bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Reproductive Tract Microbiota on Vaginal Fibroblasts in Pelvic Organ Prolapse
Authors: Duong Vi , Bergerat Agnes , Pooladanda Venkatesh , Mitchell Caroline M.
Published: December 2024

Importance

The effect of vaginal bacteria on wound healing is an evolving area of study. Bacterial vaginosis (BV), characterized by an overgrowth of anaerobic bacteria, is linked to increased surgical site infections after pelvic surgery. While BV-associated microbes are known to impair epithelial repair, their effects on fibroblasts, which are crucial for wound healing and prolapse recurrence after pelvic organ prolapsesurgery, are unclear. Understanding these interactions can deepen knowledge of vaginal tissue remodeling.

Objective

This study aimed to compare the effects of BV-associated bacteria and commensal lactobacilli on fibroblast cell number and function, using estradiol as a positive control.

Study Design

Fibroblasts were isolated from vaginal wall biopsies of 9 participants undergoing pelvic organ prolapse surgery. Cells were co-cultured in media alone, media containing estradiol, and media with cell-free supernatants (CFS) from Lactobacillus crispatus, Lactobacillus iners, and Gardnerella vaginalis. Intact cell number was assessed using an lactate dehydrogenase assay at 0, 24, and 48 hours, and ELISA measured IL-6, type I collagen, and fibronectin levels.

Results

Fibroblasts exposed to G vaginalis CFS showed significantly reduced cell number and type I collagen production, with increased fibronectin levels. Cell-free supernatants from L crispatus and L iners did not affect fibroblast proliferation. While some donor cells showed an increase in cell number with estradiol, the change was inconsistent and not statistically significant. IL-6 levels showed a nonsignificant increase with any bacterial CFS.

Conclusions

G vaginalis significantly impairs fibroblast cell number and type I collagen production, suggesting BV-associated microbes may alter fibroblast function, emphasizing the vaginal microbiome’s role in outcomes.
Symptom Documentation Before Antibiotics for Recurrent Urinary Tract Infections
Authors: Kuzma Alexandra , Critchlow Elizabeth , Koelper Nathanael , Agrawal Surbhi , Dutcher Lauren , Arya Lily
Published: December 2024

Importance

Documentation of symptoms in the medical record before prescribing antibiotics for urinary tract infection (UTI) could promote antibiotic stewardship.

Objective

The aim of this study was to describe the number and type of symptoms documented across specialties during encounters where an antibiotic was prescribed to older women with recurrent UTI.

Study Design

We conducted a retrospective cohort study of women aged 65 years or older with a diagnosis of recurrent UTI. Patients were included if they had been prescribed an antibiotic for UTI at least twice in 6 months or 3 times in 1 year. Data on number and type of symptoms and urine culture results were extracted and compared across encounters and specialties.

Results

A total of 454 encounters from 175 patients were analyzed. The majority of encounters were in primary care (61.8%), followed by urology/urogynecology (24%), obstetrics and gynecology (9.2%), and emergency department/urgent care (4.8%). The median number of UTI-specific symptoms recorded across specialties was 1 (interquartile range, 0–2) and declined in subsequent encounters. The number of UTI-specific symptoms documented was none in 25%, 1 in 26%, and 2 or more in 49% of encounters. Of the 337 encounters with positive cultures, 19% had no documented UTI-specific symptoms and 9% had no documented symptoms of any kind.

Conclusions

Documentation of urinary symptoms during encounters where antibiotics are prescribed is sparse across specialties for older patients with recurrent UTI. The gap in care identifies an opportunity for improving antibiotic stewardship through improved documentation of urinary symptoms.
Reasons for Missed Appointments
Authors: Ghandour Rachan , Miranne Jeannine M. , Shen Julia , Murphy Rachel , Taboada Mireya , Plummer Melissa , Schatzman-Bone Steph , Minassian Vatche A.
Published: December 2024

Importance

Little is known about reasons behind missed appointments in subspecialty settings, particularly in urogynecology practices.

Objective

The aim of the study was to understand patient-perceived barriers to appointment attendance at an academic urban multisite urogynecology practice.

Study Design

This was a prospective, qualitative study of patients who missed their appointments at a urogynecology practice from April to September 2023. Patients were invited to participate in semistructured interviews. Nonrandom, purposive sampling ensured a reflective sample. The interview guide addressed attendance barriers, reasons for missed appointments, and clinic accessibility. Inductive coding was applied to interview text fragments and a codebook was developed.

Results

Of the 230 eligible patients, 110 (48%) were contacted and 26/110 (24%) consented and completed interviews. Patients identified the following 3 major barriers to appointment attendance: (1) community and environmental barriers, (2) patient-related factors, and (3) clinic-related factors. Community and environmental barriers (n = 20 [77%]) included unforeseen circumstances and transportation issues, with 52% citing transportation difficulties. Patient-related factors (n = 16 [62%]) included family obligations, personal illness, mental health concerns, confusion with appointments, or competing job responsibilities. Clinic-related factors (n = 9 [35%]) included scheduling and timing issues. Participants proposed changes to facilitate attendance, which included clinics offering transportation assistance, providing interpersonal support through support groups, and improving the internet-based portal to make patient communication easier.

Conclusions

Identifying the reasons why patients miss appointments is pivotal to providing patient-centered care. Our findings provide a deeper understanding of issues underlying missed urogynecology appointments. Future research to develop an algorithm to identify barriers to attending appointments and provide interventions such as transportation support could result in more accessible, equitable care.
Implementation and sustainability of best practice guidelines: a tale of three hospitals
Authors: Qin Peiwei , Wang Haixia , Tao Zhenhui , Zhang Wenxin , Wang Juan , Ma Peifen
Published: December 2024

Objective:

This study explores factors that affect the sustainable implementation of best practice guidelines (BPGs) and provides a basis for developing corresponding action strategies to promote project sustainability.

Methods:

Using the NHS (National Health Service) questionnaire scoring system, surveys were conducted among nurses who implemented BPGs in three hospitals in China. Data were analyzed using statistical analysis. We adhered to the STROBE guidelines for cross-sectional studies.

Results:

The average total score was 85.18/100, while the average scores of the process dimension, staff dimension, and organization dimension were 25.85, 45.88, and 13.45, respectively. The average score of the three dimensions was 83.12%, 87.56%, and 81.52%, respectively. This means that the three dimensions of the NHS SM had high scores and the implemented BPGs had a high likelihood of being sustained. The sustainable implementation of guidelines involves three factors: project characteristics, staff dimensions, and organizational environment.

Conclusion:

Important factors that influence project sustainability include the clinical value of the project, a supportive environment provided by human resources and project infrastructure, and the degree of cooperation between interprofessional teams.

Spanish abstract:

http://links.lww.com/IJEBH/A305
Molecular Positron Emission Tomography and Single-Photon Emission Computed Tomography Imaging for Understanding the Neurobiological Mechanisms of Electroconvulsive Therapy
Authors: Laroy Maarten , Van Laere Koen , Vandenbulcke Mathieu , Emsell Louise , Bouckaert Filip
Published: December 2024

Electroconvulsive therapy (ECT) effectively treats severe psychiatric disorders such as depression, mania, catatonia, and schizophrenia. Although its exact mechanism remains unclear, ECT is thought to induce neurochemical and neuroendocrine changes. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) have provided vital insights into ECT's neurobiological effects. This scoping review investigates the role of molecular imaging in understanding these effects. A systematic search across PubMed, EMBASE, Web of Science, Cochrane, and Scopus databases yielded 857 unique records, from which 45 peer-reviewed articles in English with longitudinal PET or SPECT measures in ECT patients were included. The review identifies 2 main research directions: ECT's impact on brain activity and neurotransmitters. Initial research assessed regional cerebral blood flow and regional glucose metabolism during ictal (during ECT), postictal (within 24 hours), short-term (within a week), and long-term (beyond a week) follow-up as markers of brain activity. Initial findings showed an anterior-posterior regional cerebral blood flow gradient during the ictal phase, with subsequent normalization of hypoperfusion in frontal and parietal regions, and persistent long-term effects. Later, research shifted to the monoamine hypothesis of depression, examining ECT's impact on serotonin and dopamine systems via PET imaging. Results on receptor availability post-ECT were mixed, showing both reductions and no significant changes, indicating variable effects. This scoping review further highlights the need to explore new targets, tailor methodologies for patient populations, and foster multicenter studies. Although SPECT has been valuable, advances in PET imaging now make it preferable, offering unparalleled insights into ECT's molecular and neurobiological mechanisms.
Unravelling traits with complex inheritance mode: a gene panel perspective
Authors: Szyda Joanna , Suchocki Tomasz , Gołąb Monika , Budny Bartłomiej , Mielczarek Magda , Liu Jakub , Kotlarz Krzysztof , Wrotkowska Elżbieta , Ruchała Marek , Ziemnicka Katarzyna
Published: December 2024

Although gene panels for complex phenotypes target genes contributing significantly to phenotypic variation, identifying causal mutations remains challenging. We aimed to define the process of analysing gene panel data to uncover genomic insights for traits with complex inheritance. The implemented procedure included the exploration of (i) the association between phenotypic variability and the variability of SNPs within genes, (ii) the association attributed to specific variants, (iii) causality potential by analysing the genomic context in the vicinity of the significantly associated SNPs (iii_a) either through clustering – to identify variants with genotypic patterns similar to the significant SNPs, or (iii_b) through smoothing the set of original P values to incorporate the information on the impact of the particular mutations, as expressed by the SNP-specific PhRED-CADD scores. This procedure was applied to the data from the obesity gene panel. No significant gene-level associations were found. However, the SNP-level results were promising in narrowing down the initially available set of variants to determine the true causal mutations. We introduced a procedure for analysing gene panel data to identify potentially causal mutations for phenotypes with complex inheritance patterns. The procedure allows for narrowing down the originally available set of variants offered by a gene panel, consisting of genes important for the phenotype under study, to SNPs that have a statistically and genomically validated potential to be causal in modifying protein structure.
Motivation, community, and resilience in older adults’ exercise: a three-year qualitative follow-up to the BELL trial
Authors: Meigh Neil , Davidson Alexandra , Thomson Oliver P. , Keogh Justin , Hing Wayne , Schram Ben , Mickan Sharon
Published: December 2024

This qualitative study explores the long-term impact of the BELL trial’s weekly group kettlebell training on older adults’ engagement, community building, and intrinsic motivation. Three years post-trial, participants from the ‘Wednesday Friends’ group were interviewed to understand how social bonds, shared leadership, adaptability, and health benefits contributed to their sustained participation. Applying the COM-B model and the four C’s model of thematic analysis, findings reveal that social support, resilience, and self-efficacy were central to continued engagement, underscoring key motivators for older adults’ adherence to group-based exercise. These insights offer healthcare providers data-driven strategies to foster long-term engagement in community exercise programs for older adults.
Visual and vestibular processing of vertical motion: a psychophysical study
Authors: Delle Monache Sergio , La Scaleia Barbara , Agrò Anna Finazzi , Lacquaniti Francesco , Zago Myrka
Published: December 2024

The motion of objects and ourselves along the vertical is affected by gravitational acceleration. However, the visual system is poorly sensitive to accelerations, and the vestibular otoliths do not disassociate gravitational and inertial accelerations of ego-motion. Here, we tested the hypothesis that the brain resolves visual and vestibular ambiguities about vertical motion with internal models of gravity, which predict that downward motions are accelerated and upward motions are decelerated by gravity. In visual sessions, a target moved up or down while participants remained stationary. In vestibular sessions, participants were moved up or down, while they fixated an imaginary target moving along. In visual-vestibular sessions, participants were moved up or down while the visual target remained fixed. We found that downward motions of either the visual target or the participant were systematically perceived as lasting less than upward motions of the same duration, and vice-versa for the opposite direction of motion, consistent with the prior assumption that downward motion is accelerated and upward motion is decelerated by gravity. In visual-vestibular sessions, there was no significant difference in the average estimates of duration of downward and upward motion of the participant. However, there was large inter-subject variability of these estimates.
CRISPR-Cas9 RALA knockout and reconstitution. Detection and role of RALA S194 phosphorylation in RAS-dependent and RAS-independent cancers
Authors: Konde Mayuresh , Inchanalkar Siddhi , Deshpande Nilesh , Sherkhane Tushar , Virmani Mishika , Singh Kajal , Balasubramanian Nagaraj
Published: December 2024

Downstream of oncogenic RAS, RALA is critical for cancer tumorigenesis, possibly regulated by phosphorylation of its Serine194 residue. We made CRISPR-Cas9 RALA knockout (RALA KO) in three RAS-dependent and two RAS-independent cancer cells. Detection of RALA S194 phosphorylation using the commercial anti-phospho-RALA antibody lacks specificity in all three RAS-dependent cancers. siRNA knockdown of RALA and AURKA inhibition by MLN8237 (VMLN) also did not affect pS194RALA detection in these cancers. RALA KO MiaPaCa2 (RAS-dependent) and MCF7 (RAS-independent) cells, stably reconstituted with WT-RALA and S194A-RALA mutants, showed no effect on RALA activation. Tumour growth was, however, restored partly by WT-RALA, but not S194A-RALA mutant. Thus, RALA S194 phosphorylation is needed for tumor formation, not affecting its activation but possibly through its localization.
A fully 3D-printed optical microscope for low-cost histological imaging
Authors: Christopher Jay , Craig Rebecca , McHugh Rebecca E. , Roe Andrew J. , Bauer Ralf , Patton Brian , McConnell Gail , Rooney Liam M.
Published: December 2024

We present the manufacture and characterisation of a fully 3D printed, low-cost optical microscope using both a 3D printed chassis and 3D printed illumination and imaging optics. The required commercial components, consisting of a basic camera for image acquisition and light emitting diode controlled by a Raspberry Pi for illumination, are integrated into the 3D printed microscope with the full design shown for ease of replication. Our 3D printed microscope uses a single 3D printed objective lens with a 2.9x magnification and a numerical aperture of 0.07. To benchmark the imaging performance of the system, we used standard test targets and histological specimens, namely, a Giemsa-stained blood smear sample and a thin section of mouse kidney stained with Haemotoxylin and Eosin. We demonstrated that sub-cellular resolution was obtained, and we corroborated this by imaging individual red blood cells and intricate anatomical details of the stained mouse kidney section. All of this was achieved using entirely 3D printed hardware and optics, at a fraction of the cost of a commercial brightfield microscope, while presenting remarkable potential for customisation and increased accessibility for diagnostic imaging applications.
De novodesign and structure of a peptide-centric TCR mimic binding module
Authors: Householder Karsten D. , Xiang Xinyu , Jude Kevin M. , Deng Arthur , Obenaus Matthias , Wilson Steven C. , Chen Xiaojing , Wang Nan , Garcia K. Christopher
Published: December 2024

T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-MHC in cancer immunotherapy. Here, we designed ade novoα-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by HLA-A*02, achieving high on-target specificity with nanomolar affinity (Kd= 9.5 nM). The structure of the TCRm/pMHC complex at Å resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informedin silicoscreen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained a wide therapeutic window as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.
Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic
Authors: Hong Feng , Wang Jingyi , Chen Dongsheng , Wang Qian , Gan Shiyi , Ye Fang , Chen Lihua , Ren Huixia , Zhang Tongran , Xie Yinfang , Jing Xiaoyuan , Wang Ruoxi , Xu Zhibin , Ren Jiayan , Shi Cuihan , Jia Shuhui , Huang Xiaoting , Xu Xiawei , Lu Jing , Zheng Yunhua , Lin Wanhua , Dai Ji , Wang Liping , Chen Liangyi , Tang Chao , Liu Huisheng , Xu Tao , Xie Xin , Liu Xin-an , Du Yang , Nan Fajun , Chen Zuxin
Published: December 2024

Yohimbine, a potent alpha2A-adrenergic receptor (α2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of α2AAR. Importantly, CDS479-2 shows similar α2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets.

Graphic abstract
Imaging the dancing brain: Decoding sensory, motor and social processes during dyadic dance
Authors: Bigand Félix , Bianco Roberta , Abalde Sara F. , Nguyen Trinh , Novembre Giacomo
Published: December 2024

Real-world social cognition requires processing and adapting to multiple dynamic information streams. Interpreting neural activity in such ecological conditions remains a key challenge for neuroscience. This study leverages advancements in de-noising techniques and multivariate modeling to extract interpretable EEG signals from pairs of participants engaged in spontaneous dyadic dance. Using multivariate temporal response functions (mTRFs), we investigated how music acoustics, self-generated kinematics, other-generated kinematics, and social coordination each uniquely contributed to EEG activity. Electromyogram recordings from ocular, face, and neck muscles were also modelled to control for muscle artifacts. The mTRFs effectively disentangled neural signals associated with four key processes: (I) auditory tracking of music, (II) control of self-generated movements, (III) visual monitoring of partner movements, and (IV) visual tracking of social coordination accuracy. We show that the first three neural signals are driven by event-related potentials: the P50-N100-P200 triggered by acoustic events, the central lateralized readiness potential triggered by movement initiation, and the occipital N170 triggered by movement observation. Notably, the (previously unknown) neural marker of social coordination encodes the spatiotemporal alignment between dancers, surpassing the encoding of self-or partner-related kinematics taken alone. This marker emerges when partners make visual contact, relies on visual cortical areas, and is specifically driven by movement observation rather than initiation. Using data-driven kinematic decomposition, we further show that vertical movements best drive observers’ EEG activity. These findings highlight the potential of real-world neuroimaging, combined with multivariate modelling, to uncover the mechanisms underlying complex yet natural social behaviors.

Significance statement

Real-world brain function involves integrating multiple information streams simultaneously. However, due to a shortfall of computational methods, laboratory-based neuroscience often examines neural processes in isolation. Using multivariate modelling of EEG data from pairs of participants freely dancing to music, we demonstrate that it is possible to tease apart physiologically-established neural processes associated with music perception, motor control and observation of movement produced by a dance partner. Crucially, we identify a previously unknown neural marker that encodes coordination accuracy between dancers, beyond the contributions of self-or partner-related kinematics alone. These findings highlight the potential of computational neuroscience to uncover the biological mechanisms underlying real-world social and motor behaviors, advancing our understanding of how the brain supports dynamic and interactive activities.
Aperiodic exponent of brain field potentials is dependent on the frequency range it is estimated
Authors: Boncompte Gonzalo , Medel Vicente , Irani Martin , Lachaux Jean Phillip , Ossandon Tomas
Published: December 2024

The aperiodic component of brain field potentials, like EEG, LFP and intracortical recordings, has shown to be a valuable tool in basic neuroscience and in clinical applications. Aperiodic activity is modeled as a power law of the power spectral density, with the aperiodic exponent as the key parameter. Part of the interest in this parameter lies in its proposed role as a marker of the balance between excitatory and inhibitory cortical activity. In theory, a perfect power law would imply that the same behaviour exists across all frequencies, however recent evidence has suggested that low and high frequency ranges could present different aperiodic exponents. To elucidate this, we systematically evaluated the relation between frequency range and aperiodic parameters using human resting-state intracortical recordings from 62 patients. We employed two distinct estimation methods, Specparam and IRASA. We found that aperiodic parameters were indeed dependent on frequency range. Specifically, we found that low frequency ranges displayed, on average, lower aperiodic exponents (flatter power spectral density) than high frequency ranges. This behaviour was consistent for Specparam and IRASA estimations in all frequency ranges compatible with EEG. Given that there is currently no consensus for a single frequency range to be used in either clinical or basic neuroscience, our results show that care should be taken when comparing aperiodic exponents derived from different frequency ranges. We believe our results also encourage further research into the possible roles that aperiodic exponents estimated from different frequency ranges could have in reflecting distinct aspects of cortical systems.
Homogeneously crosslinkedin situhydrogel enclosing high-density human-cancer cells promotes vascularizedin vivotumor modeling for immune cell therapy
Authors: Huang Ziqi , Tsun Yip Ming , Liang Chao , Wu Zhenzhen , Aurich Theo , Liu Lu , Sugimura Rio Ryohichi , Lee Sang Jin
Published: December 2024

Cancer models in animal studies play a central role in cancer research, particularly in investigating vascularized tumor tissues for the validation of immune cell therapies. However, xenografts relying solely on cancer cells are ineffective for optimal tumor tissue formation. Additionally, tumor modeling using hydrogels with cancer cells to promote vascularization often leaves behind residual biomaterials that inhibit integration with surrounding tissues. To address these issues, we utilized a straightforwardin vivovascularized tumor modeling method with a completely degradable, crosslinker-free carboxymethyl chitosan (CMCTS)/oxidized hyaluronic acid (OHA) hydrogel that encapsulates high-density human cancer cells forin situinjection. The CMCTS/oHA hydrogel was fully degraded within 3 weeks, enabling three-dimensional (3D) cell condensationin vitro. 2 weeks after subcutaneous injection in mice, solid tumors formed, with native host vasculature infiltrating the transplanted human cancer cells, confirming spontaneous hydrogel degradation. Following this, human macrophages were administered via tail vein injection, enhancing the accumulation of mouse immune cells in the humanized tumor twofold and showing murine macrophages adjacent to the vasculature. This study thus provides proof-of-concept for a facile and fully vascularized humanized tumor model in mice for validating immune cell therapies.

HIGHLIGHTS

The oHA was prepared using sodium periodate treatment, which facilitated the formation ofin situCMCTS/oHA hydrogels

CMCTS/oHA hydrogels completely degraded within a short period, allowing for 3D cell condensation

High-density cell-laden CMCTS/oHA hydrogels were injected subcutaneously in mice, resulting in the generation of a vascularized solid tumor

The transplanted therapeutic cell was observed to adhere to the tumor tissue through the bloodstream
Global Stability and Tipping Point Prediction of the cell fate decision making model
Authors: Xu Li , Wang Jin
Published: December 2024

This study investigates global stability and tipping point prediction in cell fate decision-making systems through non-equilibrium landscape flux theory. We demonstrate that cell fate dynamics are governed by the interplay between potential landscape and curl flux, where the landscape guides systems toward stable states while curl flux mediates transitions between them.

Our analysis reveals that non-zero curl flux generates irreversible dominant pathways between multi-stable states. We identify several quantitative measures for transition prediction, including barrier heights, kinetic switching times, entropy production rates, and average flux. We introduce novel non-equilibrium early warning indicators based on time irreversibility of cross-correlations (ΔC), average flux, and entropy production rate. These indicators exhibit significant changes near bifurcations, enabling transition prediction before state stability loss, with superior predictive capability compared to traditional critical slowing down theory.

The rotational nature of curl flux is shown to destabilize attractor states, providing a dynamical foundation for phase transitions in cell differentiation, reprogramming, and transdifferentiation processes. These findings advance our understanding of non-equilibrium dynamics in cell fate decisions and offer practical implications for stem cell research and regenerative medicine, potentially enabling more precise therapeutic strategies in stem cell applications.
Bayesian Inference of NosocomialMethicillin-resistant Staphylococcus aureusTransmission Rates in an Urban Safety-Net Hospital
Authors: Corkran Kiel , Bani-Yaghoub Majid , Sutkin Gary , Arjmand Arash , Paschal Susanna
Published: December 2024

Methicillin-resistantStaphylococcus aureus(MRSA) is a strain ofStaphylococcus aureusthat poses significant challenges in treatment and infection control within healthcare settings. Recent research suggests that the incidence of healthcare-associated MRSA (HA-MRSA) is higher among patients treated in safety-net hospitals compared to those in non-safety-net hospitals.

This study aimed to identify HA-MRSA transmission patterns across various nursing units of a safety-net hospital to improve to enhance patient outcomes and facilitate the implementation of targeted infection control measures.

A retrospective analysis was conducted using surveillance data from 2019 to 2023. A compartmental disease model was applied to estimate MRSA transmission rates and basic reproduction number (R0) for each nursing unit of an urban, multicenter safety-net hospital before and during the COVID-19 pandemic. Posterior probability distributions for transmission, isolation, and hospital discharge rates were computed using the Delayed Rejection Adaptive Metropolis (DRAM) Bayesian algorithm.

Analysis of 187,040 patient records revealed that inpatient nursing units exhibited the highest MRSA transmission rates in three out of the five years studied. Notable transmission rates were observed in certain inpatient and progressive care units (0.55 per individual per month; 0.018 per individual per day) and the surgical ICU (0.44 per individual per month; 0.015 per individual per day). In contrast, the Nursery NICU and Medical ICU had the lowest transmission rates. Although MRSA transmission rates significantly declined across all units in 2021, these rates rebounded to pre-pandemic levels in subsequent years. Notably, outbreaks emerged in units such as ICUs and progressive care units that had not experienced prior MRSA outbreaks since 2019.

While MRSA transmission significantly declined during the initial phase of the pandemic, the pathogen reestablished itself in later years. These findings highlight the need for sustained resources and adaptive infection control strategies to reduce the incidence of HA-MRSA in safety-net hospitals.
A Bi-Specific T Cell-Engaging Antibody Triggers Protective Immune Memory and Glioma Microenvironment Remodeling in Immune Competent Preclinical Models
Authors: Zannikou Markella , Duffy Joseph T. , Procissi Daniele , Najem Hinda J. , Levine Rebecca N. , Hambardzumyan Dolores , Lee-Chang Catalina , Leoni Lara , Horbinski Craig M. , Zhang Bin , Heimberger Amy B , Miska Jason M. , Balyasnikova Irina V
Published: December 2024

Background

Bispecific T cell-engagers (BTEs) are engineered antibodies that redirect T cells to target antigen-expressing tumors. BTEs targeting tumor-specific antigens such as interleukin 13 receptor alpha 2 (IL13Rα2) and EGFRvIII have been developed for glioblastoma (GBM). However, there is limited mechanistic understanding of the action of BTE since prior studies were mostly conducted in immunocompromised animal models. To close this gap, the function of BTEs was assessed in the immunosuppressive glioma microenvironment (TME) of orthotopic and genetically engineered mouse models (GEMM) with intact immune systems.

Methods

A BTE that bridges CD3 epsilon on murine T cells to IL13Rα2-positive GBM cells was developed and the therapeutic mechanism investigated in immunocompetent mouse models of GBM. Multi-color flow cytometry, single-cell RNA sequencing (scRNA-Seq), multiplex immunofluorescence, and multiparametric magnetic resonance imaging (MRI) across multiple pre-clinical models of GBM were used to evaluate the mechanism and action and response.

Results

BTE-mediated interactions between murine T cells and GBM cells triggered T cell activation and antigen-dependent killing of GBM cells. BTE treatment significantly extended the survival of mice bearing IL13Rα2-expressing orthotopic glioma andde novoforming GBM in the GEMM. Quantified parametric MR imaging validated the survival data showing a reduction in glioma volume and decreased glioma viability. Flow cytometric and scRNA-seq analyses of the TME revealed robust increases in activated and memory T cells and decreases in immunosuppressive myeloid cells in the brains of mice following BTE treatment.

Conclusions

Our data demonstrate that the survival benefits of BTEs in preclinical models of glioma are due to the ability to engage the host immune system in direct killing, induction of immunological memory, and modulation of the TME. These findings provide a deeper insight into the mechanism of BTE actions in GBM.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC

Bi-specific T cell engaging antibodies (BTEs) targeting IL13Rα2 and EGFRvIII have been developed and shown to activate T cells that mediate killing of glioma cellsin vitroand in in vivo.

WHAT THIS STUDY ADDS

By using immune competent preclinical models, this study reveals that BTEs trigger in situ tumor immune memory within the central nervous system.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Insights into the mechanism of action of BTEs inform response biomarkers that should be considered for inclusion in window-of-opportunity clinical trial assessments and for the rational selection of future combinatorial strategies.
Mechanism of catalytic apparatus of human chitotriosidase-1 and its dual inactivation mode by thefirst-in-classOATD-01 inhibitor
Authors: Niedzialek Dorota , Wieczorek Grzegorz , Drzewicka Katarzyna , Antosiewicz Anna , Milewski Mariusz , Bartoszewicz Agnieszka , Olczak Jacek , Zasłona Zbigniew
Published: December 2024

Despite extensive research over the past three decades, there are still uncertainties regarding the catalytic mechanism of human chitotriosidase-1. To fill the gap, we reanalysed the structural information available for this enzyme. Based on the existing and new experimental data, complemented by multi-scale simulations, we modelled the full-length structure of human chitotriosidase-1 and proposed the general model of its catalytic mechanism. We have elucidated the catalytic role of the four highly conserved structural motifs present in glycoside hydrolases 18 family and demonstrated the impact of ions on achieving optimal catalytic conditions. Furthermore, we have identified distinct mechanical motions within the catalytic domain that collectively facilitate the catalysis. Finally, we demonstrate how subtle dynamical changes observed within the active site upon binding of the OATD-01 inhibitor correspond to long-range effects that are transmitted across enzyme subunits, leading to profound biological consequences.
Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha crystalline beta
Authors: Ganta Krishna Kumar , McManus Margaret , Blanc Ross , Wang Qixin , Jung Wonyeong , Brody Robin , Carrington Mary , Paris Robert , Chandramouli Sumana , McNamara Ryan , Luzuriaga Katherine
Published: December 2024

Epstein-Barr Virus (EBV) infects over 95% of the world’s population and is the most common cause of infectious mononucleosis (IM). Epidemiologic studies have linked EBV with certain cancers or autoimmune conditions, including multiple sclerosis (MS). Recent studies suggest that molecular mimicry between EBV proteins, particularly EBV nuclear antigen 1 (EBNA-1), and self-proteins is a plausible mechanism through which EBV infection may contribute to the development of autoimmune disorders. We used a systems immunology approach to investigate the magnitude, specificity, and functional properties of EBNA-1 specific antibodies in a cohort of 97 young adults with IM from presentation through 1-year post-primary infection compared to a control cohort of EBV-seropositive individuals. Levels of EBNA-1 specific IgG1 and IgG3 binding antibodies increased over the course of infection. EBNA-1 antibodies capable of mediating antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD) were detected at or after 6 months. Binding and ADCP- and ADCD-leveraged antibodies primarily targeted a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides in individuals with MS. Significantly higher binding and ADCD-active antibodies targeting EBNA-1 were observed in individuals with at least one HLA-DRB1*15:01 allele, a known genetic risk factor for MS; Importantly, high levels of antibodies capable of binding alpha crystalline beta (CRYAB) and mediating complement deposition were detected at 6 months and 1-year following IM; CRYAB antibodies were resistant to denaturing forces, indicating an affinity matured response. Blocking experiments confirmed that CRYAB antibodies were cross-reactive with EBNA-1. Altogether, these results demonstrate that high levels of functional antibodies targeting EBNA-1 are generated in early EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine how these antibody responses may contribute to the subsequent development of MS.
Continuous Titration Based Method For Rapid In-solution Analysis Of Non-covalent Interactions
Authors: Willmer Philipp , Hundahl Adam C. , Marie Rodolphe , Jensen Henrik
Published: December 2024

Development of new drugs typically involves the identification and validation of molecular inhibitors or promotors of endogenous biological processes. The identification of ligands that can bind the target of interest is typically achieved by screening large libraries of small molecules, using analytical methods that only provide yes/no answers. These methods are only qualitative and often associated with unacceptable amounts of false positives and negatives. Quantitative methods are in general more accurate but time intensive. This is mainly due to repeating measurements of a dilution series in order to generate a titration curve and measure the dissociation constant (Kd). In this work, we introduce Continuous Titration Based Spectral Related Intensity Change (cSPRING), that combines Taylor dispersion analysis (TDA) with ratiometric fluorescence detection to measure aKdin a single experiment. cSPRING is an in-solution method that reduces the sample preparation time 8-fold and requires only nanograms of protein. We show a good agreement of cSPRING with other quantitative methods for three well-known protein-small molecule interactions with binding affinities ranging from the low nanomolar to high micromolar. In addition, we show that cSPRING is able to measure binding affinities in under a minute, highlighting its efficiency and potential for screening applications.
A Leadfield-Free Optimization Framework for Transcranially Applied Electric Currents
Authors: Weise Konstantin , Madsen Kristoffer H. , Worbs Torge , Knösche Thomas R. , Korshøj Anders , Thielscher Axel
Published: December 2024

Background

Transcranial Electrical Stimulation (TES), Temporal Interference Stimulation (TIS), Electroconvulsive Therapy (ECT) and Tumor Treating Fields (TTFields) are based on the application of electric current patterns to the brain.

Objective

The optimal electrode positions, shapes and alignments for generating a desired current pattern in the brain vary between persons due to anatomical variability. The aim is to develop a flexible and efficient computational approach to determine individually optimal montages based on electric field simulations.

Methods

We propose a leadfield-free optimization framework that allows the electrodes to be placed freely on the head surface. It is designed for the optimization of montages with a low to moderate number of spatially extended electrodes or electrode arrays. Spatial overlaps are systematically prevented during optimization, enabling arbitrary electrode shapes and configurations. The approach supports maximizing the field intensity in target region-of-interests (ROI) and optimizing for a desired focality-intensity tradeoff.

Results

We demonstrate montage optimization for standard two-electrode TES, focal center-surround TES, TIS, ECT and TTFields. Comparisons against reference simulations are used to validate the performance of the algorithm. The system requirements are kept moderate, allowing the optimization to run on regular notebooks and promoting its use in basic and clinical research.

Conclusion(s)

The new framework complements existing optimization methods that require small electrodes, a predetermined discretization of the electrode positions on the scalp and work best for multi-channel systems. It strongly extends the possibilities to optimize electrode montages towards application-specific aims and supports researchers in discovering innovative stimulation schemes. The framework is available in SimNIBS.
The genetic architecture of cortical similarity networks
Authors: Sebenius Isaac , Warrier Varun , Bethlehem Richard A.I. , Dear Richard , Stauffer Eva-Maria , Gu Yuanjun , Romero-Garcia Rafael , Seidlitz Jakob , Bullmore Edward , Morgan Sarah
Published: December 2024

The genetic architecture of human brain networks is central to understanding the organization and evolution of the cortex, the causal relationships between brain structure and function, and the pathogenesis of heritable neuropsychiatric disorders. However, the current understanding of the genetics of brain networks remains fragmented. Here, we investigated common genetic effects on Morphometric INverse Divergence (MIND), a biologically-validated, heritable, and multimodal MRI metric of inter-areal similarity and connectivity. Using a discovery dataset (N>30,000 adults), we estimated subject-specific MIND networks from the multivariate distributions of four MRI features at each of 23 cortical areas and performed genome-wide association studies (GWAS) at each of the 276 inter-areal edges. These edge-level genetic effects were highly replicated by parallel GWAS of an independent validation dataset (N>18,000 adults). We found that strong genetic correlations between multiple edges were largely reducible to two gradients of genetically-determined cortical similarity, each of which was aligned with geodesic distance from one of the two phylogenetically primitive areas (paleocortex and archicortex) predicted by the dual origin theory of cortical evolution. Genetic MIND gradients were more heritable than comparable gradients derived from GWAS of functional MRI connectivity networks; and the paleocortical trend was genetically correlated with, and causally predictive of, functional connectivity. Finally, we identified multiple global and local genetic correlations between both MIND gradients and nine clinical diagnoses or biomedical traits, indicating that the normative genetic architecture of human brain networks is pleiotropically associated with inherited risk of neuropsychiatric disorders and systemic metabolic and immune traits. These results provide fresh insight into the dual origins of the human cortex and their implications for brain function and health.
Exploring Meiosis in Brown Algae: Meiotic Axis Proteins in the model brown algaEctocarpus
Authors: Kane Emma I. , Trefs Lioba S. , Eckert Lena , Coelho Susana M. , Weir John R.
Published: December 2024

Most extant eukaryotic systems share core meiosis-specific genes, suggesting meiosis evolved only once in the last eukaryotic common ancestor (LECA). These genes have been characterized as master regulators of meiotic recombination, ensuring genetically diverse lineages. However, our understanding is limited as eukaryotic organisms beyond the animal, plant, and yeast lineages remain poorly understood. Recently, core meiotic genes have been identified in the genome of the model brown algaEctocarpus, but currently lack proper characterization. Here, we combine bioinformatic, structural, and biochemical approaches to characterise the axial element orthologs, meioticEctocarpusHORMA domain protein (ecHOP1) and its interactor, reductional division protein 1 (ecRED1), in order to elucidate the molecular mechanisms of synaptonemal complex (SC) and double strand break (DSB) formation in brown algae. We highlight novel domain architecture within ecHOP1 and ecRED1 that support HORMA domain conformational switches and quantify the thermodynamic parameters of these interactions. Together, our data suggests that brown algae may employ alternative HORMA domain regulation mechanisms compared with animal, plant and yeast systems, and provide clues for future studies on the evolutionary constraints and adaptation of meiosis across the tree of life.
Cortical connectivity, local dynamics and stability correlates of global conscious states
Authors: Zhao Yun , Tsuchiya Naotsugu , Boley Mario , Liu Yueyang , Karoly Philippa J. , Pelentritou Andria , Woods William , Liley David , Kuhlmann Levin
Published: December 2024

Consciousness emerges from complex neural processes, yet its precise neurobiological correlates remain uncertain. Here a space-time-resolved inference-based framework is applied to estimate the neurophysiological variables of a wholecortex model and analyze the neural mechanism correlates of global consciousness by way of a correlation analysis between behavioural and neural variable time-series. Using magnetoencephalography (MEG) data from 15 participants under Xenon-induced anesthesia, interconnected neural mass models (NMMs) were developed and time-evolving regional neurophysiological variables and inter-regional connectivity strengths were inferred from the data. Analyses revealed significant correlations between consciousness levels and inter-regional connectivity, particularly in posterior parietal, occipital, and prefrontal regions. Moreover, results support a parietal, rather than frontal, network backbone to facilitate global consciousness. Regional-level analyses further identified correlates of consciousness within the posterior parietal and occipital regions. Lastly, reductions in consciousness were linked to stabilized cortical dynamics, reflected by changes in the eigenmodes of the system. This framework provides a novel, inference-based approach to investigating consciousness, offering a time-resolved perspective on neural mechanism correlates during altered states.