bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Doxycycline and Other Antibiotics as Bacterial Sexually Transmitted Infection Prophylaxis in a US Sample of Primarily Gay and Bisexual Men
Authors: Traeger Michael W. , Krakower Douglas S. , Mayer Kenneth H. , Jenness Samuel M. , Marcus Julia L.
Published: August 2024

Background

Doxycycline used as postexposure prophylaxis (doxyPEP) within 72 hours of sex reduces the risk of bacterial sexually transmitted infections (STIs) in people assigned male sex at birth. Little is known about current use of antibiotics as STI prophylaxis in US populations likely to benefit from doxyPEP.

Methods

We conducted an online survey in September 2023 of US adults recruited via sexual networking apps used mainly by gay and bisexual men (GBM). Respondents were asked about the use of antibiotics around the time of sex to prevent bacterial STIs.

Results

Of 903 respondents, most (96.2%) identified as GBM; 19.0% were living with HIV and 42.5% were using HIV preexposure prophylaxis (PrEP). Half (49.1%) had heard of using antibiotics to prevent STIs, and 95.6% were interested in use. Overall, 21.0% had used antibiotic STI prophylaxis, and 15.9% had done so in the past year. Among those reporting any use, most (78.1%) had used doxycycline; some used amoxicillin (16.7%), azithromycin (14.5%), or other antibiotics (14.1%). Among those reporting use in the past year, 46.9% used it for some, 28.1% for most, and 25.0% for all sex acts with casual partners during that period. Most (78.3%) of STI prophylaxis users reported their condom use did not change during periods of STI prophylaxis use, 17.2% indicated their condom use declined, and 4.5% indicated their condom use increased. For doxyPEP specifically, 35.7% had heard of it, and 13.0% had used it in the past year, of whom 21.0% had used a dosage other than the 200-mg dose shown to be effective.

Conclusions

In this sample of primarily GBM, interest in bacterial STI prophylaxis was nearly universal. However, some of the use was not informed by current clinical guidance or evidence from research studies. Efforts are needed to increase awareness of effective dosing and monitor real-world use.
Census Tract–Level Social Vulnerability and Gonorrhea Rates in Central Ohio: Results From the STD Surveillance Network, 2020–2021
Authors: Chang Gregory C. , Ramesh Balaji , Liebhard Brittany M. , Borrasca Will E. , Loux Tory , Horan Jessica , Turner Abigail Norris
Published: August 2024

Background

Gonorrhea remains a significant burden in central Ohio, particularly in socially disadvantaged communities. This study evaluates gonorrhea case rates and changes from 2020 to 2021, focusing on geographic patterns associated with social vulnerability.

Methods

We analyzed gonorrhea case data from the Columbus STD Surveillance Network for 2020 and 2021. Cases were linked to census tracts and categorized into low (0–0.66) or high (0.67–1.0) vulnerability groups based on the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Social Vulnerability Index (SVI). We mapped gonorrhea case rates per 100,000 population, stratified by SVI group, and compared changes using Jenks natural breaks to determine cutpoints. High case rates were defined as ≥605 (2020) and ≥532 (2021). A change in case rates was defined as <154 (decrease/no change) or ≥154 (increase). Demographic factors were summarized for both years.

Results

In 2020 and 2021, nearly half of high-SVI tracts had high gonorrhea rates, compared with about 4% to 7% of low-SVI tracts. Median rates in high-SVI tracts were approximately 5 times higher than in low-SVI tracts, with rates of 546 and 598 per 100,000 in 2020 and 2021, compared with 98 and 104 per 100,000, respectively. Gonorrhea rates increased in 23 (9%) of low-SVI tracts and 37 (25%) of high-SVI tracts. Demographic characteristics remained consistent between the 2 years.

Conclusions

Gonorrhea rates increased in central Ohio between 2020 and 2021, with higher burdens in high-SVI census tracts. Understanding the dynamics of social vulnerability at the community level is crucial for targeting limited STD resources effectively.
Development and Validation of a Prognostic Model to Predict Late Seizures After Traumatic Brain Injury: A Retrospective Analysis
Authors: Ou Sijie , Sun Lanfeng , Lu Yuling , Qian Kai , Chen Suyi , Zhang Lin , Wu Yuan
Published: August 2024

Posttraumatic epilepsy (PTE) is considered to be one of the most severe and enduring outcomes that can arise from traumatic brain injury (TBI). The authors’ study aims to create and authenticate a prognostic model for forecasting the PTE occurrence after TBI. The clinical prognostic model was developed in 475 people who had a TBI history in Nanning using a multivariate logistic regression model. The score in the authors’ prognostic model participants was subjected to external validation from other cities in Guangxi and assessed its performance with the area under the receiver operating characteristic curve (area under the curve), calibration plots, and decision curve analysis. Six variables were selected to establish the nomogram for PTE, including time, Glasgow Coma Scale, location, cranial imaging (midline shift), intracranial infection, and titanium mesh cranioplasty. The area under the curve was found to be 0.860 in the training cohort and 0.735 in the validation cohort, revealing that the nomogram exhibited a satisfactory level of discriminative ability. The calibration plots exhibited a substantial degree of concordance between the prognostic predictions generated by the nomogram and the observed outcomes in both the training and validation groups. In addition, the decision curve analysis demonstrated the clinical utility of the nomogram. The cutoff value for the training cohort was determined to be 0.381, whereas for the validation cohort, it was 0.380. This suggests that patients with a probability >0.381 should be given special consideration. A prognostic nomogram was formulated and verified to aid health care clinicians in assessing the prognosis of patients with PTE.
High School Curriculum and Cognitive Function in the Eighth Decade of Life
Authors: Moorman Sara M. , Khani Saber
Published: August 2024

Introduction:

Formal educational attainment, or years of schooling, has a well-established positive effect on cognitive health across the life course. We hypothesized that the content and difficulty of the curriculum influence this relationship, such that more challenging curricula in high school lead to higher levels of socioeconomic attainment in adulthood and, in turn, to better cognitive outcomes in older adulthood.

Methods:

We estimated multilevel structural equation models (MSEMs) in data from 2,405 individuals who attended one of 1,312 US high schools in 1960 and participated in the Project Talent Aging Study in 2018.

Results:

A college preparatory curriculum and a greater number of semesters of math and science in high school were positively related to word recall and verbal fluency at an average age of 75. Effects were robust to controlling for adolescent cognitive ability, academic performance, socioeconomic background, and school characteristics.

Discussion:

We discuss the implications of these findings for educational policy.
A practitioner’s field guide to the behaviour settings method
Authors: Lucas Miranda
Published: August 2024

Since the 1950s, Roger Barker’s theory of behaviour settings has been useful for a wide number of disciplines. Few realize, however, that behaviour settings theory is also a methodology. Barker fully describes how to identify, describe and measure behaviour settings in his seminal book
Ecological psychology: concepts and methods for studying the environment of human behavior
(1968), and this method is further delineated in Phil Schoggen’s
Behavior settings: a revision and extension of Roger G. Barker’s ecological psychology
(1989). Nevertheless, beyond these two (rather expensive) books there are few other resources available to twenty-first century researchers who wish to systematically describe and measure behaviour in its ecological context using the principles of behaviour settings theory. In this article, I offer a practitioner’s field guide to implementing the behaviour settings method, which includes a contemporary illustration of defining a behaviour setting using a recent observational study of an art gallery in Lethbridge, Canada. I discuss how researchers can use Barker’s original methodology to determine what is a behaviour setting and how to define its boundaries, and I suggest best practices, offering practitioners the tools to replicate Barker’s procedures.

This article is part of the theme issue ‘People, places, things, and communities: expanding behaviour settings theory in the twenty-first century’.
Enactive behaviour settings: situating agency, normativity and transformation
Authors: Sepúlveda-Pedro Miguel A. , Mojica Laura
Published: August 2024

Behaviour settings are sociocultural places defined by three main ecological aspects: the affordances of material structures, typical patterns of skilful action and socially situated norms. These aspects explain the observed regularities of human behaviour associated with the material characteristics of places. However, the focus of ecological theories on how individual agents attune their actions to the pre-established order of behaviour settings neglects the agents' active role in sustaining or motivating transformations in this order. We therefore propose an alternative enactive approach to behaviour settings that accounts for the role of agents as active supporters and transformers of behaviour settings. Based on the enactive concepts of agency, normativity and dialectics, we argue that agents, as participants of behaviour settings, simultaneously respond to multiple normative dimensions (e.g. biological, sensorimotor and interactive). To sustain the order of behaviour settings, agents sometimes need to inhibit other normative responses of their bodies, which sometimes is detrimental to one or many aspects of their lives. Nonetheless, agents can collectively trigger the transformation of behaviour settings. This transformation can occur dialectically as tensions between two or more norms to which human bodies respond are resolved, even if new tensions arise and the process of changing behaviour setting continues.

This article is part of the theme issue ‘People, places, things and communities: expanding behaviour settings theory in the twenty-first century’.
Large Language Model Influence on Management Reasoning: A Randomized Controlled Trial
Authors: Goh Ethan , Gallo Robert , Strong Eric , Weng Yingjie , Kerman Hannah , Freed Jason , Cool Joséphine A. , Kanjee Zahir , Lane Kathleen P. , Parsons Andrew S. , Ahuja Neera , Horvitz Eric , Yang Daniel , Milstein Arnold , Olson Andrew P.J , Hom Jason , Chen Jonathan H , Rodman Adam
Published: August 2024

Importance

Large language model (LLM) artificial intelligence (AI) systems have shown promise in diagnostic reasoning, but their utility in management reasoning with no clear right answers is unknown.

Objective

To determine whether LLM assistance improves physician performance on open-ended management reasoning tasks compared to conventional resources.

Design

Prospective, randomized controlled trial conducted from 30 November 2023 to 21 April 2024.

Setting

Multi-institutional study from Stanford University, Beth Israel Deaconess Medical Center, and the University of Virginia involving physicians from across the United States.

Participants

92 practicing attending physicians and residents with training in internal medicine, family medicine, or emergency medicine.

Intervention

Five expert-developed clinical case vignettes were presented with multiple open-ended management questions and scoring rubrics created through a Delphi process. Physicians were randomized to use either GPT-4 via ChatGPT Plus in addition to conventional resources (e.g., UpToDate, Google), or conventional resources alone.

Main Outcomes and Measures

The primary outcome was difference in total score between groups on expert-developed scoring rubrics. Secondary outcomes included domain-specific scores and time spent per case.

Results

Physicians using the LLM scored higher compared to those using conventional resources (mean difference 6.5 %, 95% CI 2.7-10.2, p<0.001). Significant improvements were seen in management decisions (6.1%, 95% CI 2.5-9.7, p=0.001), diagnostic decisions (12.1%, 95% CI 3.1-21.0, p=0.009), and case-specific (6.2%, 95% CI 2.4-9.9, p=0.002) domains. GPT-4 users spent more time per case (mean difference 119.3 seconds, 95% CI 17.4-221.2, p=0.02). There was no significant difference between GPT-4-augmented physicians and GPT-4 alone (-0.9%, 95% CI -9.0 to 7.2, p=0.8).

Conclusions and Relevance

LLM assistance improved physician management reasoning compared to conventional resources, with particular gains in contextual and patient-specific decision-making. These findings indicate that LLMs can augment management decision-making in complex cases.

Trial Registration

ClinicalTrials.govIdentifier:NCT06208423;

https://classic.clinicaltrials.gov/ct2/show/NCT06208423

Key Points

Question

Does large language model (LLM) assistance improve physician performance on complex management reasoning tasks compared to conventional resources?

Findings

In this randomized controlled trial of 92 physicians, participants using GPT-4 achieved higher scores on management reasoning compared to those using conventional resources (e.g., UpToDate).

Meaning

LLM assistance enhances physician management reasoning performance in complex cases with no clear right answers.
Image retrieval based on closed-loop visual–semantic neural decoding
Authors: Fukuma Ryohei , Yanagisawa Takufumi , Sugano Hidenori , Tamura Kentaro , Oshino Satoru , Tani Naoki , Iimura Yasushi , Khoo Hui Ming , Suzuki Hiroharu , Yang Huixiang , Iwata Takamitsu , Nakajima Madoka , Nishimoto Shinji , Kamitani Yukiyasu , Kishima Haruhiko
Published: August 2024

Neural decoding via the latent space of deep neural network models can infer perceived and imagined images from neural activities, even when the image is novel for the subject and decoder. Brain-computer interfaces (BCIs) using the latent space enable a subject to retrieve intended image from a large dataset on the basis of their neural activities but have not yet been realized. Here, we used neural decoding in a closed-loop condition to retrieve images of the instructed categories from 2.3 million images on the basis of the latent vector inferred from electrocorticographic signals of visual cortices. Using a latent space of contrastive language-image pretraining (CLIP) model, two subjects retrieved images with significant accuracy exceeding 80% for two instructions. In contrast, the image retrieval failed using the latent space of another model, AlexNet. In another task to imagine an image while viewing a different image, the imagery made the inferred latent vector significantly closer to the vector of the imagined category in the CLIP latent space but significantly further away in the AlexNet latent space, although the same electrocorticographic signals from nine subjects were decoded. Humans can retrieve the intended information via a closed-loop BCI with an appropriate latent space.
A single-nucleus census of immune and non-immune cell types for the major immune organ systems of chicken
Authors: Sculley Elaina R. , Ricemeyer Edward S. , Carroll Rachel C. , Driver John , Smith Jacqueline , Kaufman Jim , Hearn Cari , Balic Adam , Chen Paula , Lamont Susan , Kramer Skyler , Drechsler Yvonne , Cheng Hans , Warren Wesley C.
Published: August 2024

In the avian host, comprehensively cataloging immune cell types, their transcriptome profiles, and varying molecular responses to pathogen challenges are necessary steps toward a better understanding of the interplay between genetics and disease resilience. We present a first nuclei atlas of immune cell types derived from the three main immune organs of layer chickens, including spleen, bursa, and thymus. In bursa we also present, an accounting of cell type activation with the bacterial toxin lipopolysaccharide (LPS). Our analysis includes 36,370 total nuclei and 16, 12, and 12 transcriptionally distinct clusters for spleen, bursa, and thymus, respectively. We discover nuclei molecular profiles that uniquely distinguish states of the transcriptome within cell type that could serve as new means to characterize avian immune subtypes. We further subcluster refined immune cell type classifications, specifically highlighting the transcriptomic diversity of B and T cell subtypes. In the bursa, inferred intercellular communication and signaling pathway enrichment analyses across immune and non-immune cell types demonstrate the unappreciated complexity of the B cell repertoire in a model mimicking systemic bacterial infection. This census of all cell types in both primary and one major secondary avian immune organ system, although preliminary, provides a first review of how nuclei transcribe numerous genes, known and unknown, a critical prerequisite for the study avian immunogenetics by cell type.
Formation of an Enduring Ensemble of Accumbens Neurons Leads to Prepotent Seeking for Cocaine Over Natural Reward Cues
Authors: Chalhoub Reda M , Testen Anze , Hopkins Jordan , Carthy Camille , Kalivas Peter W
Published: August 2024

Neuronal activity in the nucleus accumbens core (NAcore) is necessary for reward-seeking behaviors. We hypothesized that the differential encoding of natural and drug rewards in the NAcore contributes to substance use disorder. We leveraged single-cell calcium imaging of dopamine D1- and D2-receptor-expressing medium spiny neurons (MSNs) in the NAcore of mice to examine differences between sucrose and cocaine rewarded (self-administration) and unrewarded (abstinent and cue-induced) seeking. Activity was time-locked to nose-poking for reward, clustered, and compared between sucrose and cocaine. Only in cocaine-trained mice were excited D1-MSNs securely stable, capable of decoding nose-poking in all rewarded and unrewarded sessions and correlated with the intensity of nose-poking for unrewarded seeking. Furthermore, D1-MSNs formed a stable ensemble predictive of seeking behavior after extended cocaine, but not sucrose abstinence. The excited D1-MSN ensemble uniquely drives cue-induced cocaine seeking and may contribute to why drug seeking is prepotent over natural reward seeking in cocaine use disorder.
Zinc and Metformin Co-Functionalized Polyetheretherketone: A Novel Dental Implant Material Tailored for the Elderly
Authors: Liu Zhengwei , Zhao Enze , Huang Hanwei , Wu Yuxun , He Yicong , Bai Shuting , Wang Suwen , Fan Shirou , Cao Shuaishuai , Tang Bin , Wang Yansong
Published: August 2024

This study focuses on addressing the challenges of dental implants in the geriatric population by enhancing the bioactivity of polyetheretherketone (PEEK) through surface modification. PEEK, with its elastic modulus close to alveolar bone, mitigates stress shielding but faces limitations in osseointegration due to low bioactivity. We introduced zinc (Zn) and metformin (MF) onto PEEK surfaces via a dopamine-assisted physical adhesion method, creating a functionalized derivative called ZnMF@PEEK. This combination targets diminished osteogenic potential, persistent inflammation, and cell senescence, which are common issues in elderly patients. Comprehensive physicochemical characterizations confirmed the successful preparation of ZnMF@PEEK, and invitroand invivoexperiments systematically evaluated its biocompatibility and bioactivity. The results indicate that ZnMF@PEEK holds promise as a dental implant material tailored to the specific needs of the elderly, addressing multifaceted challenges in osseointegration.
CryoEM structure of an MHC-I/TAPBPR peptide bound intermediate reveals the mechanism of antigen proofreading
Authors: Sun Yi , Pumroy Ruth Anne , Mallik Leena , Chaudhuri Apala , Wang Chloe , Hwang Daniel , Danon Julia N. , Goli Kimia Dasteh , Moiseenkova-Bell Vera , Sgourakis Nikolaos G.
Published: August 2024

Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive. Here, we leverage a high-fidelity TAPBPR variant and conformationally stabilized MHC-I, to determine the solution structure of the human antigen editing complex bound to a peptide decoy by cryogenic electron microscopy (cryo-EM) at an average resolution of 3.0 Å. Antigen proofreading is mediated by transient interactions formed between the nascent peptide binding groove with the P2/P3 peptide anchors, where conserved MHC-I residues stabilize incoming peptides through backbone-focused contacts. Finally, using our high-fidelity chaperone, we demonstrate robust peptide exchange on the cell surface across multiple clinically relevant human MHC-I allomorphs. Our work has important ramifications for understanding the selection of immunogenic epitopes for T cell screening and vaccine design applications.
Assessing the effects of female protections on size structure and spawning potential in two clawed lobster fisheries subject to varying exploitation levels
Authors: Theberge Kaitlyn , Sørdalen Tonje K. , Pugh Tracy L. , Kindsvater Holly K.
Published: August 2024

Current fishery management practices in both the U.S. Gulf of Maine and Norwegian clawed lobster fisheries primarily focus on conserving mature females to maximize egg production. While abundance of adult American lobsters (Homarus americanus) in the Gulf of Maine remains high, declines appear to be on the horizon. Similarly, the European lobster (Homarus gammarus), is facing its lowest recorded population size in southern Norway. Understanding how management strategies and fishing practices impact lobster size structure and spawning potential could inform management to improve resiliency to climate-induced changes. In the Gulf of Maine fishery, egg-bearing (ovigerous) female lobsters are not only protected from harvest, but also v-notched which offers additional protection up to several years. Norway, however, protects egg-bearing females without v-notching. Comparing these fisheries allows us to test the effect of the different management practices and how they interact with key vital rates, including growth and natural mortality rates. We used deterministic size- and age-structured models and empirically estimated growth and molt functions to simulate relative changes in abundance, size structure, egg production, and sex ratios in response tothesetwo female protection strategies. Our findings suggest that in all scenarios, controlling total fishing effort to low or moderate levels - relative to theF> 1 that has been estimated for American lobster - is most important for the effectiveness of size-based restrictions on harvest of larger individuals. Both forms of female protection enhance overall egg production in both species across levels of fishing intensity, but also result in a skewed sex ratio in favor of females and a more pronounced size disparity between female and male lobsters. Moreover, our results suggest that American and European lobster populations exhibit differential responses to the management strategies, likely due to variations in estimates of natural mortality rates and growth rates. Our results highlight the sensitivity of management effectiveness to assumptions regarding the underlying biology, but also provide a clear message that current intense fishing practices have likely depleted the ability of both species to compensate for fishing mortality in the long term.
Quadrant darkfield (QDF) for label-free imaging of intracellular puncta
Authors: Moustafa Tarek E. , Belote Rachel L. , Polanco Edward R. , Judson-Torres Robert L. , Zangle Thomas A
Published: August 2024

Measuring changes in cellular structure and organelles is crucial for understanding disease progression and cellular responses to treatments. A label-free imaging method can aid in advancing biomedical research and therapeutic strategies. This study introduces a computational darkfield imaging approach named quadrant darkfield (QDF) to separate smaller cellular features from large structures, enabling label-free imaging of cell organelles and structures in living cells. Using a programmable LED array as illumination source, we vary the direction of illumination to encode additional information about the feature size within cells. This is possible due to the varying level of directional scattering produced by features based on their sizes relative to the wavelength of light used. QDF successfully resolved small cellular features without interference from larger structures. QDF signal is more consistent during cell shape changes than traditional darkfield. QDF signals correlate with flow cytometry side scatter measurements, effectively differentiating cells by organelle content. QDF imaging enhances the study of subcellular structures in living cells, offering improved quantification of organelle content compared to darkfield without labels. This method can be simultaneously performed with other techniques such as quantitative phase imaging to generate a multidimensional picture of living cells in real-time.
Trophic transfer and bioaccumulation of nanoplastics inCoryphaena hippurus(Mahi-mahi) and effect of depuration
Authors: Dey Preyojon , Bradley Terence M. , Boymelgreen Alicia
Published: August 2024

Ocean plastic pollution is a global concern, exacerbated by the distinctive physiochemical characteristics of nanoplastics (NPs), making it crucial to study the impacts on marine animals. While most studies focus on the impacts of waterborne NP exposure, trophic transfer is another key transport mechanism that may also provide insight into the potential transfer of NPs to humans through the food chain. This study investigates polystyrene NP transfer toCoryphaena hippurus(mahi-mahi) larvae, a widely consumed fish and significant marine predator, during the early life stage. Using a two-step food chain,Brachionus plicatilis(rotifers) were exposed to NPs, and subsequently fed toC. hippuruslarvae, with exposure durations ranging from 24 to 96 h. Significant NP transfer was observed via the food chain, varying with exposure duration. A depuration study over 72 h, simulating environmental intermittent NP exposure, revealed substantial NP excretion but also notable retention in the larvae. Biodistribution analysis indicated that most NPs accumulated in the gut, with a significant portion remaining post-depuration and some translocating to other body parts. Despite no significant effects on body length and eye diameter during this short study period, histopathological analysis revealed intestinal tissue damage in the larvae.

Graphical abstract
Ethanol exposure model in zebrafish causes phenotypic, behavioral and gene expression changes that mimic Fetal Alcohol Spectrum Disorders in human birth cohorts
Authors: Yilmaz Elanur , Nelson Nastasia , Tosto Giuseppe , Carter R. Colin , Kizil Caghan
Published: August 2024

Fetal Alcohol Spectrum Disorders (FASD) represent a significant global health challenge, characterized by physical and neurodevelopmental abnormalities in offspring resulting from prenatal alcohol exposure. This study aims to utilize the zebrafish to examine the phenotypic, behavioral, and molecular changes associated with embryonic ethanol exposure, providing a model for human FASD conditions. Our study exposed zebrafish embryos to 0.5% ethanol during a critical developmental window (2-24 hours post-fertilization) and documented significant craniofacial and cardiac deformities, which recapitulate what has been observed in human FASD in humans. Notably, exposed zebrafish exhibited reduced skull and eye sizes, thickened jaw size, and enlarged heart chambers. We found reduced burst swim distance following a touch stimulus, a novel behavioral assessment of potential deficits in sensory processing such as processing speed and/or stress/startle response, both of which are affected in human FASD. Whole-organism gene expression was found to be altered by ethanol for orthologs of four of five inflammation-related genes for which placental expression was previously found to be altered in response to alcohol in human placentas (SERPINE1, CRHB, BCL2L1, PSMB4, PTGS2A). We conclude that the zebrafish model effectively mimics several FASD phenotypes observed in humans, confirming gene expression changes we have previously documented in a human observational study and providing a valuable platform for exploring the underlying mechanisms of alcohol-induced embryonic alterations and for developing diagnostic markers and therapeutic targets for early intervention.
Evolution ofsex hormone-binding globulingene expression in the primate testis
Authors: Meyers Warren M. , Hammond Geoffrey L.
Published: August 2024

In lower mammals testicular sex hormone-binding globulin (SHBG), also known as androgen binding protein, is well known to be a product of the Sertoli cells. However in humans, testicular SHBG is a product of the germ cells, is expressed from an upstream promoter and contains an alternative first exon 1A. Examination of testicularSHBGtranscripts from members across primate suborders revealed that transcripts containing exon 1A are unique to Hominoids and Old World Monkeys. In contrast testicularSHBGtranscripts in gray mouse lemur contained the proximal exon 1, while no evidence forSHBGexpression could be detected in marmoset monkey testes. In general, the exonic identity of primate testicularSHBGtranscripts could be predicted based on the structure of their gene’s 5’ regulatory region and we show that they change through the primate clade. This work provides insights into how molecular evolution of higher primateSHBGgenes has resulted in distinct changes in how it is expressed in their testes.
Taking on colonial institutions: making room for an Indigenous Research Paradigm in prospective biomedical research in tertiary hospitals
Authors: O’Brien Jessica , Gutman Sarah J , Wade Vicki , Walker Toni , Taylor Andrew J , Adams Karen
Published: August 2024

Background

A paradigmatic clash exists between biomedical and Indigenous research frameworks. Problematically, when ill-fit biomedical research frameworks are applied Indigenous peoples can experience exclusion from biomedical studies and consequent potential health benefits. To overcome these issues, community based participatory research methodologies are often recommended. However, these can prove difficult to apply in tertiary healthcare research where prospective Indigenous peoples and families participating in research will come from unforeseen and numerous Indigenous communities. Adding further complexity, there appears a dearth of information for achieving incorporation of decolonising and Indigenous research frameworks into this type of prospective research.

Methods

We sought to reflect on and describe inclusion of an Indigenous Research Paradigm into the establishment of a prospective multi-site tertiary healthcare study on improving diagnosis and treatment of acute rheumatic fever. To generate reflection, the First Nations’ Yarning method was employed allowing qualitative findings to be generated via Indigenous epistemology and ontology.

Findings

Four main areas were identified as requiring significant change to align with an Indigenous Research Paradigm: stakeholder engagement, project design, consent processes, and multi-site approach. Multi-layered Indigenous leadership was recognised as a crucial component of the transformation and of the project’s success more broadly.

Interpretation

With extensive local First Nations involvement and a First Nations-led research team, a multi-site institution-based biomedical research project can be successfully adapted to be more in keeping with an Indigenous Research Paradigm.
Incidence of TB-IRIS Among HIV+ve Patients in North India: A Prospective Study
Authors: Gupta Priyanka , Tripathi Anil Kumar , Singh Kaleshwar Prasad , Gupta Abhishek
Published: August 2024

Introduction

TB-IRIS is an important cause of morbidity and mortality in patients with HIV disease who are initiated on ART. This prospective study investigates the incidence and associated risk factors of TB-IRIS among HIV+ve patients initiating ART in North India.

Methods

The study included 400 ART-naive HIV+ve patients with or without pre-existing TB. Participants underwent clinical evaluation, laboratory tests, and imaging at baseline, followed by monthly follow-ups to monitor the development of TB-IRIS over a year.

Results

The study identified a TB-IRIS incidence of 9.5% among the cohort. The mean duration for TB-IRIS onset was 2.87 months, with a higher prevalence noted in patients within the first two months of ART initiation. Key baseline factors associated with TB-IRIS included low CD4 count, Hb levels, high total leukocyte count, serum creatinine, and TC levels. Notably, the CD4 count, and inflammatory markers such as CRP and ESR significantly increased from baseline to the development of TB-IRIS. The study also highlighted a significantly higher mortality rate among TB-IRIS patients compared to those without IRIS.

Conclusion

The findings underscore the necessity for vigilant monitoring and early detection of TB-IRIS in HIV+ve patients undergoing ART in TB-endemic regions to mitigate morbidity and mortality.
Repetitive sensory stimulation potentiates and recruits sensory-evoked cortical population activity
Authors: Williams Leena Eve , Küffer Laura , Bawa Tanika , Husi Elodie , Pagès Stéphane , Holtmaat Anthony
Published: August 2024

Sensory experience and learning are thought to be associated with plasticity of neocortical circuits. Repetitive sensory stimulation can induce long-term potentiation (LTP) of cortical excitatory synapses in anesthetized mice; however, it is unclear if these phenomena are associated with sustained changes in activity during wakefulness. Here we used time-lapse, calcium imaging of layer (L) 2/3 neurons in the primary somatosensory cortex (S1), in awake male mice, to assess the effects of a bout of rhythmic whisker stimulation (RWS) at a frequency by which rodents sample objects. We found that RWS induced a 1h-increase in whisker-evoked L2/3 neuronal activity. This was not observed for whiskers functionally connected to distant cortical columns. We also found that RWS altered whether individual neurons encoded subsequent stimulus representation by either being recruited or suppressed. Vasoactive intestinal-peptide-expressing (VIP) interneurons, which promote plasticity through disinhibition of pyramidal neurons, were found to exclusively elevate activity during RWS. These findings indicate that cortical neurons’ representation of sensory input can be modulated over hours through repetitive sensory stimulation, which may be gated by activation of disinhibitory circuits.

SIGNIFICANCE STATEMENT

Sensory experience and learning are thought to be associated with the plasticity of cortical synaptic circuits. Here, we tested how repeated sensory stimulation changes subsequent sensory-evoked responses, using the mouse somatosensory cortex as a model. This cortical area processes, among others, sensory information from the whiskers. We found that rhythmic whisker stimulation potentiated excitatory neuronal activity for an hour, and identified a disinhibitory interneuron-mediated mechanism that could gate this plasticity. This work increases our understanding of sensory learning and experience-dependent plasticity processes by demonstrating that cortical representations of sensory input are dynamic and are effectively modulated by repeated sensory stimulation.
Magnetoelectric Microrobots for Spinal Cord Injury Regeneration
Authors: Ye Hao , Zang Jingjing , Zhu Jiawei , Arx Denis von , Pustovalov Vitaly , Mao Minmin , Tang Qiao , Veciana Andrea , Torlakcik Harun , Zhang Elric , Sevim Semih , Sanchis-Gual Roger , Chen Xiang-Zhong , Ahmed Daniel , Sanchez-Vives Maria V. , Puigmartí-Luis Josep , Nelson Bradley J. , Neuhauss Stephan C. F. , Pané Salvador
Published: August 2024

Regenerative medicine continually seeks effective methods to address spinal cord injuries (SCI), which are known for their limited regenerative potential. Despite advances in neural progenitor cell (NPC) transplants for spinal cord injuries, challenges related to graft survival, reliablein vivodifferentiation, and neural integration significantly hinder real functional recovery and limit clinical outcomes. This study introduces ‘NPCbots’, biohybrid microrobots engineered by integrating human-induced pluripotent stem cell-derived NPCs with magnetoelectric nanoparticles composed of cobalt ferrite-barium titanate. These enable magnetic navigation and neuronal stimulation, enhancing targeted therapeutic interventions. Our lab-on-a-chip system allows for the mass production of NPCbots, ensuring their differentiation and biocompatibility. Remarkably, in a zebrafish model of SCI, NPCbots stimulated by an alternating magnetic field demonstrated rapidin vivodifferentiation and integration into damaged neural pathways, significantly enhancing neural regeneration. Within three days, injured zebrafish treated with NPCbots exhibited almost normal swimming behavior and significantly improved exploratory behavior, showcasing the potential of NPCbots to swiftly repair neural structures and restore the central nervous system’s functionality in spinal cord injury models through non-invasive means. Additionally, precisein vitroandin vivomanipulation of NPCbots indicates their broader application in various neurodegenerative disorders, offering a promising route for effective spinal cord and neurological recovery.
SARM1 orthosteric base exchange inhibitors cause subinhibitory SARM1 activation
Authors: Leahey Rebecca , Weber Martin , Cho Chang Hoon , Hur Seong , Cramer Amber , Manzanares Karla , Babin Brett , Boenig Gladys , Kring Taylor , Liu Liling , Cui Yusi , Ganti Anjani , Evans John P. , Nespi Marika , Ly Justin , Nugent Alicia A. , Green Samantha , Chan Bryan , Hoogenraad Casper C. , Delwig Anton , Hinz Flora I.
Published: August 2024

SARM1, an octameric NADase, is a key regulator of axon degeneration and an emerging target in small molecule drug discovery to treat a wide range of neurodegenerative diseases. Recently, a structurally diverse series of adduct-forming, orthosteric SARM1 inhibitors have been discovered. Here, we show that subinhibitory concentrations of these orthosteric inhibitors, under mildly SARM1 activating conditions, cause sustained SARM1 activation. This synergistic adverse effect leads to increased nicotinamide adenine dinucleotide (NAD) consumption, neurodegeneration and release of the biomarker neurofilament-light (NfL) in cultured cortical neurons. In two distinct animal models, we found that low-dose treatment with these orthosteric SARM1 inhibitors results in increased plasma NfL and adverse events when combined with cellular stress or injury conditions. This may present a critical liability for orthosteric SARM1 inhibitors in certain patient populations.
50-year fire legacy regulates soil microbial carbon and nutrient cycling responses to new fire
Authors: Revillini Daniel , Searcy Christopher A. , Afkhami Michelle E.
Published: August 2024

Fire disturbances are becoming more common, more intense, and further-reaching across the globe, with consequences for ecosystem functioning. Importantly, fire can have strong effects on the soil microbiome, including community and functional changes after fire, but surprisingly little is known regarding the role of soil fire legacy in shaping responses to recent fire. To address this gap, we conducted a manipulative field experiment administering fire across 32 soils with varying fire legacies, including combinations of 1-7 historic fires and 1-33 years since most recent fire. We analyzed soil metatranscriptomes, determining for the first time how fire and fire legacy interactively affect metabolically-active soil taxa, the microbial regulation of important carbon (C), nitrogen (N) and phosphorus (P) cycling, expression of carbohydrate-cycling enzyme pathways, and functional gene co-expression networks. Experimental fire strongly downregulated fungal activity while upregulating many bacterial and archaeal phyla. Further, fire decreased soil capacity for microbial C and N cycling and P transport, and drastically rewired functional gene co-expression. Perhaps most importantly, we highlight a novel role of soil fire legacy in regulation of microbial C, N, and P responses to recent fire. We observed a greater number of functional genes responsive to the interactive effects of fire and fire legacy than those affected solely by recent fire, indicating that many functional genes respond to fire only under certain fire legacy contexts. Therefore, without incorporating fire legacy of soils, studies will miss important ways that fire shapes microbial roles in ecosystem functioning. Finally, we showed that fire caused significant downregulation of carbon metabolism and nutrient cycling genes in microbiomes under abnormal soil fire histories, producing a novel warning for the future: human manipulation of fire legacies, either indirectly through global change-induced fire intensification or directly through fire suppression, can negatively impact soil microbiome functional responses to new fires.
Two TAL effectors ofXanthomonas citripv.malvacearumtargetGhSWEET15as the susceptibility genes for bacterial blight of cotton
Authors: Ali Shah Syed Mashab , Haq Fazal , Huang Kunxuan , Wang Qi , Liu Linlin , Li Ying , Wang Yong , Khan Asaf , Yang Ruihuan , Khojasteh Moein , Xu Xiameng , Xu Zhengyin , Chen Gongyou
Published: August 2024

Bacterial Blight of Cotton (BBC) caused byXanthomonas citripv.malvacearum(Xcm) is an important and destructive disease affecting cotton plants. Transcription activator-like effectors (TALEs) released by the pathogen regulate cotton resistance to the susceptibility. In this study, we sequenced the whole genome ofXcmXss-V2-18 and identified eighttalgenes; seven on the plasmids and one on the chromosome. Deletion and complementation experiments of Xss-V2-18talgenes demonstrated that Tal1b is required for full virulence on cotton. Transcriptome profiling coupled with TALE-binding element prediction revealed that Tal1b targetsGhSWEET15A04/D04andGhSWEET15D02simultaneously. Expression analysis confirmed the independent inducibility ofGhSWEET15A04/D04andGhSWEET15D02by Tal1b, whereasGhSWEET15A04/D04is additionally targeted by Tal1. Moreover, GUS (β-glucuronidase) andXa10-mediated HR (hypersensitive response) assays indicated that the EBEs are required for the direct and specific activation of the candidate targets by Tal1 and Ta1b. These findings may advance our understanding of the dynamics between TALEs and EBEs, and decipher a simple and effective DNA-binding mechanism that could lead to the development of more efficient methods for gene editing and transgenic research.
Local Mean Gradient Pattern (LMGP): A novel approach made for the classification of brain CT scan images
Authors: Singh Kavya , Koundal Anil Kumar , Kaur Navjeet
Published: August 2024

Objective

The visual descriptor methods like Local Binary Pattern (LBP) capture anatomical structures in captured images along with their disparities, which can be exploited by suitable methods for the diagnosis of medical anomalies. We developed a Local Mean Gradient Pattern (LMGP), based partly on LBP, a feature extraction algorithm for the classification of Computed Tomography (CT) images of the brain into normal, ischemic, or hemorrhage categories.

Methods

The ASID dataset comprises of 397 acute ischemic stroke CT scan images and the Kaggle dataset consists of 200 CT scan images, out of which, 100 images were of the abnormal brain type (hemorrhage), and the remaining 100 images which don’t show any abnormalities were categorized as normal cases. The results of LMGP were compared with eight other feature extraction methods using linear, sigmoid, polynomial, and RBF kernels of the SVM classifier.

Results

The effectiveness of our methodology was evaluated using recall, logarithmic loss, accuracy (ACC), confusion matrix and area under curve (ROC) metrics. The LMGP performed best when RBF-SVM was used for the classification and gave an accuracy of 93% and 95% in the case of five-fold and ten-fold cross-validation respectively. The ten-fold cross-validation gave a precision score of 0.9410, a recall score of 0.9521, an F1 score of 0.9458, and a negative log loss of -0.1645.

Conclusion

LMGP combines a unique and robust approach of CT scan image feature extraction by combining local information along with gradient change in pixels of the image. The present results of the study suggest the improved performance of the LMGP method over other methods compared in this study effectively.
Mixture-of-Experts Approach for Enhanced Drug-Target Interaction Prediction and Confidence Assessment
Authors: Lu Yijingxiu , Lee Sangseon , Kang Soosung , Kim Sun
Published: August 2024

In recent years, numerous deep learning models have been developed for drug-target interaction (DTI) prediction. These DTI models specialize in handling data with distinct distributions and features, often yielding inconsistent predictions when applied to unseen data points. This inconsistency poses a challenge for researchers aiming to utilize these models in downstream drug development tasks. Particularly in screening potential active compounds, providing a ranked list of candidates that likely interact with the target protein can guide scientists in prioritizing their experimental efforts. However, achieving this is difficult as each current DTI model can provide a different list based on its learned feature space. To address these issues, we propose EnsDTI, a Mixture-of-Experts architecture designed to enhance the performance of existing DTI models for more reliable drug-target interaction predictions. We integrate an inductive conformal predictor to provide confidence scores for each prediction, enabling EnsDTI to offer a reliable list of candidates for a specific target. Empirical evaluations on four benchmark datasets demonstrate that EnsDTI not only improves DTI prediction performance with an average accuracy improvement of 2.7% compared to the best performing baseline, but also offers a reliable ranked list of candidate drugs with the highest confidence, showcasing its potential for ranking potential active compounds in future applications.

CCS CONCEPTS

•Applied computing→Bioinformatics; •Computing methodologies→Artificial intelligence.