bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary tract infections: a retrospective cohort study of (mis)matching antimicrobial therapy and clinical outcome among Finnish adults
Authors: Patjas Anu , Jokiranta T Sakari , Kantele Anu
Published: November 2024

Objectives

With the global spread of antimicrobial resistance, treating urinary tract infections (UTIs) is becoming more challenging. Clinical data on UTI outcomes are scarce in cases with antimicrobial treatment mismatching the uropathogens’ in vitro susceptibility profiles. We explored the association of (mis)matching antimicrobial treatment and clinical outcomes among patients with either ESBL-producing Enterobacterales (ESBL-PE) or non-ESBL-PE identified in urine samples.

Patients and methods

In 2015–2019, we recruited 18–65-year-old patients with laboratory-confirmed, community-acquired ESBL-PE (n = 130) or non-ESBL-PE (n = 187) UTI. Our study involved collecting data on in vitro susceptibility profiles, antimicrobial therapy (microbiological match/mismatch) and clinical outcomes, and a follow-up of relapses/reinfections.

Results

Non-beta-lactam co-resistance was found more frequent among ESBL-PE than non-ESBL-PE isolates. The initial antimicrobial matched the in vitro susceptibility for 91.6% (164/179) of those with non-ESBL-PE and 46.9% (38/81) with ESBL-PE UTI (P < 0.001). The clinical cure rates in the non-ESBL-PE and ESBL-PE UTI groups were 82.6% (142/172) and 62.2% (74/119) (P < 0.001) for all, 87.3% (131/150) and 83.3% (30/36) for those treated with matching antimicrobials, and 33.3% (5/15) and 41.9% (18/43) for those given mismatching antimicrobials, respectively. Mismatching antimicrobial therapy was not associated with relapse/reinfection over the 3-month follow-up (P = 0.943).

Conclusions

In our data, (mis)matching microbiological susceptibility is only partially associated with the clinical outcome of UTI: microbiological matching appears to predict clinical cure better than mismatching predicts clinical failure.
Hip arthroscopy failure rates: a healthcare database analysis in the United States
Authors: Thakkar Akshar P , Scheidt Michael D , Jadidi Shaheen , Ellman Michael B , Bare Aaron A , Stover Michael D , Bhatia Sanjeev
Published: November 2024

With hip arthroscopy cases, there has been a concomitant increase in complications and the need for revision surgery. This study aims to further contribute to the literature regarding hip arthroscopy failure rates and associated patient factors following an index hip arthroscopy procedure. The PearlDiver database was queried for patients who had undergone hip arthroscopy. International Classification of Diseases, 10th Revision, Clinical Modification codes were used to ensure that follow-up was performed on the ipsilateral limb. Hip arthroscopy failure was defined specifically as subsequent ipsilateral total hip arthroplasty (THA) and reoperation, which were examined in all patients that met inclusion criteria. Independent patient variables, including psychiatric comorbidities, preoperative SSRI use, smoking, and obesity, were examined to identify an association with failure rates. A Student t-test, with a significance set at P < 0.05, was used for statistical comparisons of postoperative outcomes. Odds ratios were used to calculate the probability of short-term hip reoperation in patients with the above independent variables. A total of 19 067 hip arthroscopy patients were included in this study. Within 2 years from the index hip arthroscopy, there was an 11.42% failure rate as defined by subsequent reoperation and 7.16% failure rate as defined by revision to THA, with a total revision surgery rate of 18.58%. The most common reoperation procedure was revision femoroplasty (72%). Patients with an active diagnosis of a psychiatric comorbidity in the year leading up to a hip arthroscopy procedure were 1.74 times more likely to require a hip reoperation within 1 year (95% CI, 1.55–1.95).
Skin Color Representation in Infectious Disease Textbooks
Authors: Thornton Jessica , Giuffre Allison , Donohue Sarah , Hollnagel Fauzia , Tischendorf Jessica
Published: November 2024

Darker skin is underrepresented in medical textbooks. This may contribute to inequity in our system. We assessed skin color representation in infectious disease textbooks and compared diseases associated with social stigma to those not stigmatized. Images depicting conditions associated with social stigma were significantly more common on darker skin.
Utilizing Technology to Enhance the Ecological Validity of Cognitive and Functional Assessments in Schizophrenia: An Overview of the State-of-the-Art
Authors: Horan William P , Moore Raeanne C , Belanger Heather G , Harvey Philip D
Published: November 2024

Cognitive impairment is a core feature of schizophrenia and a key determinant of functional outcome. Although conventional paper-and-pencil based cognitive assessments used in schizophrenia remained relatively static during most of the 20th century, this century has witnessed the emergence of innovative digital technologies that aim to enhance the ecological validity of performance-based assessments. This narrative review provides an overview of new technologies that show promise for enhancing the ecological validity of cognitive and functional assessments. We focus on 2 approaches that are particularly relevant for schizophrenia research: (1) digital functional capacity tasks, which use simulations to measure performance of important daily life activities (e.g., virtual shopping tasks), delivered both in-person and remotely, and (2) remote device-based assessments, which include self-administered cognitive tasks (e.g., processing speed test) or functionally-focused surveys regarding momentary activities and experiences (e.g., location, social context), as well as passive sensor-based metrics (e.g., actigraphy measures of activity), during daily life. For each approach, we describe the potential for enhancing ecological validity, provide examples of select measures that have been used in schizophrenia research, summarize available data on their feasibility and validity, and consider remaining challenges. Rapidly growing evidence indicates that digital technologies have the potential to enhance the ecological validity of cognitive and functional outcome assessments, and thereby advance research into the causes of, and treatments for, functional disability in schizophrenia.
Assessing Gender Diversity in American Society for Dermatologic Surgery Fellowship Leadership: A 2013 to 2022 Trend Analysis
Authors: Richmond Alexandra , Aristizabal Miguel , Greywal Tanya , Gregoski Mathew J. , Almukhtar Rawaa
Published: November 2024

BACKGROUND

While there has been improved gender representation in dermatology, there remains areas for improvement, especially in leadership positions. Studies have evaluated diversity in various dermatology subspecialties, but evaluation of gender diversity in cosmetic dermatology is lacking.

OBJECTIVE

To evaluate the temporal trends in gender diversity within the American Society for Dermatologic Surgery (ASDS) Cosmetic Dermatologic Surgery Fellowship Programs from 2013 to 2022. To discuss strategies for improvement.

MATERIALS AND METHODS

The ASDS Cosmetic Dermatologic Surgery Fellowship program directors and fellows were reviewed from 2013 to 2022. Gender was determined through online professional websites and biographies. The number and proportion of each gender was determined for each year, and the change over time was calculated.

RESULTS

The number of fellowship positions and program directors has increased from 2013 to 2022. Most of the fellows have been women. The average yearly rate of change for fellows is +1.67 and +0.67 for men and women. Most of the fellowship directors have been men. The average yearly rate of change is +1.56 and +0.44 for men and women.

CONCLUSION

Gender inequalities remain across leadership positions and further studies are necessary to better determine why these discrepancies exist and how to improve this inequality.
A Review of Best Practices for Gender-Affirming Laser Hair Removal
Authors: Yanes Daniel A. , Smith Payton , Avram Mathew M.
Published: November 2024

BACKGROUND

Permanent hair reduction is an integral part of gender-affirming medical care, especially for transgender patients undergoing surgeries such as phalloplasty and vaginoplasty. Hair removal helps reduce complications and alleviate gender dysphoria associated with unwanted facial and body hair.

OBJECTIVE

To examine the methods, efficacy, and access issues of hair removal in transgender patients, with a focus on its role in surgical preparation and gender dysphoria reduction.

MATERIALS AND METHODS

A literature review was conducted to analyze the effectiveness of laser hair removal (LHR) and electrolysis for permanent hair reduction. The review also explored regional regulatory barriers and insurance coverage limitations affecting access to these services.

RESULTS

Laser hair removal and electrolysis are both effective for hair removal, with LHR being less painful and faster. Laser hair removal is often preferred but requires multiple treatments and proper laser settings. Insurance coverage remains inconsistent, limiting access to these procedures. Postoperative hair regrowth in neovaginal or neourethral sites can be managed with hormonal adjustments and further treatments.

CONCLUSION

Hair removal plays an essential role in reducing surgical complications and gender dysphoria in transgender patients. A multidisciplinary approach between dermatologists and surgeons is essential, and addressing regulatory and access barriers is critical for equitable care.
TENORM Regulation in the United States of America post-West Virginia vs. EPA
Authors: Lynn Spenser , Wilson Charles , Caffrey Emily
Published: November 2024

The regulation of technologically enhanced naturally occurring radioactive materials (TENORM) in the United States of America consists of fragmentary rules split between the federal and state governments. The US Environmental Protection Agency (EPA) has recognized the complex nature of TENORM regulation but has not issued explicit TENORM rules at the federal level. Some states have enacted their own TENORM statutes and regulations to fill this gap, while others claim the authority to regulate TENORM under their general radiation protection regulations. The Supreme Court of the United States (SCOTUS) ruling in West Virginia vs. EPA created a new lens through which environmental regulations should be viewed and may have implications for the regulation of TENORM. This paper presents an overview of West Virginia vs. EPA, the major questions doctrine on which SCOTUS based its opinion, and how it might apply to TENORM regulations at the federal and state levels. Two states, one with explicit TENORM regulations and another with only general radiation protection statutes, are considered in the context of a hypothetical legal challenge to TENORM regulations. The role and impact of West Virginia vs. EPA in administrative law is still to be determined, but it does prompt an opportunity to conduct a new, more thorough review of TENORM regulation at the federal and state level.
Complications in Pelvic Organ Prolapse With 3-Month Versus 6-Month Pessary Care: Pilot Study
Authors: Giorgenon Geovana Volta , Galhardo Letícia Martineli , de Araujo Camila Carvalho , de Castro Edilson Benedito , Brito Luiz Gustavo Oliveira , Juliato Cássia Raquel Teatin
Published: November 2024

Importance

Despite evidence emphasizing the necessity of routine care for women with pelvic organ prolapse (POP) using pessaries, the frequency of follow-up is unclear.

Objective

The aim of this study was to compare the presence of complications in women with POP using vaginal pessaries with cleaning and gynecological examination every 3 or 6 months.

Study Design

This pilot study was a randomized clinical trial of women with advanced POP using a ring pessary. The women were randomized into 2 groups (“3-month group” and a “6-month group”) that returned for evaluation by a health care professional that monitored the vagina, removed the pessary, cleaned it, and reinserted it. Sociodemographic and clinical data were collected. During their follow-up, the women answered a questionnaire regarding the presence of vaginal symptoms and had a physical examination and vaginal sampling for microbiological analysis.

Results

A total of 38 women were randomized into 2 groups: the 3-month group (n = 18) and the 6-month group (n = 20). Baseline characteristics of the groups were similar except for age, which was 70.7 (±7.4) years in the 3-month group and 74.7 (±6.6) years in the 6-month group (P = 0.022). Regarding physical examination, after 12 months of follow-up, 4 women in each group presented erosions or ulcers in each group, but without difference (P = 1). The presence of bacterial vaginosis was more frequent in the group with cleaning every 6 months (P = 0.026).

Conclusions

The prevalence of ulcerations was similar in both groups with cleaning every 3 or 6 months, but the group with cleaning every 6 months showed a higher prevalence of bacterial vaginosis.
Biofilm and Its Characteristics in Venous Ulcers
Authors: Frison Susiane Sucasas , Borges Eline Lima , Guedes Antônio Carlos Martins , Honorato-Sampaio Kinulpe
Published: November 2024

PURPOSE

The aim of the study was to analyze the characteristics of the biofilm of venous ulcers in terms of location and formation and to relate the presence of the biofilm to ulcer characteristics including duration, injured area, and necrotic tissue.

DESIGN

Descriptive clinical study.

MATERIALS AND METHODS

We obtained 2 biopsy fragments (tissue samples) from 44 patients with venous ulcers treated at a public outpatient clinic in a university hospital in Belo Horizonte, Brazil. Ulcers were photographed and classified according to the duration. In addition, the wound size and proportion of wound surface covered by necrotic tissue were measured. One fragment from each ulcer underwent microbiological analysis, while the other was analyzed using transmission electron microscopy. Data analysis was limited to fragments from patients with bacteria in the microbiological analysis.

RESULTS

Data analysis is based on samples obtained from 21 ulcers in 21 patients who had bacteria in their ulcer based on microbiologic analysis of a tissue sample. Most ulcers were open for 2 to 10 years, 57% (n = 12) were 16 cm2 or smaller, and the proportion of the wound bed covered by necrotic tissue coverage varied widely. Of the 21/44 patients (48%) with bacteria in their ulcers, only 3 patients had bacterial biofilm present in the transmission electron microscopy, corresponding to 7% of the 44 patients. Pseudomonas aeruginosa was the most frequent bacterium, identified in 10 fragments. The biofilm was not present on the surface but in a layer slightly below it. The detection of biofilms was not directly related to the duration of the ulcer. It was not possible to establish a correlation between the size of the lesion and the presence of these microorganisms due to the small sample size.

CONCLUSIONS

Our findings indicate that detecting biofilm in venous ulcers is challenging, as it does not uniformly occur throughout the wound bed, can occur at different depths, and is often not present on the wound surface. There is a need to develop studies that can contribute to the detection of biofilm in clinical practice.
Genomic profiling and assessment of the plant growth-enhancing traits in the novel actinomycete, Plantactinospora soli sp. nov.
Authors: Wang Lili , Ma Zhouai , Zhang Ya , Chen Qiuyu , Shen Qi , Yao Jiaqi , Cao Chengliang , Li Rongpeng , Jiang Jihong
Published: November 2024

Strain KLBMP 9567T, an isolate from weathered soil, was identified as a new actinobacterial species through a comprehensive polyphasic approach. Phylogenetic evaluations relying on 16S rRNA gene sequence placed KLBMP 9567T within the genus Plantactinospora, alongside its close relatives Plantactinospora veratri NEAU-FHS4T and Plantactinospora sonchi NEAU-QY2T, both sharing 98.6% sequence similarity. However, KLBMP 9567T demonstrated low digital DNA–DNA hybridization values with P. veratri NEAU-FHS4T and P. sonchi NEAU-QY2T, recorded at 48.5 and 29.1%, respectively. Meanwhile, the average nucleotide identity values were correspondingly recorded at 91.1 and 83.1%. The cell wall of KLBMP 9567T contained meso-diaminopimelic acid, with xylose, mannose, glucose and galactose as diagnostic sugars. The diagnostic dominant phospholipids included diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Given phenotypic and genotypic data, KLBMP 9567T is recognized as a new species within the Plantactinospora genus, named Plantactinospora soli sp. nov., with the type strain KLBMP 9567T (= CGMCC 4.7773T = NBRC 115787T). Genome mining revealed genes associated with plant growth promotion, specifically those encoding enzymes for synthesizing plant hormones like indole acetic acid and gibberellic acid. Experimental validation demonstrated that KLBMP 9567T can produce significant quantities of indole acetic acid (20.6 mg l−1) and gibberellic acid (42.6 mg l−1). Moreover, co-culture with Arabidopsis showed marked growth enhancements: a 56.3% increase in lateral root proliferation, a 16.7% elongation in primary root length and a 44.8% boost in biomass accumulation. These findings underscore the strain’s potent plant growth-promoting attributes, providing profound insights into the mechanisms by which KLBMP 9567T enhances plant growth.
African lineage 1a West Nile virus isolated from crocodiles exhibits low neuroinvasiveness in mice
Authors: Kobayashi Hiroko , Chambaro Herman , Tabata Koshiro , Ariizumi Takuma , Phongphaew Wallaya , Ndashe Kunda , Ndebe Joseph , Fandamu Paul , Kobayashi Shintaro , Ito Naoto , Sasaki Michihito , Hang’ombe Bernard M. , Simulundu Edgar , Orba Yasuko , Sawa Hirofumi
Published: November 2024

West Nile virus (WNV) is a mosquito-borne flavivirus that causes encephalitis in humans and infects crocodiles, resulting in rashes and neurological signs. In Zambia, two distinct lineages of WNV have been detected in neighbouring areas: lineage 2 in mosquitoes and lineage 1a in farmed crocodiles. Considering the risk of direct or vector-mediated WNV transmission from crocodiles to mammals, it is necessary to elucidate the pathogenicity of WNV strains derived from crocodiles. In this study, WNV was successfully isolated from naturally infected farmed crocodiles (Croc110/2019/1/ZM, Croc110). We then investigated its proliferation and pathogenicity in mice in comparison with a WNV isolate from mosquitoes in Zambia (Zmq16) and two reference strains, including one highly pathogenic (NY99) and one low pathogenic (Eg101) strain. Although viral proliferation in Vero and mammalian neuronal cells was comparable among the strains, Croc110 exhibited low cell-to-cell transmission efficiency. In vivo, more than 70% of mice (C57BL/6) intracerebrally inoculated with Croc110 displayed neurological signs, and Croc110-infected mice exhibited similarly high mortality rates as NY99- and Zmq16-infected mice. Meanwhile, comparable virus growth was observed among the strains in the brain. However, the virulence of Croc110 was significantly lower than that of Zmq16 and NY99 following intradermal (ID) and intraperitoneal inoculation. Consistently, Croc110 displayed lower growth than Zmq16 and NY99 in the brain and peripheral tissues after ID inoculation. Our study revealed that the crocodile-derived WNV strain is less neuroinvasive in mice, and it exhibits distinct pathogenicity from the highly pathogenic mosquito-derived WNV strain circulating in Zambia.
Number of interventional clinical trials registered per million population per country worldwide
Authors: Bjerg Jonas Leth , Nikolova Dimitrinka , Gluud Christian
Published: November 2024

Background

Historically, Sweden and Denmark have excelled in clinical trial publications per million population, but many trials have remained unpublished. Enforceable policies for trial registration before launch, made global and national clinical research assessments possible. The World Health Organisation (WHO) hosts the International Clinical Trials Registry Platform (ICTRP) for interventional clinical trials, with data from 1999.

Objective

To find out if the retrospective or prospective trial registration activities per million population per country during the 2009 to 2022 period have improved after establishing the number of interventional clinical trials registered per million population per country during the 1999 to 2022 period.

Methods

We used the WHO ICTRP to extract the numbers of registered interventional clinical trials. We entered data in Microsoft Excel to analyse two separate periods, 1999 to 2022 and 2009 to 2022. The second period aimed at filtering out the pickup of the registration requirements. To obtain the trial registration activity by country, we divided the number of interventional clinical trials registered by the country’s population in millions. Information on population numbers originated from the World Bank, the Central Intelligence Agency World Factbook, and The National Institute of Statistics and Economic Studies (of France) as of 2022. We collected data as of 03-01-2024.

Results

In February 2023, there were 943.113 interventional clinical trials on the ICTRP. After excluding 32.309 trials with unknown country of origin, 910.804 trials from 229 countries and territories were analysed. For countries or territories with populations over 1 million, the top five in interventional clinical trial registrations per million during 1999-2022 were Denmark, Estonia, Belgium, The Netherlands, and Latvia. For 2009-2022, they were Denmark, Estonia, Belgium, The Netherlands, and New Zealand. The top five overall, irrespective of population, for both periods were Pitcairn, The Vatican, Tokelau, Niue, and Denmark.

Conclusions

Since 1999, there has been worldwide growth in interventional trial registrations, especially among top-contributing countries. The global average stands at approximately 115 registered trials per million people from 1999 to 2022, highlighting the need for continued efforts to improve trial registration and production. Smaller Western countries lead in interventional clinical trials per million population.
Tiled PCR amplification-based Whole Genome Sequencing and Phylogenetic Classification Accelerate the Implementation of Respiratory Syncytial Virus Genomic surveillance in Canada as a Pilot Study
Authors: Gao Ruimin , Buchanan Cody , Dust Kerry , Van Caeseele Paul , Wong Henry , Sjaarda Calvin , Sheth Prameet M. , Jassem Agatha N. , Minion Jessica , Bastien Nathalie
Published: November 2024

Whole genome sequencing (WGS) has emerged as a powerful tool to facilitate the study of existing and emerging infectious diseases. WGS-based genomic surveillance provides information on the genetic diversity and tracks the evolution of important viral pathogens including Respiratory Syncytial Virus (RSV). Development and implementation of robust tiled multiplex PCR amplification-based WGS assays will facilitate high-throughput RSV surveillance initiatives. In this study, we developed multiplex PCR assays for targeted enrichment of viral genomes using PrimalScheme (http://primal.zibraproject.org) to amplify over 97% of the genome in the majority of contemporaneous specimens tested. A pilot dataset comprising 52 RSVA and 37 RSVB genomes derived from Canadian clinical specimens during the 2022-2023 respiratory virus season were used to perform phylogenetic analyses using both near complete genome and Glycoprotein (G) sequences. Overall, the RSV phylogenetic tree built with whole genomes showed identical lineage clusters as that compared to the G gene, but showed more confidence and discriminatory features within individual lineage. Moreover, availability of whole genomes enabled the identification of a broader range of mutations, for instance the identified S377N, K272M, S276N, S211N, S206I and S209Q in Canadian fusion proteins that could be potentially associated with effectiveness of vaccines or antiviral-based therapeutics. In conclusion, the tiled-PCR amplification assays described offer a more streamlined approach to facilitate high-throughput, high sensitivity of RSV WGS, which is capable of supporting enhanced genomic surveillance initiatives, as well as the more comprehensive genomic analyses required to inform public health strategies for the development and usage of vaccines and antiviral drugs.

IMPORTANCE

We present assays to efficiently sequence genomes of the RSVA and RSVB. This enables researchers and public health agencies to acquire high-quality genomic data using rapid and cost-effective approaches. Genomic data based comparative analysis can be used to conduct surveillance and monitor circulating isolates for efficacy of vaccines and antiviral therapeutics.
Cumulative dose responses for adapting biological systems
Authors: Gupta Ankit , Sontag Eduardo D.
Published: November 2024

This paper introduces the notion of cumulative dose response (cDR). The cDR is the area under the plot of a response variable, an integral taken over a fixed time interval and seen as a function of an input parameter. This work was motivated by the accumulation of cytokines resulting from T cell stimulation, where a non-monotonic cDR has been observed experimentally. However, the notion is of general applicability. A surprising conclusion is that incoherent feedforward loops studied in the systems biology literature, though capable of non-monotonic dose responses, can be mathematically shown to always result in monotonic cDR.
Perfusion via chemicals removes the DNA content of rabbit hearts while keeping the collagen and glycosaminoglycan unaltered
Authors: Seitzhaparova Banu , Kadyr Sanazar , Timur Leya , Mirasbek Baisunkar , Zhakypbekova Aida , Lesbekov Timur , Erisken Cevat
Published: November 2024

Despite new approaches in the treatment of cardiovascular disease (CVD) such as percutaneous coronary intervention, coronary artery bypass graft, and left ventricular assist devices, which cannot fully compensate for the effectiveness of the original heart, heart transplantation still remains as the most effective solution.

A growing body of literature recognizes the importance of developing a whole heart constructed from living tissues to provide an alternative option for patients suffering from diseases of the cardiovascular system. A potential solution that shows a promise is to generate cell-free, i.e., decellularized, scaffolds using native heart tissue to be later cellularized and transplanted. This study reports the decellularization process and efficiency in an effort to create a whole heart scaffold. The hearts harvested from rabbits were perfused and the final bioartificial scaffolds were characterized for the efficiency of decellularization in terms of DNA content, collagen, and glycosaminoglycan. The compressive biomechanical properties of decellularized and native hearts were also determined and compared. Findings revealed that the DNA content of decellularized hearts was significantly reduced while keeping collagen and GAG content unchanged. Biomechanical properties of the hearth became inferior upon removal of the nuclear material. Decellularized hearts have significant importance in treating CVD as they serve as bioartificial hearts, providing a more clinically relevant model for potential human use.

Future work will focus on the recellularization of the heart using induced pluripotent or embryonic stem cells to test its functionality.
Covalent inhibition of the SARS-CoV-2 NiRAN domain via an active-site cysteine
Authors: Hernandez Genaro , Osinski Adam , Majumdar Abir , Eitson Jennifer L. , Antczak Monika , Pawłowski Krzysztof , Niederstrasser Hanspeter , Servage Kelly A. , Posner Bruce , Schoggins John W. , Ready Joseph A. , Tagliabracci Vincent S.
Published: November 2024

The kinase-like NiRAN domain of nsp12 in SARS-CoV-2 catalyzes the formation of the 5’ RNA cap structure. This activity is required for viral replication, offering a new target for the development of antivirals. Here, we develop a high-throughput assay to screen for small molecule inhibitors targeting the SARS-CoV-2 NiRAN domain. We identified NCI-2, a compound with a reactive chloromethyl group that covalently binds to an active site cysteine (Cys53) in the NiRAN domain, inhibiting its activity. NCI-2 can enter cells, bind to, and inactivate ectopically expressed nsp12. A cryo-EM reconstruction of the SARS-CoV-2 replication-transcription complex (RTC) bound to NCI-2 offers a detailed structural blueprint for rational drug design. Although NCI-2 showed limited potency against SARS-CoV-2 replication in cells, our work lays the groundwork for developing more potent and selective inhibitors targeting the NiRAN domain. This approach presents a promising therapeutic strategy for effectively combating COVID-19 and potentially mitigating future coronavirus outbreaks.
Improved Deep Learning Prediction of TCR-HLA Associations
Authors: Li Fumin , Liu Si , Sun Wei
Published: November 2024

Understanding the relationship between T cell receptors (TCRs) and human leukocyte antigens (HLAs) is essential for elucidating immune response specificity, uncovering mechanisms of autoimmunity, and advancing targeted immunotherapies. We have previously developed a deep learning method, DePTH (Deep Learning Prediction of TCR-HLA associations), to predict the association between a TCR and an HLA based on their amino acid sequences. In this work, we evaluated the performance of DePTH in two additional datasets, and investigated the influence of two potential confounding factors: TCR generation probability and the sequence length of CDR3 (Complementarity-Determining Region 3), which is a key region in the antigen-binding site of TCRs. Building on these insights, we combined training data from two datasets to train a new version of DePTH: DePTH 2.0.
Key Regulatory Elements of the TGFβ-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types
Authors: Storey Claire M. , Cheng Michael , Altai Mohamed , Park Julie E. , Tran Julie , Lueong Smiths S. , Thorek Daniel , Mao Liqun , Zedan Wahed , Yuen Constance , Ridley Alexander , Trajovic-Arsic Marija , Herrmann Ken , Subuhdi Sumit K. , Siddiqui Bilal A. , Lückerath Katharina , Siveke Jens , Damoiseaux Robert , Yang Xia , Ulmert David
Published: November 2024

Transforming growth factor-beta (TGFβ) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGFβ have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGFβ-regulated antigen expressed by mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGFβ-driven LRRC15+ CAFs increased tumor infiltration of CD8+ T cells. However, the underlying pathobiological mechanisms prompting TGFβ’s upregulation of LRRC15 expression are unclear. Using an integrated approach combining functional compound screening with single-cell RNA sequencing, we reveal key genomic features regulating TGFβ’s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes—MMP2, SPARC, TGFβR2,andWNT5B—central to TGFβ-induced LRRC15 pathobiology. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing co-treatment options.
ApoDock: Ligand-Conditioned Sidechain Packing for Flexible Molecular Docking
Authors: Luo Ding , Qu Xiaoyang , Lu Dexin , Wang Yiqiu , Dong Lina , Wang Binju
Published: November 2024

Molecular docking is a crucial technique for elucidating protein-ligand interactions. Machine learning-based docking methods offer promising advantages over traditional approaches, with significant potential for further development. However, many current machine learning-based methods face challenges in ensuring the physical plausibility of generated docking poses. Additionally, accommodating protein flexibility remains difficult for existing methods, limiting their effectiveness in real-world scenarios. Diffusion based models has already show a good solution of those problems, such as Alphafold3(AF3). Herein, we present ApoDock, a modular docking paradigm that combines machine learning-driven conditional sidechain packing based on protein backbone and ligand information with traditional sampling methods to ensure physically realistic poses. With accurate sidechain packing and physical based pose sampling, ApoDock demonstrates competitive performance across diverse applications, highlighting its potential as a valuable tool for protein-ligand binding studies and related applications.
DeepAssembly2: A Web Server for Protein Complex Structure Assembly Based on Domain-Domain Interactions
Authors: Xia Yuhao , Pu Yilin , Wang Suhui , Zhuang Jianan , Liu Dong , Hou Minghua , Zhang Guijun
Published: November 2024

Proteins often perform biological functions by forming complexes, thereby accurately predicting the structure of protein complexes is crucial to understanding and mastering their functions, as well as facilitating drug discovery. Protein monomeric structure prediction has made a breakthrough in recent years, but the accurate prediction of complex structure remains a challenge. In this work, we present DeepAssembly2, a web server for automatically assembling protein complex structure based on domain-domain interactions. First, the features are constructed according to the input complex sequence and monomeric structures, then these features are used to predict the inter-chain residue distance through a deep learning model, and finally, the complex structure is assembled under the guidance of inter-chain residue distances. Compared with the previously developed version, DeepAssembly2 is trained on a newly constructed inter-chain domain-domain interaction dataset. Meanwhile, several important features have been added, such as Interface Residue Propensity and Ultrafast Shape Recognition. In addition, we introduced the inter-chain residue distance from the AlphaFold-Multimer model to further improve the accuracy. Finally, we also integrate our recently developed model quality assessment method to select the output models. The performance of DeepAssembly2 is significantly improved compared with the previous version, providing a solution for large protein complex structure modeling through divide-and-conquer assembly strategy, and is expected to provide new insights and an effective tool for drug development, vaccine design, etc. The web server of DeepAssembly2 is freely available athttp://zhanglab-bioinf.com/DeepAssembly/.
Diverse patterns of intra-host genetic diversity in chronically infected SARS-CoV-2 patients
Authors: Rutsinsky Natalie , Ben Zvi Adi , Fabian Ido , Segev Shir T. , Jacobi Bar , Harari Sheri , Meijers Suzy , Paran Yael , Stern Adi
Published: November 2024

In rare individuals with a severely immunocompromised system, chronic infections of SARS-CoV-2 may develop, where the virus replicates in the body for months. Sequencing of some chronic infections has uncovered dramatic adaptive evolution and fixation of mutations reminiscent of lineage-defining mutations of variants of concern (VOCs). This has led to the prevailing hypothesis that VOCs emerged from chronic infections. To examine the mutation dynamics and intra-host genomic diversity of SARS-CoV-2 during chronic infections, we focused on a cohort of nine immunocompromised individuals with chronic infections and performed longitudinal sequencing of viral genomes. We show that sequencing errors may cause erroneous inference of high genetic diversity, and to overcome this we used duplicate sequencing across patients and time-points, allowing us to distinguish errors from low frequency mutations. We further find recurrent low frequency mutations that we flag as most likely sequencing errors. This stringent approach allowed us to reliably infer low frequency mutations and their dynamics across time. We inferred a synonymous divergence rate of the virus of ~2x10-6 mutations/base/day, consistent with the SARS-CoV-2 mutation rate estimated in tissue culture. The rate of non-synonymous divergence varied widely among the different patients. We highlight two patients with opposing patterns: in one patient the rate of divergence was zero, yet this patient harbored multiple presumably defective viruses at low frequencies throughout the infection. Another patient exhibited dramatic adaptive evolution, including clonal competition. Overall, our results suggest that the emergence of highly divergent variants from chronic infections is likely a very rare event and this emphasizes the need to better understand the conditions that allow such emergence events.
Leveraging Persistent Homology of Eye Movements for Neural Disorder Screening
Authors: He Dongcheng , Wang Shaoying , Ogmen Haluk
Published: November 2024

Abnormal ocular behaviors are associated with numerous neural disorders, detectable through specific eye movement patterns. Eye tracking—a non-invasive, accessible method—has thus been investigated as a tool for the automated diagnosis of these disorders. However, traditional eye movement feature extraction methods have limitations and are not universally applicable across diverse tasks. In this study, we present a novel feature extraction approach using Persistent Homology, a topological data analysis technique, to capture spatial and temporal topological features from eye movement data. Topological features retain multiple theoretical properties, making them robust for identifying abnormal eye movements and broadly applicable across tasks. By using only spatio-temporal topological features, our approach demonstrated promising performance in screening dyslexia and ADHD with a simple shallow perceptron classifier containing one or two hidden layers. These results support the informative validity of topological features as well as the efficacy of our proposed methods for extracting them.
The Lorenz’s side of Gene Set Enrichment Analysis: Similarity and divergences of the Gene Set Enrichment Analysis from the measure of wealth inequality
Authors: Pagnotta Stefano Maria
Published: November 2024

In the age of microarrays (about 20 years ago), the poor quality of expression levels prompted the development of methods for associating a set of significant genes with their biological meaning. A fundamental shift in methodology was the consideration of the entire gene profile, summarizing the differential level of genes measured in two conditions. A preliminary proposal was to mimic the two samples Kolmogorov-Smirnov test. Still, the winning idea was to introduce a system of weights in constructing the empirical distribution functions. Since 2005, the Gene Set Enrichment Analysis has emerged as the most well-known methodology from these premises.

This method is always referred to as based on a weighted Kolmogorov-Smirnov test. Sometimes, what is introduced as an innovation that improves a standard methodology leads to a well-known tool in a different science subject. While the accumulation of counts generates the empirical distribution function, the accumulation of weights, as defined in GSEA, leads to a function known as the Lorenz curve, introduced in 1905. Such a tool is a cornerstone in welfare studies to measure the concentration or equidistribution of richness in populations.

This paper reviews the essentials of the Lorenz curve and Gene Set Enrichment Analysis. It shows that the test statistic of the last is linked to the null hypothesis comparing two Lorenz curves. The new light of the enrichment procedure makes consistent analytical tools and conceptual formulation of the methodology.
Molecular patterns of evolutionary changes throughout the whole nervous system of multiple nematode species
Authors: Toker Itai Antoine , Ripoll-Sánchez Lidia , Geiger Luke T. , Saini Karan S. , Beets Isabel , Vértes Petra E. , Schafer William R. , Ben-David Eyal , Hobert Oliver
Published: November 2024

One avenue to better understand brain evolution is to map molecular patterns of evolutionary changes in neuronal cell types across entire nervous systems of distantly related species. Generating whole-animal single-cell transcriptomes of three nematode species from theCaenorhabditisgenus, we observed a remarkable stability of neuronal cell type identities over more than 45 million years of evolution. Conserved patterns of combinatorial expression of homeodomain transcription factors are among the best classifiers of homologous neuron classes. Unexpectedly, we discover an extensive divergence in neuronal signaling pathways. While identities of neurotransmitter-producing neurons (glutamate, acetylcholine, GABA and several monoamines) remain stable, ionotropic and metabotropic receptors for all these neurotransmitter systems show substantial divergence, resulting in more than half of all neuron classes changing their capacity to be receptive to specific neurotransmitters. Neuropeptidergic signaling is also remarkably divergent, both at the level of neuropeptide expression and receptor expression, yet the overall dense network topology of the wireless neuropeptidergic connectome remains stable. Novel neuronal signaling pathways are suggested by our discovery of small secreted proteins that show no obvious hallmarks of conventional neuropeptides, but show similar patterns of highly neuron-type-specific and highly evolvable expression profiles. In conclusion, by investigating the evolution of entire nervous systems at the resolution of single neuron classes, we uncover patterns that may reflect basic principles governing evolutionary novelty in neuronal circuits.
The Relationship between Latent Inhibition, Divergent Thinking, and Eyewitness Memory: A Study on Attention to Irrelevant Stimuli
Authors: Badiola-Lekue Ixone , Arriola Naiara , Rodríguez Gabriel
Published: November 2024

Latent inhibition is a retardation in learning about a stimulus due to its prior exposure without explicit consequences. It has been suggested that individuals who tend to show less latent inhibition possess a "leaky" attentional style, finding it difficult to inhibit the processing of irrelevant information, which would manifest as an ability to generate uncommon and creative ideas. In the present study, we tested this hypothesis within a new framework—the field of eyewitness memory—by investigating whether the degree of attenuated latent inhibition is associated with the inclusion of more peripheral (seemingly irrelevant) information in testimonies about a witnessed event. In an experiment involving 116 university students, the LI Group was pre-exposed without masking to a target auditory stimulus without consequences, while the CTRL Group did not receive this pre-exposure. Subsequently, both groups engaged in a learning phase where they had to learn the association between the target stimulus and a novel outcome. A latent inhibition effect was observed, with participants in the LI Group showing retardation in learning this association compared to the CTRL Group.

Additionally, all participants completed the Alternative Uses Task to assess divergent thinking and provided eyewitness testimonies based on the viewing of a video of a criminal event. We confirmed the known relationship between attenuated latent inhibition and creativity, finding that the lesser the latent inhibition exhibited, the higher the performance on the Alternative Uses Task. Moreover, we found that a lower degree of latent inhibition was associated with a higher number of peripheral details included in the testimonies. These results are discussed in terms of the leaky attention hypothesis, and an alternative explanation based on cognitive flexibility. According to this, individuals exhibiting attenuated latent inhibition may have an intact capacity to ignore irrelevant stimuli but would be highly efficient at rapidly redirecting their attention when changes occur.
Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function
Authors: Rawnsley David R. , Islam Moydul , Zhao Chen , Kargar Gaz Kooh Yasaman , Mendoza Adelita , Navid Honora , Kumari Minu , Guan Xumin , Murphy John T. , Nigro Jess , Kovacs Attila , Mani Kartik , Huebsch Nathaniel , Ma Xiucui , Diwan Abhinav
Published: November 2024

Background

Protein quality control (PQC) is critical for maintaining sarcomere structure and function in cardiac myocytes, and mutations in PQC pathway proteins, such as CRYAB (arginine to glycine at position 120, R120G) and BAG3 (proline to lysine at position 209, P209L) induce protein aggregate pathology with cardiomyopathy in humans. Novel observations in yeast and mammalian cells demonstrate mitochondrial uptake of cytosolic protein aggregates. We hypothesized that mitochondrial uptake of cytosolic protein aggregates and their removal by mitophagy, a lysosomal degradative pathway essential for myocardial homeostasis, facilitates cytosolic protein quality control in cardiac myocytes.

Methods

Mice with inducible cardiac myocyte specific ablation of TRAF2 (TRAF2icKO), which impairs mitophagy, were assessed for protein aggregates with biochemical fractionation and super-resolution imaging in comparison to floxed controls. Induced pluripotent stem cell (iPSC)-derived cardiac myocytes with R120G knock-in to theCRYABlocus were assessed for localization of the CRYAB protein. Transgenic mice expressing R120G CRYAB protein (R120G-TG) were subjected to both TRAF2 gain-of-function (with AAV9-cardiac Troponin T promoter-driven TRAF2 transduction) and TRAF2 loss-of-function (with tamoxifen-inducible ablation of oneTraf2allele) in cardiac myocytes to determine the effect of mitophagy modulation on cardiac structure, function, and protein aggregate pathology.

Results

Cardiomyocyte-specific ablation of TRAF2 results accumulation of mitochondrial and cytosolic protein aggregates and DESMIN mis-localization to protein aggregates. Isolated mitochondria take up cardiomyopathy-associated aggregate-prone cytosolic chaperone proteins, namely arginine to glycine (R120G) CRYAB mutant and proline to lysine (P209L) BAG3 mutant. R120G-CRYAB mutant protein increasingly localizes to mitochondria in human and mouse cardiomyocytes. R120G-TG mice demonstrate upregulation of TRAF2 in the mitochondrial fraction with increased mitophagy as compared with wild type. Adult-onset inducible haplo-insufficiency of TRAF2 resulted in accelerated mortality, impaired left ventricular systolic function and increased protein aggregates in R120G-TG mice as compared with controls. Conversely, AAV9-mediated TRAF2 transduction in R120G-TG mice reduced mortality and attenuated left ventricular systolic dysfunction, with reduced protein aggregates and restoration of normal localization of DESMIN, a cytosolic scaffolding protein chaperoned by CRYAB, as compared with control AAV9-GFP group.

Conclusions

TRAF2-mediated mitophagy in cardiac myocytes facilitates removal of cytosolic protein aggregates and can be stimulated to ameliorate proteotoxic cardiomyopathy.