to Runx2 protein expression and Osterix, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) mRNA expression. In addition, this process was suppressed by CBX4, which stabilized the nuclear localization of HDAC3. miR-181b, the expression of which was increased in Bmp2-induced ACP cells, directly targeted and decreased CBX4 expression and inhibited the nuclear localization of HDAC3.

Conclusions

Our results demonstrate that Bmp2 increases miR-181b levels to directly target and inhibit CBX4 expression, leading to a reduction in the CBX4-dependent regulation of HDAC3 nuclear translocation, which results in Runx2 activation/osteoblastic differentiation and calcium deposition in ACP. Further studies targeting these cascades may contribute to therapeutic interventions used for recurrent ACP.
Small extracellular vesicles: from mediating cancer cell metastasis to therapeutic value in pancreatic cancer
Authors: Zhang Wenjie , Xing Juan , Liu Tian , Zhang Jie , Dai Zhujiang , Zhang Huan , Wang Daorong , Tang Dong
Published: January 2022

Pancreatic cancer is a highly malignant tumor and, is extremely difficult to diagnose and treat. Metastasis is one of the critical steps in the development of cancer and uses cell to cell communication to mediate changes in the microenvironment. Small extracellular vesicles (sEVs)-carry proteins, nucleic acids and other bioactive substances, and are important medium for communication between cells. There are two primary steps in sVEs-mediated metastasis: communication between pancreatic cancer cells and their surrounding microenvironment; and the communication between primary tumor cells and distant organ cells in distant organs that promotes angiogenesis, reshaping extracellular matrix, forming immunosuppressive environment and other ways to form appropriate pre-metastasis niche. Here, we explore the mechanism of localization and metastasis of pancreatic cancer and use sEVs as early biomarkers for the detection and treatment of pancreatic cancer.

Graphical Abstract
Scavenger receptors in host defense: from functional aspects to mode of action
Authors: Taban Qamar , Mumtaz Peerzada Tajamul , Masoodi Khalid Z. , Haq Ehtishamul , Ahmad Syed Mudasir
Published: January 2022

Scavenger receptors belong to a superfamily of proteins that are structurally heterogeneous and encompass the miscellaneous group of transmembrane proteins and soluble secretory extracellular domain. They are functionally diverse as they are involved in various disorders and biological pathways and their major function in innate immunity and homeostasis. Numerous scavenger receptors have been discovered so far and are apportioned in various classes (A-L). Scavenger receptors are documented as pattern recognition receptors and known to act in coordination with other co-receptors such as Toll-like receptors in generating the immune responses against a repertoire of ligands such as microbial pathogens, non-self, intracellular and modified self-molecules through various diverse mechanisms like adhesion, endocytosis and phagocytosis etc. Unlike, most of the scavenger receptors discussed below have both membrane and soluble forms that participate in scavenging; the role of a potential scavenging receptor Angiotensin-Converting Enzyme-2 has also been discussed whereby only its soluble form might participate in preventing the pathogen entry and replication, unlike its membrane-bound form. This review majorly gives an insight on the functional aspect of scavenger receptors in host defence and describes their mode of action extensively in various immune pathways involved with each receptor type.
Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis
Authors: Wang Renxi
Published: January 2022

Background

Observational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk.

Methods

To date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran’s Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias.

Results

One hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = − 0.940, p = 0.001; OR = 0.391), weighted median (Beta = − 0.835, p = 0.000; OR = 0.434), IVW (Beta = − 0.781, p = 0.000; OR = 0.458), simple mode (Beta = − 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = − 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS.

Conclusions

Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.
GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages
Authors: Cao Weijie , Fan Wenjuan , Wang Fang , Zhang Yinyin , Wu Guanghua , Shi Xiaojing , Shi Jian xiang , Gao Fengcai , Yan Meimei , Guo Rong , Li Yingmei , Li Wei , Du Chunyan , Jiang Zhongxing
Published: January 2022

Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.
Comparison of assessment scores for fatigue between multidimensional fatigue inventory (MFI-K) and modified chalder fatigue scale (mKCFQ)
Authors: Lim Eun-Jin , Son Chang-Gue
Published: January 2022

Background

Because of the absence of biological parameters for fatigue, appropriate instruments for assessing the degree of fatigue are important in the diagnosis and management of people complaining of fatigue-like symptoms. This study statistically analyzed the fatigue scores from two typical questionnaire-based instruments: the Korean version of the Multidimensional Fatigue Inventory (MFI-K) and the modified Chalder Fatigue Scale (mKCFQ).

Methods

Seventy participants (males n  = 40, females n  = 30, median age 48 years old, range of 25–67) were grouped into three groups (‘mild’  = 20, ‘moderate’  = 42, and ‘severe’  = 8) according to self-reported fatigue levels using a 7-point Likert scale. The similarities and differences between two instrument-derived scores were analyzed using correlations (r) and multidimensional scaling (MDS).

Results

The total scores of the two assessments were significantly correlated (r  = 75%, p  < 0.001), as were the subscores (‘Total Physical fatigue’: r  = 76%, p  < 0.001, ‘Total Mental fatigue’: r  = 56%, p  < 0.001). Relative overestimation of the MFI-K (45.8 ± 11.3) compared to the mKCFQ (36.1 ± 16.2) was observed, which was especially prominent in the ‘mild’ group. The scores of the three groups were more easily distinguished by the mKCFQ than by the MFI-K. In terms of the five dimension scores, we found a higher correlation of the two assessments for ‘general fatigue’ (r  = 79%, p  < 0.001) and ‘physical fatigue’ (r  = 66%, p  < 0.001) than for the reductions in ‘motivation’ (r  = 41%, p  < 0.01) and ‘activity’ (r  = 26%, p  > 0.05).

Conclusions

Our results may indicate the usefulness of the two instruments, especially for the physical symptoms of fatigue (‘general’ and ‘physical’ fatigue). Furthermore, the MFI-K may be useful for conditions of moderate-to-severe fatigue, such as chronic fatigue syndrome, but the mKCFQ may be useful for all spectra of fatigue, including in subhealthy people.
The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study
Authors: Chen Jingxian , Titanji Kehmia , Sheth Anandi N. , Gandhi Rajesh , McMahon Deborah , Ofotokun Ighovwerha , Weitzmann M. Neale , De Paris Kristina , Dumond Julie B.
Published: January 2022

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.
Molecular detection, phylogenetic analysis and genetic diversity of recently isolated foot-and-mouth disease virus serotype A African topotype, Genotype IV
Authors: Hassan Ayah M. , Zaher Mostafa R. , Hassanien Rabab T. , Abd-El-Moniem Mervat I. , Habashi Ahmed R. , Ibraheem Essam M. , Shahein Momtaz A. , El Zowalaty Mohamed E. , Hagag Naglaa M.
Published: January 2022

Background

Surveillance for circulating emerging diseases of economic importance has a major role in the rapid response to major pathogen outbreaks. Foot-and-mouth disease virus (FMDV) is one of the significant endemic viruses in Egypt. FMDV is periodically investigated for monitoring evolution and emergence of new variants. The genetic characterization of foot-and-mouth disease (FMD) virus serotype A responsible for recent outbreaks of FMD in Egypt was determined.

Methods

Samples were collected from different locations and virus isolation was performed using BHK-21 cells. Viral RNA was extracted and samples were screened for FMDV using real-time RT-PCR. DNA sequence analysis was performed and computational and bioinformatics analyses were used to determine the substitution rates and phylogenetic relationship.

Results

Sequence and phylogenetic analyses of full-length 1D region of FMDV samples collected from different governorates in 2020 showed close similarity to Egyptian FMDV strains from serotype A-African topotype-G-IV with genetic variation of 6.5%. Recently isolated FMDV strains showed high genetic variations from locally used vaccine strains in the major antigenic sites of VP1 region.

Conclusions

Although, efforts made by the veterinary authorities to implement an effective mass vaccination plan, the recently detected FMDV strains in this study could not be subtyped using the FMDV primers routinely used for molecular serotyping. These dissimilarities raise the alarm for reconsideration of the FMDV isolates used in vaccine manufacture. Clearly close monitoring of FMD in Egypt is urgently required to define the risks of future outbreaks and to ensure appropriate control measures against FMD major outbreaks.
Charting the evidence for climate change impacts on the global spread of malaria and dengue and adaptive responses: a scoping review of reviews
Authors: Kulkarni Manisha A. , Duguay Claudia , Ost Katarina
Published: January 2022

Background

Climate change is expected to alter the global footprint of many infectious diseases, particularly vector-borne diseases such as malaria and dengue. Knowledge of the range and geographical context of expected climate change impacts on disease transmission and spread, combined with knowledge of effective adaptation strategies and responses, can help to identify gaps and best practices to mitigate future health impacts. To investigate the types of evidence for impacts of climate change on two major mosquito-borne diseases of global health importance, malaria and dengue, and to identify the range of relevant policy responses and adaptation strategies that have been devised, we performed a scoping review of published review literature. Three electronic databases (PubMed, Scopus and Epistemonikos) were systematically searched for relevant published reviews. Inclusion criteria were: reviews with a systematic search, from 2007 to 2020, in English or French, that addressed climate change impacts and/or adaptation strategies related to malaria and/or dengue. Data extracted included: characteristics of the article, type of review, disease(s) of focus, geographic focus, and nature of the evidence. The evidence was summarized to identify and compare regional evidence for climate change impacts and adaptation measures.

Results

A total of 32 reviews met the inclusion criteria. Evidence for the impacts of climate change (including climate variability) on dengue was greatest in the Southeast Asian region, while evidence for the impacts of climate change on malaria was greatest in the African region, particularly in highland areas. Few reviews explicitly addressed the implementation of adaptation strategies to address climate change-driven disease transmission, however suggested strategies included enhanced surveillance, early warning systems, predictive models and enhanced vector control.

Conclusions

There is strong evidence for the impacts of climate change, including climate variability, on the transmission and future spread of malaria and dengue, two of the most globally important vector-borne diseases. Further efforts are needed to develop multi-sectoral climate change adaptation strategies to enhance the capacity and resilience of health systems and communities, especially in regions with predicted climatic suitability for future emergence and re-emergence of malaria and dengue. This scoping review may serve as a useful precursor to inform future systematic reviews of the primary literature.
Outcomes from the medication assisted treatment pilot program for adults with opioid use disorders in rural Colorado
Authors: Amura Claudia R. , Sorrell Tanya R. , Weber Mary , Alvarez Andrea , Beste Nancy , Hollins Ursula , Cook Paul F.
Published: January 2022

Background

As Colorado ranked among the top nationally in non-medical use of opioids, a pilot medication for opioid use disorder (MOUD) program was developed to increase the number of NPs and PAs providing MOUD in order to bring this evidence- based treatment to 2 counties showing disproportionally high opioid overdose deaths. Over the first 18 months, the MOUD Pilot Program led to 15 new health care providers receiving MOUD waiver training and 1005 patients receiving MOUD from the 3 participating organizations. Here we evaluate patient centered clinical and functional outcomes of the pilot MOUD program implemented in 2 rural counties severely affected by the opioid crisis.

Methods

Under state-funded law (Colorado Senate Bill 17–074), three rural agencies submitted de-identified patient-level data at baseline (N = 1005) and after 6 months of treatment (N = 190, 25%) between December 2017 and January 2020. The Addiction Severity Index, PhQ9 and GAD-7 with McNemar-Bowker, and Wilcoxon Signed Rank tests analysis were used to measure patient outcomes across after participation in the program. .

Results

Patients in treatment reported using less heroin (52.1% vs 20.4%), opioids (22.3% vs 11.0%), and alcohol (28.6% vs 13.1%, all P < 0.01). Patients reported improved health (53.4% vs. 68.2%, P = 0.04), less frequency of disability (8.69 vs. 6.51, P = 0.02), symptoms (29.8% vs 21.3%), pain (67.5% to 53.6), worry (45.3% vs 62.3%), anxiety (49.7% vs 23.2%), depression (54.1% vs 23.3%, all P < 0.02) after treatment.

Conclusions

This study shows decreased substance use, improved physical and mental health, and reduced symptoms after 6 months of MOUD. Although more research on retention and long-term effects is needed, data shows improved health outcomes after 6 months of MOUD. Lessons learned from implementing this pilot program informed program expansion into other rural areas in need to address some of Colorado’ major public health crises.
Integrating pathway knowledge with deep neural networks to reduce the dimensionality in single-cell RNA-seq data
Authors: Gundogdu Pelin , Loucera Carlos , Alamo-Alvarez Inmaculada , Dopazo Joaquin , Nepomuceno Isabel
Published: January 2022

Background

Single-cell RNA sequencing (scRNA-seq) data provide valuable insights into cellular heterogeneity which is significantly improving the current knowledge on biology and human disease. One of the main applications of scRNA-seq data analysis is the identification of new cell types and cell states. Deep neural networks (DNNs) are among the best methods to address this problem. However, this performance comes with the trade-off for a lack of interpretability in the results. In this work we propose an intelligible pathway-driven neural network to correctly solve cell-type related problems at single-cell resolution while providing a biologically meaningful representation of the data.

Results

In this study, we explored the deep neural networks constrained by several types of prior biological information, e.g. signaling pathway information, as a way to reduce the dimensionality of the scRNA-seq data. We have tested the proposed biologically-based architectures on thousands of cells of human and mouse origin across a collection of public datasets in order to check the performance of the model. Specifically, we tested the architecture across different validation scenarios that try to mimic how unknown cell types are clustered by the DNN and how it correctly annotates cell types by querying a database in a retrieval problem. Moreover, our approach demonstrated to be comparable to other less interpretable DNN approaches constrained by using protein-protein interactions gene regulation data. Finally, we show how the latent structure learned by the network could be used to visualize and to interpret the composition of human single cell datasets.

Conclusions

Here we demonstrate how the integration of pathways, which convey fundamental information on functional relationships between genes, with DNNs, that provide an excellent classification framework, results in an excellent alternative to learn a biologically meaningful representation of scRNA-seq data. In addition, the introduction of prior biological knowledge in the DNN reduces the size of the network architecture. Comparative results demonstrate a superior performance of this approach with respect to other similar approaches. As an additional advantage, the use of pathways within the DNN structure enables easy interpretability of the results by connecting features to cell functionalities by means of the pathway nodes, as demonstrated with an example with human melanoma tumor cells.
Cavβ surface charged residues contribute to the regulation of neuronal calcium channels
Authors: Tran-Van-Minh Alexandra , De Waard Michel , Weiss Norbert
Published: January 2022

Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Cavα1) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Cavβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Cavβ onto Cavα1 and is mediated by the alpha interacting domain (AID) within the Cavα1 subunit and the α binding pocket (ABP) within the Cavβ subunit. However, additional interactions between Cavα1 and Cavβ have been proposed. In this study, we analyzed the importance of Cavβ3 surface charged residues in the regulation of Cav2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Cavβ3 subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.
Long noncoding RNA TINCR facilitates hepatocellular carcinoma progression and dampens chemosensitivity to oxaliplatin by regulating the miR-195-3p/ST6GAL1/NF-κB pathway
Authors: Mei Jie , Lin Wenping , Li Shaohua , Tang Yuhao , Ye Zhiwei , Lu Lianghe , Wen Yuhua , Kan Anna , Zou Jingwen , Yu Chengyou , Wei Wei , Guo Rongping
Published: January 2022

Background

Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response.

Methods

The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment.

Results

TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo.

Conclusions

Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.
Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages
Authors: Chen Yaxin , Liu Yanzhuo , Wang Yang , Chen Xuewei , Wang Chenlong , Chen Xuehan , Yuan Xi , Liu Lilong , Yang Jing , Zhou Xiaoyang
Published: January 2022

Background

Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity.

Methods

A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson’s trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student’s t-test for two-group comparisons, and one-way ANOVA followed by Student–Newman–Keul test for multiple-group comparisons.

Results

We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis.

Conclusions

Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity.

Graphical abstract
N4-acetyldeoxycytosine DNA modification marks euchromatin regions in Arabidopsis thaliana
Authors: Wang Shuai , Xie Hairong , Mao Fei , Wang Haiyan , Wang Shu , Chen Zhenglin , Zhang Yuxia , Xu Zhihui , Xing Jinming , Cui Zhaokang , Gao Xiquan , Jin Hongmei , Hua Jian , Xiong Bo , Wu Yufeng
Published: January 2022

Background

Direct analogs of chemically modified bases that carry important epigenetic information, such as 5-methylcytosine (m5C)/5-methyldeoxycytosine (5mC), 5-hydroxymethylcytosine (hm5C)/5-hydroxymethyldeoxycytosine (5hmC), andN6-methyladenosine (m6A)/N6-methyldeoxyadenosine (6mA), are detected in both RNA and DNA, respectively. The modified baseN4-acetylcytosine (ac4C) is well studied in RNAs, but its presence and epigenetic roles in cellular DNA have not been explored.

Results

Here, we demonstrate the existence ofN4-acetyldeoxycytosine (4acC) in genomic DNA ofArabidopsiswith multiple detection methods. Genome-wide profiling of 4acC modification reveals that 4acC peaks are mostly distributed in euchromatin regions and present in nearly half of the expressed protein-coding genes inArabidopsis. 4acC is mainly located around transcription start sites and positively correlates with gene expression levels. Imbalance of 5mC does not directly affect 4acC modification. We also characterize the associations of 4acC with 5mC and histone modifications that cooperatively regulate gene expression. Moreover, 4acC is also detected in genomic DNA of rice, maize, mouse, and human by mass spectrometry.

Conclusions

Our findings reveal 4acC as a hitherto unknown DNA modification in higher eukaryotes. We identify potential interactions of this mark with other epigenetic marks in gene expression regulation.
Social Mobile Approaches to Reducing Weight (SMART) 2.0: protocol of a randomized controlled trial among young adults in university settings
Authors: Mansour-Assi Shadia J. , Golaszewski Natalie M. , Costello Victoria Lawhun , Wing David , Persinger Hailey , Coleman Aaron , Lytle Leslie , Larsen Britta A. , Jain Sonia , Weibel Nadir , Rock Cheryl L. , Patrick Kevin , Hekler Eric , Godino Job G.
Published: January 2022

Background

Excess weight gain in young adulthood is associated with future weight gain and increased risk of chronic disease. Although multimodal, technology-based weight-loss interventions have the potential to promote weight loss among young adults, many interventions have limited personalization, and few have been deployed and evaluated for longer than a year. We aim to assess the effects of a highly personalized, 2-year intervention that uses popular mobile and social technologies to promote weight loss among young adults.

Methods

The Social Mobile Approaches to Reducing Weight (SMART) 2.0 Study is a 24-month parallel-group randomized controlled trial that will include 642 overweight or obese participants, aged 18–35 years, from universities and community colleges in San Diego, CA. All participants receive a wearable activity tracker, connected scale, and corresponding app. Participants randomized to one intervention group receive evidence-based information about weight loss and behavior change techniques via personalized daily text messaging (i.e., SMS/MMS), posts on social media platforms, and online groups. Participants in a second intervention group receive the aforementioned elements in addition to brief, technology-mediated health coaching. Participants in the control group receive a wearable activity tracker, connected scale, and corresponding app alone. The primary outcome is objectively measured weight in kilograms over 24 months. Secondary outcomes include anthropometric measurements; physiological measures; physical activity, diet, sleep, and psychosocial measures; and engagement with intervention modalities. Outcomes are assessed at baseline and 6, 12, 18, and 24 months. Differences between the randomized groups will be analyzed using a mixed model of repeated measures and will be based on the intent-to-treat principle.

Discussion

We hypothesize that both SMART 2.0 intervention groups will significantly improve weight loss compared to the control group, and the group receiving health coaching will experience the greatest improvement. We further hypothesize that differences in secondary outcomes will favor the intervention groups. There is a critical need to advance understanding of the effectiveness of multimodal, technology-based weight-loss interventions that have the potential for long-term effects and widespread dissemination among young adults. Our findings should inform the implementation of low-cost and scalable interventions for weight loss and risk-reducing health behaviors.

Trial registration

ClinicalTrials.govNCT03907462. Registered on April 9, 2019
Effect of low-load resistance training with different degrees of blood flow restriction in patients with knee osteoarthritis: study protocol for a randomized trial
Authors: Wang Hao-Nan , Chen Yan , Cheng Lin , Wang Shen-Tao , Hu De-Xin , Wang Li-Na , Ni Guo-Xin
Published: January 2022

Background

Knee osteoarthritis (KOA) is a common degenerative disease that causes pain, functional impairment, and reduced quality of life. Resistance training is considered as an effective approach to reduce the risk of muscle weakness in patients with KOA. Blood flow restriction (BFR) with low-load resistance training has better clinical outcomes than low-load resistance training alone. However, the degree of BFR which works more effectively with low-load resistance training has not been determined. The purpose of this study is to evaluate the effectiveness of different degrees of BFR with low-load resistance training in patients with KOA on pain, self-reported function, physical function performance, muscle strength, muscle thickness, and quality of life.

Methods

This is a study protocol for a randomized, controlled trial with blinded participants. One hundred individuals will be indiscriminately assigned into the following groups: two training groups with a BFR at 40% and 80% limb occlusion pressure (LOP), a training group without BFR, and a health education group. The three intervention groups will perform strength training for the quadriceps muscles twice a week for 12 weeks, while the health education group will attend sessions once a week for 12 weeks. The primary outcome is pain. The secondary outcomes include self-reported function, physical function performance, muscle strength of the knee extensors, muscle mass of the quadriceps, quality of life, and adverse events. Intention-to-treat analysis will be conducted for individuals who withdraw during the trial.

Discussion

Previous studies have shown that BFR with low-load resistance training is more effective than low-load resistance training alone; however, a high degree of BFR may cause discomfort during training. If a 40% LOP for BFR could produce similar clinical outcomes as an 80% LOP for BFR, resistance training with a low degree of BFR can be chosen for patients with KOA who are unbearable for a high degree of BFR.

Trial registration

Chinese Clinical Trial Registry ChiCTR2000037859 (http://www.chictr.org.cn/edit.aspx?pid=59956&htm=4). Registered on 2 September 2020
Unraveling heterogeneity within ACPA-negative rheumatoid arthritis: the subgroup of patients with a strong clinical and serological response to initiation of DMARD treatment favor disease resolution
Authors: Verstappen M. , van Steenbergen H. W. , de Jong P. H. P. , van der Helm-van Mil A. H. M.
Published: January 2022

Background

Rheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR.

Methods

In 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized.

Results

ACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS4 months < 1.6). This latter was replicated in independent ACPA-negative RA patients.

Conclusions

ACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.
A new and spontaneous animal model for ankylosing spondylitis is found in cynomolgus monkeys
Authors: Jia Huanhuan , Chen Meili , Cai Yanzhen , Luo Xiaoling , Hou Gang , Li Yongfeng , Cai Chunmei , Chen Jun , Li Qingnan , Miu Kai-Kei , Fung Sin-Hang , Wang Zhangting , Huang Ren , Shen Huiyong , Lu Li
Published: January 2022

Background

Ankylosing spondylitis is a progressive, disabling joint disease that affects millions worldwide. Given its unclear etiology, studies of ankylosing spondylitis relied heavily on drug-induced or transgenic rodent models which retain only partial clinical features. There is obviously a lack of a useful disease model to conduct comprehensive mechanistic studies.

Methods

We followed a group of cynomolgus monkeys having joint lesions reported of spinal stiffness for 2 years by conducting hematological testing, radiographic examination, family aggregation analysis, pathological analysis, and genetic testing.

Results

The results confirmed that these diseased animals suffered from spontaneous ankylosing spondylitis with clinical features recapitulating human ankylosing spondylitis disease progression, manifested by pathological changes and biochemical indicators similar to that of ankylosing spondylitis patients.

Conclusion

The study offers a promising non-human primate model for spontaneous ankylosing spondylitis which may serve as an excellent substitute for its pre-clinical research.