bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Clinical Diagnosis and Treatment Modes for Congenital Branchial Cleft Anomalies
Authors: Cai Jian-sheng , Wang Yi-e , Wu Yu-qi , Chen Jing-han , Wang Jia-rong
Published: September 2024

Objective:

The objective of this study was to investigate and assess the clinical data of 123 patients diagnosed with congenital branchial cleft anomalies (CBCAs), to summarize pivotal aspects concerning their clinical diagnosis and treatment process.

Materials and Methods:

The authors conducted a retrospective analysis of 123 patients who underwent surgical intervention for CBCAs at our institution between August 2005 and September 2021. The clinical demographic characteristics of the patients, primary symptoms, treatment chronology, preoperative diagnostic assessments, surgical strategies, occurrences of postoperative complications, and rates of recurrence were subjected to statistical analysis.

Results:

Among the enrolled patients, there were 43 cases (34.9%) of congenital first branchial cleft anomalies (CFBCA), 76 cases (61.8%) of congenital second branchial cleft anomalies (CSBCA), and 4 cases (3.3%) of congenital third branchial cleft anomalies (CTBCA), with no cases of congenital fourth branchial anomalies (CFBA). Notably, among all cases, 43 anomalies were situated in the upper one-third of the sternocleidomastoid muscle, while 80 anomalies were located in the lower one-third. Different surgical approaches were selected for patients based on the specific type of anomaly presented. Following surgery, there was recurrence in 14 cases, with factors such as patient age, clinical categorization, lesion type, and history of preoperative infection and surgical intervention identified as primary risk factors for it.

Conclusion:

CBCAs represent comparatively uncommon disorders affecting the head and cervical regions in clinical practice. Diagnostic modes such as ultrasonography and lipiodol contrast radiography can be used for accurate diagnosis, with surgical intervention serving as the primary therapeutic method.
Outcomes of Older Primary Kidney Transplant Recipients by Induction Agent and High-risk Viral Discordance Status in the United States
Authors: Ryan Randi J. , Bentall Andrew J. , Issa Naim , Dean Patrick G. , Smith Byron H. , Stegall Mark D. , Riad Samy M.
Published: September 2024

Background.

The impact of induction type or high-risk viral discordance on older kidney transplant recipients is unclear. Herein, we analyzed the association between induction type, viral discordance, and outcomes for older recipients.

Methods.

We analyzed the Scientific Registry of Transplant Recipients standard analysis file for all primary kidney transplant recipients older than 55 y who were transplanted between 2005 and 2022. All transplants were crossmatch negative and ABO-compatible. Recipients were discharged on tacrolimus and mycophenolate ± steroids. Recipients were categorized into 3 groups by induction received: rabbit antithymocyte globulin (r-ATG; N = 51 079), interleukin-2 receptor antagonist (IL-2RA; N = 22 752), and alemtuzumab (N = 13 465). Kaplan-Meier curves were generated for recipient and graft survival, and follow-up was censored at 10 y. Mixed-effect Cox proportional hazard models examined the association between induction type, high-risk viral discordance, and outcomes of interest. Models were adjusted for pertinent recipient and donor characteristics.

Results.

Induction type did not predict recipient survival in the multivariable model, whereas Epstein-Barr virus high-risk discordance predicted 14% higher mortality (1.14 [1.07-1.21], P < 0.01). In the multivariable model for death-censored graft survival, alemtuzumab, but not IL-2RA, was associated with an increased risk of graft loss (1.18 [1.06-1.29], P < 0.01) compared with r-ATG. High-risk cytomegalovirus discordance predicted 10% lower death-censored graft survival (1.10 [1.01-1.19], P < 0.02). Live donor and preemptive transplantation were favorable predictors of survival.

Conclusions.

In this large cohort of older transplant recipients, alemtuzumab, but not IL-2RA, induction was associated with an increased risk of graft loss compared with r-ATG. Cytomegalovirus and Epstein-Barr virus high-risk viral discordance portended poor graft and recipient survival, respectively.
Clinical Translation and Implementation of a Bioartificial Pancreas Therapy: A Qualitative Study Exploring the Perspectives of People With Type 1 Diabetes
Authors: de Jongh Dide , Lapré Silke , Özcan Behiye , Zietse Robert , Bunnik Eline M. , Massey Emma K. ,   the VANGUARD consortium
Published: September 2024

Background.

The development of a hybrid beta-cell replacement approach, referred to as a personalized, transplantable bioartificial pancreas (BAP), holds promise to treat type 1 diabetes (T1D). This interview study aimed to explore patients’ expectations, needs, concerns, and considerations when considering to undergo a BAP transplantation.

Research Design and Methods.

Semistructured interviews were conducted with 24 participants diagnosed with T1D. Data collection stopped once data saturation was reached. Audio recordings of the interviews were transcribed verbatim. The interviews were independently analyzed by 2 researchers. A qualitative content analysis using an inductive approach was used.

Results.

Three main themes emerged as follow: (1) hoped-for benefits, (2) concerns and decision-making considerations, and (3) procedural aspects. First, the participants expected benefits across medical, psychological, and social domains. Over these 3 domains, 9 subthemes were identified, including improved clinical outcomes, a cure for diabetes, more headspace, emotional relief, a shift in responsibility, protection of privacy, improved flexibility in daily life, less visible diseases, and improved relationships with others. Second, concerns and considerations about undergoing a BAP transplant comprised adverse events, the functionality of the BAP, the surgery procedure, the biological materials used, the transplant location, and the intrusiveness associated with follow-up care. Finally, procedural considerations included equitable access, patient prioritization, and trust and control.

Conclusions.

Incorporating insights from this study into the clinical development and implementation of the BAP is crucial to ensure alignment of the product and procedures with the needs and expectations of people with T1D.
Assortative mating across nine psychiatric disorders is consistent and persistent over cultures and generations
Authors: Fan Chun Chieh , Dehkordi Saeid Rasekhi , Border Richard , Shao Lucy , Xu Bohan , Loughnan Robert , Thompson Wesley K. , Hsu Le-Yin , Lin Mei-Chen , Cheng Chi-Fung , Lai Rou-Yi , Su Mei-Hsin , Kao Wei-Yi , Werge Thomas , Wu Chi-Shin , Schork Andrew J. , Zaitlen Noah , Demur Alfonso Buil , Wang Shi-Heng
Published: September 2024

Emerging evidence has shown that assortative mating (AM) is a key factor that shapes the landscape of complex human traits. It can increase the overall prevalence of disorders, influence occurrences of comorbidities, and bias estimation of genetic architectures. However, there is lack of large-scale studies to examine the cultural differences and the generational trends of AM for psychiatric disorders. Here, using national registry datasets, we conduct the largest scale of AM analyses on nine psychiatric disorders, with up to 1.4 million mated cases and 6 million matched controls. We performed meta-analyses on AM estimates from Taiwan, Denmark, and Sweden, to examine the potential impact of cultural differences. Generational changes for people born after 1930s were investigated as well. We found that AM of psychiatric disorders are consistent across nations and persistent over generations, with a small proportion of disorders showing generational changes of AM. Our results provide additional insight into the mechanisms of AM across psychiatric disorders and have evident implications on the estimation of the genetic architectures of psychiatric disorders.
The impact of sugar diet on humidity preference, survival, and host landing in mosquitoes
Authors: Chen Shyh-Chi , Holmes Christopher J. , Ajayi Oluwaseun M. , Goodhart Grace , Eaton Daniel , Catlett Nathan , Cady Tabitha , Tran Hannah , Lutz Luke E. , Wang Lyn , Girard Ella , Savino Jaida , Bidiwala Amena , Benoit Joshua B.
Published: September 2024

Mosquito-borne diseases have caused more than one million deaths each year. There is an urgent need to develop an effective way to reduce mosquito-host interaction to mitigate disease transmission. Sugar diets have long been linked to abnormal physiology in animals, making them potential candidates for mosquito control. Here, we show the impact of sugar diets on humidity preference and survival inAedes aegyptiandCulex pipiens. With two-choice assays between 100% and 75% relative humidity (RH), we demonstrate that the effect of sugar diets on humidity preference is species-specific whereAe. aegyptishowed significant differences and the reduced effects were noted inCx. pipiens. Among the sugar diets, arabinose significantly reduced the survival rate of mosquitoes even at low concentrations. Moreover, we found that host landing was not impacted by feeding on different sugar types. Our study suggests that specific sugar treatments could be applied to mosquito control by dampening their humidity preference and reducing their lifespan, thus reducing mosquito-borne disease transmission.
SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis
Authors: Iyer Rema , Deshpande Anagha , Pedgaonkar Aditi , Bala Pramod Akula , Kim Taehee , Brien Gerard L. , Finlay Darren , Vuori Kristiina , Soragni Alice , Murad Rabi , Deshpande Aniruddha J.
Published: September 2024

Synovial Sarcoma (SySa) is an aggressive soft tissue sarcoma that accounts for 5 – 10% of all soft tissue sarcomas. Current treatment involves radiation and radical surgery including limb amputation, highlighting the urgent need to develop targeted therapies. We reasoned that transcriptional rewiring by the fusion protein SS18-SSX, the sole oncogenic driver in SySa, creates specific vulnerabilities that can be exploited for treatment. To uncover genes that are selectively essential for SySa, we mined The Cancer Dependency Map (DepMap) data to identify genes that specifically impact the fitness of SySa compared to other tumor cell lines. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) was one of the strongest dependencies bothin vitroas well asin vivo. TAK-981, a clinical-stage small molecule SUMO2 inhibitor potently inhibited growth and colony-forming ability. Strikingly, transcriptomic studies showed that pharmacological SUMO2 inhibition with TAK-981 treatment elicited a profound reversal of a gene expression program orchestrated by SS18-SSX fusions. Of note, genetic or pharmacological SUMO2 inhibition reduced global and chromatin levels of the SS18-SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark that plays an important role in SySa pathogenesis. Taken together, our studies identify SUMO2 as a novel, selective vulnerability in SySa. Since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for other cancers, our findings present a novel avenue for targeted treatment of synovial sarcoma.

SIGNIFICANCE

Our study identifies SUMO2 as a selective dependency in synovial sarcoma. We demonstrate that the SUMO2/3 inhibitor TAK-981 impairs sarcomagenesis and reverses the SS18-SSX fusion-driven oncotranscriptome. Our study indicates that SUMO2 inhibition may be an attractive therapeutic option in synovial sarcoma.
Assembly and dynamics of the outer membrane exopolysaccharide transporter PelBC ofPseudomonas aeruginosa
Authors: Benedens Marius , Hernandez Cristian Rosales , Straathof Sabine A.P. , Loschwitz Jennifer , Berninghausen Otto , Maglia Giovanni , Beckmann Roland , Kedrov Alexej
Published: September 2024

The infamous opportunistic pathogenPseudomonas aeruginosaenhances its virulence and antibiotic resistance upon formation of durable biofilms. The biofilm stability is mediated by its matrix built of secreted exopolysaccharides, eDNA, and structural proteins. Exopolysaccharides ofP. aeruginosa– Pel, Psl and alginate – have the highest biomedical relevance, but the mechanisms behind their synthesis and secretion are poorly understood. Here, we employ cryogenic electron microscopy to resolve the 2.5 Å structure of the outer membrane complex PelBC for Pel exopolysaccharide, which is uniquely composed of the membrane-embedded β-barrel PelB and the asymmetrical ring of 12 lipoproteins PelC at the periplasmic interface. The assembly captured in the lipid-based nanodisc is stabilized by electrostatic contacts of PelC with the periplasmic loops of PelB and multiple interactions with PelB N-terminal helical domains. Within the membrane, the resolved acyl chains of the PelC lipoproteins are alternated by the tryptophan residues immersed into the lipid leaflet, thus offering a stable anchoring architecture. The highly anionic interior of the PelB β-barrel is sealed by three loops at the extracellular side, where the short Plug-S loop is aligned with the periplasmic helical scaffold, being the potential gating element for the Pel exopolysaccharide tunneling. Molecular dynamic simulations of PelB in native-like membrane environments suggest that Plug-S is sufficiently flexible to open a tunnel, and so serve as a gate. The gating model is further supported by single-channel conductivity measurements, which identify two conductance states of PelB. Via mutational analysis we confirm that Plug-S mediates opening of a narrow tunnel, as required for the controlled exopolysaccharide transport. Our structural and functional analysis of the pathogenicity-relevant complex offer a detailed and comprehensive view on this unique machinery and suggest the route taken by the exopolysaccharide at the final secretion step.
Leveraging neural networks to correct FoldX free energy estimates
Authors: Barnes Jonathan E. , América Chi L. , Marty Ytreberg F. , Patel Jagdish Suresh
Published: September 2024

Proteins play a pivotal role in many biological processes, and changes in their amino acid sequences can lead to dysfunction and disease. These changes can affect protein folding or interaction with other biomolecules, such as preventing antibodies from inhibiting a viral infection or causing proteins to misfold. The ability to predict the effects of mutations in proteins is crucial. Although experimental techniques can accurately quantify the effect of mutations on protein folding free energies and protein-protein binding free energies, they are often time-consuming and costly. By contrast, computational techniques offer fast and cost-effective alternatives for estimating free energies, but they typically suffer from lower accuracy. Enhancing the accuracy of computational predictions is therefore of high importance, with the potential to greatly impact fields ranging from drug design to understanding disease mechanisms. One such widely used computational method, FoldX, is capable of rapidly predicting the relative folding stability (ΔΔGfold) for a protein as well as the relative binding affinity (ΔΔGbind) between proteins using a single protein structure as input. However, it can suffer from low accuracy, especially for antibody-antigen systems. In this work, we trained a neural network on FoldX output to enhance its prediction accuracy. We first performed FoldX calculations on the largest datasets available for mutations that affect binding (SKEMPIv2) and folding (ProTherm4) with experimentally measured ΔΔG. Features were then extracted from the FoldX output files including its prediction for ΔΔG. We then developed and optimized a neural network framework to predict the difference between FoldX’s estimated ΔΔG and the experimental data, creating a model capable of producing a correction factor. Our approach showed significant improvements in Pearson correlation performance. For single mutations affecting folding, the correlation improved from a baseline of 0.3 to 0.66. In terms of binding, performance increased from 0.37 to 0.61 for single mutations and from 0.52 to 0.81 for double mutations. For epistasis, the correlation for binding affinity (both singles and doubles) improved from 0.19 to 0.59. Our results also indicated that models trained on double mutations enhanced accuracy when predicting higher-order mutations (such as triple or quadruple mutations), whereas models trained on singles did not. This suggests that interaction energy and epistasis effects present in the FoldX output are not fully utilized by FoldX itself. Once trained, these models add minimal computational time but provide a substantial increase in performance, especially for higher-order mutations and epistasis. This makes them a valuable addition to any free energy prediction pipeline using FoldX. Furthermore, we believe this technique can be further optimized and tested for predicting antibody escape, aiding in the efficient development of watch lists.
Impact of Antiretroviral Therapy on Anemia, Hepatotoxicity, and Immune Reconstitution Inflammatory Syndrome in HIV-Tuberculosis Co-Infected Patients
Authors: Gupta Priyanka , Tripathi Anil Kumar , Gupta Shikha , Gupta Abhishek
Published: September 2024

Introduction

HIV continues to pose a significant global health challenge, causing gradual immune system decline and, if left untreated, progressing to AIDS. Although antiretroviral therapy (ART) has transformed the treatment landscape for HIV, it is frequently associated with adverse effects, including anemia, hepatotoxicity, and immune-related issues such as Immune Reconstitution Inflammatory Syndrome (IRIS), particularly in patients co-infected with tuberculosis (TB).

Materials and methods

In this prospective cohort study, 400 ART-naive, HIV-positive patients undergoing anti-tuberculosis therapy (ATT) at King George’s Medical University, Lucknow, India, were enrolled. The study evaluated the occurrence of opportunistic infections (OIs), ART regimen effectiveness, and key laboratory markers, including CD4 counts and hemoglobin levels.

Results

TB emerged as the most common OI, affecting 20.25% of the participants, with anemia present in 85% of the cohort. The prevalence of IRIS was notably higher in patients with a positive tuberculin skin test (20.6%) compared to those with a negative test (7.4%). Patients with IRIS exhibited significantly lower CD4 counts and hemoglobin levels compared to those without IRIS.

Conclusion

This study underscores the importance of integrated management approaches for HIV patients co-infected with TB, focusing on the complex interaction between immune status, ART effectiveness, and comorbidities like anemia and hepatotoxicity. Properly addressing these factors is crucial for improving patient outcomes in this high-risk population.
Sex disparities in outcome of medication-assisted therapy of opioid use disorder: Nationally representative study
Authors: Butelman Eduardo R. , Huang Yuefeng , McFarlane Alicia , Slattery Carolann , Goldstein Rita Z. , Volkow Nora D. , Alia-Klein Nelly
Published: September 2024

Question

The opioid epidemic causes massive morbidity, and males have substantially greater overdose mortality rates than females. It is unclear whether there are sex-related disparities at different stages in the trajectory of opioid use disorders, in “real world” settings.

Goal

To determine sex disparities in non-medical opioid use (NMOU) at the end of outpatient medication-assisted treatment (MAT), using nationally representative data.

Design

Observational epidemiological study of publicly funded outpatient MAT programs in the national “Treatment episode data set-discharges” (TEDS-D) for 2019.

Participants

Persons aged ≥18 in their first treatment episode, in outpatient MAT for use of heroin or other opioids (N=11,549). The binary outcome was presence/absence of NMOU.

Results

In univariate analyses, males had significantly higher odds of NMOU, compared to females (odds ratio=1.27; Chi2[df:1]=39.08; uncorrected p<0.0001; p=0.0041 after Bonferroni correction). A multivariable logistic regression detected a male>female odds ratio of 1.19 (95%CI=1.09-1.29; p<0.0001), adjusting for socio-demographic/clinical variables. Several specific conditions were revealed in which males had greater odds of NMOU compared to females (e.g., at ages 18-29 and 30-39; corrected p=0.012, or if they used opioids by inhalation; corrected p=0.0041).

Conclusions

This nationally representative study indicates that males have greater odds of NMOU in their first episode of MAT, indicating more unfavorable outcomes. The study reveals specific socio-demographic and clinical variables under which this sex disparity is most prominent.

Highlights

*It is unclear if there are sex-related disparities in outcomes for outpatient opioid medication-assisted therapy (MAT), in large-scale “real world” settings.

*In this nationally representative “real world” study, adult males had significantly greater odds of non-medical opioid use (NMOU) in the month prior to discharge from their first MAT episode compared to females, adjusting for socio-demographic and clinical variables. Males were at higher risk than females for this undesirable outcome under several conditions (e.g., in younger age categories, or if their route of NMOU was by inhalation.

*Sex disparities in MAT outcomes occur under specific conditions that can be examined and potentially addressed, with the goal of improving personalized approaches for OUD.
BRDKRM: An Explainable Framework for Disease Modifying Drug Identification
Authors: Chanda Aishik , Dey Ashmita , Chakraborty Mrittika , Maulik Utsav B. , Bandyopadhyay Sanghamitra
Published: September 2024

Drug classification into disease-modifying (DM) and symptomatic (SYM) categories is crucial for clinical decision-making and therapeutic strategy development. To address the limitations of current methods, which often lack transparency and interpretability, we propose the Boundary Restricted Dynamic Key Route Mapping (BRDKRM) framework. This novel approach leverages the contextual overlap between disease and drug nodes in a heterogeneous graph, aggregating genes from the top K shortest paths to delineate disease neighborhood boundaries. Inspired by the classic Hansel and Gretel folklore, BRDKRM metaphorically marks boundary nodes along metapaths from disease to drug, akin to Hansel‘s breadcrumbs, which are then used to classify the therapeutic effect of candidate drugs. Our method achieved 86.78% accuracy in categorizing drug-disease treatments and identified 530 genes involved in both disease modification and symptomatic relief. The efficacy of BRDKRM is demonstrated through case studies on multiple sclerosis, offering an explainable approach to drug classification that bypasses extensive clinical trials. By providing biologically sound interpretations of drug classifications, our framework enhances understanding of therapeutic interventions, paving the way for more precise and efficient healthcare solutions while offering a novel approach to mapping disease-drug interactions.
High Frequency MHz-Order Nanovibration Enables Cell Membrane Remodelling and Lipid Microdomain Manipulation
Authors: Ambattu Lizebona A. , del Rosal Rabes Blanca , Conn Charlotte E. , Yeo Leslie Y.
Published: September 2024

We elucidate the mechanism underpinning a recently discovered phenomenon in which cells, quite unexpectedly, respond to MHz-order mechanostimuli. Deformations induced along the plasma membrane under these external mechanical cues are observed to decrease the membrane tension, which, in turn, drives transient and reversible remodelling of its lipid structure. In particular, the increase and hence coalescence of ordered lipid microdomains leads to closer proximity to mechanosensitive ion channels—Piezo1, in particular—that due to crowding, results in their activation to mobilise influx of calcium (Ca2+) ions into the cell. It is such modulation of this second messenger that is responsible for the downstream signalling and cell fates that ensue. Additionally, we show that such spatiotemporal control over the membrane microdomains in cells—without necessitating biochemical factors—facilitates aggregation and association of intrinsically disordered tau proteins in neuroblastoma cells, and their transformation to pathological conditions implicated in neurodegenerative diseases, thereby paving the way for the development of therapeutic intervention strategies.
Disruption of the Social Visual Pathway in Autism Spectrum Disorder
Authors: Li Chenhao , Park Haesoo , Awasthi Jitendra , Rolison Max , Li Mingfei , Scheinost Dustin , Chawarska Katarzyna , Hampson Michelle
Published: September 2024

The social visual pathway, which diverges from the dorsal pathway at the visual motion area (MT/V5) and runs from posterior down to anterior portions of the superior temporal sulcus (STS), specializes in processing dynamic social information. This study examined resting-state functional connectivity within this pathway in children with autism spectrum disorder (ASD) and typically developing (TD) children. Using data from the ABIDE (Autism Brain Imaging Data Exchange) repository, we found significant underconnectivity between the posterior and middle STS (pSTS-mSTS) in the right hemisphere in children with ASD compared to TD children. Weaker connectivity in this region of the pathway correlated with more severe social impairment symptoms in ASD and reduced social function across both ASD and TD groups. These findings suggest a specific disruption in the right hemisphere social visual pathway in ASD, potentially contributing to social deficits observed in the disorder.
Dominant harmonic pattern as an ictal marker of the epileptogenic zone in focal neocortical epilepsy
Authors: Ye Lingqi , Hu Lingli , Ye Hongyi , Chen Yihe , Zhu Junming , Zheng Zhe , Jiang Hongjie , Yang Dongping , Chen Cong , Wang Shan , Wang Zhongjin , Ming Wenjie , Wang Yi , Xu Cenglin , Wang Jin , Ding Meiping , Wang Shuang
Published: September 2024

Objective

The ictalHarmonicpattern (Hpattern), produced by the non-linear characteristics of EEG waveforms, may hold significant potential for localizing the epileptogenic zone (EZ) in focal epilepsy. However, further validation is needed to establish theHpattern’s effectiveness as a biomarker for measuring the EZ.

Methods

We retrospectively enrolled 131 patients diagnosed with drug-resistant focal epilepsy, all of whom had complete stereo-electroencephalographic (SEEG) data. From this cohort, we selected 85 patients for outcome analysis. We analyzed the morphological and time-frequency (TF) features of theHpattern using TF plots. A third quartile (Q3) threshold was applied to classify channels expressing either dominant (ChanneldHpattern) or non-dominantHpatterns (Channelnon-dHpattern). We then examined associations between the morphological features of theHpattern and patients’ clinical characteristics, as well as the correlations between the extent of channel removal and seizure outcomes.

Results

We found no significant correlations between the morphological features of the ictalHpattern and clinical factors, including lesional MRI findings, epileptic onset patterns, epilepsy type, pathology, or surgical outcomes. The non-localizableHpattern appeared exclusively in patients with non-focal onset patterns. Notably, the proportion ofChanneldHpatternwas higher in the seizure-onset zone (SOZ) compared to the early propagation zone. The seizure-free group demonstrated significantly higher removal proportions ofChanneldHpattern, both within and outside the SOZ (p= 0.014;p= 0.036), with AUCs of 0.606 and 0.660, respectively, in a seizure freedom prediction model. Survival analysis confirmed that complete removal of these regions correlated with long-term seizure freedom (p= 0.008;p= 0.028). Further subgroup analysis showed a significant correlation in neocortical epilepsy (p= 0.0004;p= 0.011), but not in mesial temporal lobe epilepsy. Additionally, multivariate analysis identified the complete removal ofChanneldHpatternas the only independent predictor for seizure freedom (p= 0.022; OR 6.035, 95% CI 1.291-28.211).

Conclusions

Our study supports the notion that the dominance of the ictalHpattern, regardless of its morphology, serves as a novel biomarker for the EZ in focal epilepsy. The non-linearity in EEG waveforms provides new insights into understanding ictal spreading propagation and offers potential improvements for surgical planning in neocortical epilepsy.
Fundamental trade-offs in the robustness of biological systems with feedback regulation
Authors: Tran Nguyen Hoai Nam , Nguyen An , Rahman Tasfia Wasima , Baetica Ania-Ariadna
Published: September 2024

Natural biological systems use a complex network of feedback regulation to effectively respond to their changing environment. Even though in engineered systems we understand how accurate feedback can be depending on the electronic or mechanical parts that it is implemented with, we largely lack a similar theoretical framework to study biological feedback. Specifically, it is not fully understood or quantified how accurate or robust the implementation of biological feedback actually is. In this paper, we study the sensitivity of biological feedback to variations in biochemical parameters using five example circuits: positive autoregulation, negative autoregulation, double-positive feedback, positive-negative feedback and double-negative feedback (the toggle switch). We find that of these examples of biological feedback are subjected to fundamental trade-offs, and we propose multi-objective optimisation as a framework to study them. The impact of this work is to improve robust circuit design for synthetic biology and to improve our understanding of systems biology.
Split RNA switch: Programmable and precise control of gene expression by ensemble of pre- and post-translational regulation
Authors: Abe Itsuki , Ohno Hirohisa , Mochizuki Megumi , Hayashi Karin , Saito Hirohide
Published: September 2024

Regulating gene expression in response to biomolecules is a powerful strategy for monitoring intracellular environments and controlling cellular programs. RNA switch is a synthetic mRNA-based technology that controls gene expression at the translational level in response to cellular RNA and protein molecules, thus enabling cell type-specific gene regulation and showing promise for gene therapy, regenerative medicine, and cell therapy. However, single RNA switches often lack the specificity required for practical applications due to low ON/OFF ratios and difficulty in finding distinct and single biomolecule targets. To address these issues, we developed “split RNA switches” that integrate outputs from multiple RNA switches by exploiting protein splicing, a post-translational modification mechanism. We demonstrated that split RNA switches significantly improve the ON/OFF ratio of microRNA (miRNA)-responsive ON switch systems by canceling undesirable leaky OFF level. We achieved efficient and robust target cell purification based on endogenous miRNA profiles, which was impossible with an ON switch alone. Additionally, we constructed multi-output and multi-input RNA-based synthetic circuits using split RNA switches to enable the detection of multiple miRNAs for precise gene control with logical operations. Split RNA switches illustrate a novel application of protein splicing and demonstrate the potential of post-translational processing as a comprehensive solution for advancing translational control technologies toward widespread mRNA therapies.
Identification of a novel mycovirus belonging to the “flexivirus”-related family with icosahedral virion
Authors: Wu Chien-Fu , Okada Ryo , Neri Uri , Chang Yi-Cheng , Takashi Ogawara , Kitaura Kentaro , Komatsu Ken , Moriyama Hiromitsu
Published: September 2024

The orderTymoviralescurrently comprises five viral families with positive-sense RNA ((+)RNA) genomes that infect plants, fungi, and insects. Virion morphologies within the orderTymoviralesdiffer between families, with icosahedral virions in theTymoviridaeand filamentous virions in the other “flexi”viridaefamilies. Despite their different morphologies, these viruses are placed in the same order based on phylogenetic analyses of replicase-associated polyproteins. However, one of the families in theTymovirales, Deltaflexiviridae, is considered to be capsidless because there have been no published reports of virion isolation. Here we report that a new “flexivirus”-related (+)RNA virus, prospectively namedFusariumoxysporum icosahedralvirus1(FoIV1), is icosahedral, and that most deltaflexiviruses may have icosahedral virions. Phylogenetic analyses based on replicase-associated polyproteins indicated that FoIV1 forms a distinct group in theTymoviraleswith some viruses originally assigned to theDeltaflexiviridae. Electron microscopy, protein analysis, and protein structure predictions indicate that FoIV1 ORF4 encodes a single jelly-roll (SJR)-like coat protein (CP) that constitutes the icosahedral virions. Results of clustering analyses based on amino acid sequences and predicted CP structures suggested that most of the deltaflexiviruses have icosahedral virions composed of SJR-like CPs as in FoIV1, rather than having filamentous virions or capsidless. These results challenge the conventional understanding of viruses in the orderTymovirales, with important implications for revising its taxonomic framework and providing insights into the evolutionary relationships within this diverse and broad host range group of (+)RNA viruses.
Real-time imaging reveals a role for macrophage protrusive motility in melanoma invasion
Authors: Ramakrishnan Gayathri , Miskolci Veronika , Hunter Miranda , Giese Morgan A. , Münch Daniela , Hou Yiran , Eliceiri Kevin W , Lasarev Michael R. , White Richard M. , Huttenlocher Anna
Published: September 2024

Macrophages are primary cells of the innate immune system that mediate tumor progression. However, the motile behavior of macrophages and interactions with tumor cells are not well understood. Here, we exploit the optical transparency of larval zebrafish and perform real time imaging of macrophage-melanoma interactions. We found that macrophages are highly motile in the tumor microenvironment. Macrophages extend dynamic projections between tumor cells that precedes invasive melanoma migration. Modulating macrophage motility with a dominant inhibitory mutation in Rac2 inhibits recruitment to the tumor and impairs tumor invasion. However, a hyperactivating mutation in Rac2 does not affect macrophage recruitment but limits macrophage projections into the melanoma mass and reduces invasive melanoma cell migration. Taken together, these findings reveal a role for Rac2-mediated macrophage protrusive motility in melanoma invasion.
A human mitochondrial isoform of TRPV1 regulates intracellular Ca2+ simultaneously with mitochondrial thermolysis
Authors: Beignon Florian , Ducreux Sylvie , Tuifua Lea , Le Dantec Yannick , Lemao Morgane , Goudenege David , Chevrollier Arnaud , Khiati Salim , Tricoire-leignel Helene , Gueguen Naig , Mattei Cesar , LENAERS Guy
Published: September 2024

Mitochondria are the cornerstones of cellular and body thermogenesis, with an inner temperature possibly reaching 50 degrees. Here, we report the identification of a human Transient Receptor Potential Vanilloid 1 alternative isoform located in mitochondria. This isoform, which we have termed mitoTRPV1, acts as a thermostat to restrict the mitochondrial temperature. The mitoTRPV1 open reading frame overlaps TRPV1 exons 1 and 2 and intron 2 in a +1 frame, encoding for a predicted 150 amino-acid N-terminal mitochondrial targeting sequence (MTS) conserved amongst mammalian species, followed by the 687 amino acids of TRPV1 C-terminal. This ORF is ubiquitously expressed in most human organs, underscoring its broad relevance. The deduced MTS, conserved among mammalian species, effectively addresses this TRPV1 isoform to the mitochondrial inner membrane. Our experiments, using heterologous wild-type and mutated mitoTRPV1 expression, combined with Ca2+ imaging, mitochondrial temperature and oxygraphy measurements, disclosed that mitoTRPV1 activation induces Ca2+ efflux and mitochondrial cooling, without modification of mitochondrial respiration and ATP production. Notably, the loss of function mitoTRPV1-G684V isoform, responsible for exertional heat stroke predisposition in humans, abolished mitochondrial Ca2+ efflux and cooling. These findings reveal a new thermolysis function for TRPV1 in preventing mitochondrial overwarming while not affecting the OXPHOS efficiency. They also highlight the potential implications of mitoTRPV1 in human diseases related to temperature dysregulation.
Spatial transcriptomics reveals modulation of transcriptional networks across brain regions after auditory threat conditioning
Authors: Otten Joy , Dan Shu , Rostin Luise , Profetto Alex E. , Lardenoije Roy , Klengel Torsten
Published: September 2024

Prior research has demonstrated genome-wide transcriptional changes related to fear and anxiety across species, often focusing on individual brain regions or cell types. However, the extent of gene expression differences across brain regions and how these changes interact at the level of transcriptional connectivity remains unclear. To address this, we performed spatial transcriptomics RNAseq analyses in an auditory threat conditioning paradigm in mice. We generated a spatial transcriptomic atlas of a coronal mouse brain section covering cortical and subcortical regions, corresponding to histologically defined regions. Our finding revealed widespread transcriptional responses across all brain regions examined, particularly in the medial and lateral habenula, and the choroid plexus. Network analyses highlighted altered transcriptional connectivity between cortical and subcortical regions, emphasizing the role of steroidogenic factor 1. These results provide new insights into the transcriptional networks involved in auditory threat conditioning, enhancing our understanding of molecular and neural mechanisms underlying fear and anxiety disorders.
Anterior hypothalamic nucleus drives distinct defensive responses through cell-type-specific activity
Authors: Hong Cindy Yookyung , Din Jessica Sofia , Chang Hannah , Bang Jee Yoon , Kim Jun Chul
Published: September 2024

Innate defensive behaviors, such as freezing, fleeing, and fighting, are essential for survival, enabling animals to effectively respond to predatory threats. These behaviors involve a complex interplay of sensory processing, decision-making, and motor output. As a core component of the medial hypothalamic defense system, the anterior hypothalamic nucleus (AHN) is a key brain region implicated in orchestrating innate defensive responses. Although the AHN is predominantly GABAergic, it also contains a smaller population of excitatory neurons, reflecting a sophisticated balance between inhibitory and excitatory signaling within this region. However, despite its importance, the specific behavioral functions of these diverse neuronal populations have not been systemically examined. In this study, we utilized fiber photometry and optogenetic stimulation to investigate the roles of AHN GABAergic, glutamatergic, and CaMKIIa+ neuronal activities in mediating innate defensive behaviors. Our results indicate that AHN GABAergic neurons mediate anxiety-associated investigatory behaviors, likely facilitating risk assessment during the pre-encounter stage. Conversely, AHN glutamatergic neurons drive escape initiation and freezing responses associated with the post-encounter stage. The AHN CaMKIIa+ neurons, which exhibit significant heterogeneity, suggest a more nuanced role, potentially balancing escape and freezing responses. By elucidating the functional specialization of different AHN neuron subtypes, this study provides a foundation for future investigations into the neural circuits underlying innate defensive behaviors and its dysregulation in neuropsychiatric conditions characterized by dysregulated responses to threats, such as PTSD and panic disorder.
A diagnostic protein assay for differentiating follicular thyroid adenoma and carcinoma
Authors: Sun Yaoting , Wang He , Li Lu , Wang Jianbiao , Chen Wanyuan , Peng Li , Hu Pingping , Yu Jing , Cai Xue , Yao Nan , Zhou Yan , Wang Jiatong , Wang Yingrui , Qian Liqin , Ge Weigang , Chen Mengni , Yang Feng , Gui Zhiqiang , Sun Wei , Wang Zhihong , Ge Minghua , He Yi , Wang Guangzhi , Zhao Yongfu , Chen Huanjie , Wu Xiaohong , Du Yuxin , Wei Wenjun , Wu Fan , Luo Dingcun , Lin Xiangfeng , Zheng Haitao , Zhu Xin , Wei Bei , Shen Jiafei , Yao Jincao , Yuan Zhennan , Liu Tong , Pan Jun , Zhang Yifeng , Lv Yangfan , Guo Qiaonan , Wu Qijun , Gong Tingting , Chen Ting , Zheng Shu , Zhu Jingqiang , Liu Hanqing , Chen Chuang , Han Hong , Selvarajan Sathiyamoorthy , Xing Mingzhao , Kakudo Kennichi , Alexander Erik K. , Wu Yijun , Wang Yu , Xu Dong , Zhang Hao , Nie Xiu , Kon Oi Lian , Gopalakrishna Iyer N. , Liu Zhiyan , Zhu Yi , Guan Haixia , Guo Tiannan ,   We-TEC Investigators
Published: September 2024

Differentiating follicular thyroid adenoma (FTA) from carcinoma (FTC) remains challenging due to similar histological features separate from invasion. In this study, we aim to develop and validate DNA and protein-based classifiers for FTA/FTC differentiation. We collected 2443 samples from 1568 patients across 24 centers and applied next-generation sequencing, as well as discovery and targeted proteomics. Machine learning models were developed and compared utilizing DNA and/or protein features. The discovery protein-based model (AUC 0.899) outperformed the gene-based model (AUC 0.670). Consequently, we generated a protein-based model with targeted mass spectrometry and further validated it in three independent testing sets. The 24-protein-based model achieved high performance in the retrospective sets (AUC 0.871 and 0.853) and the prospective fine-needle aspiration biopsies (AUC 0.781). The classifier notably illustrated a 95.7% negative predictive value for ruling out malignant nodules. This study offers a promising protein-based approach for differential diagnosis of FTA and FTC.

Highlights

Genetic and proteomic profiling of follicular thyroid tumors from 1568 patients across 24 centers

AI model based on proteins (AUC 0.899) outperformed that based on gene mutations (AUC 0.670) for differentiation of FTA and FTC

Validation of the protein model in two retrospective cohorts (AUCs: 0.871, 0.853) and a prospective (AUC 0.781)

The protein model has 95.7% negative predictive value for ruling out malignant nodules
A Network Medicine Approach to Investigating ME/CFS Pathogenesis in Severely Ill Patients: A Pilot Study
Authors: Hung Li-Yuan , Wu Chan-Shuo , Chang Chia-Jung , Li Peng , Hicks Kimberly , Taurog Becky , Dibble Joshua J , Morrison Braxton , Smith Chimere L , Davis Ronald W , Xiao Wenzhong
Published: September 2024

This pilot study harnessed the power of network medicine to unravel the complex pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). By utilizing a network analysis on whole genome sequencing (WGS) data from the Severely Ill Patient Study (SIPS), we identified ME/CFS-associated proteins and delineated the corresponding network-level module, termed the SIPS disease module, together with its relevant pathways. This module demonstrated significant overlap with genes implicated in fatigue, cognitive disorders, and neurodegenerative diseases. Our pathway analysis revealed potential associations between ME/CFS and conditions such as COVID-19, Epstein-Barr virus (EBV) infection, neurodegenerative diseases, and pathways involved in cortisol synthesis and secretion, supporting the hypothesis that ME/CFS is a neuroimmune disorder. Additionally, our findings underscore a potential link between ME/CFS and estrogen signaling pathways, which may elucidate the higher prevalence of ME/CFS in females. These findings provide insights into the pathogenesis of ME/CFS from a network medicine perspective and highlight potential therapeutic targets. Further research is needed to validate these findings and explore their implications for improving diagnosis and treatment.
Analytical insights into the interplay of momentum, multiplicity, and the speed of sound in heavy-ion collisions
Authors: Soares Rocha Gabriel , Gavassino Lorenzo , Singh Mayank , Paquet Jean-François
Published: September 2024

We introduce a minimal model of ultracentral heavy-ion collisions to study the relation between the speed of sound of the produced plasma and the final particles' energy and multiplicity. We discuss how the particles' multiplicity Ntot and average energy Etot/Ntot is related to the speed of sound cs by cs2=dln(Etot/Ntot)/dlnNtot if the fluid is inviscid, its speed of sound is constant and all final particles can be measured. We show that finite rapidity cuts on the particles' multiplicity N and energy E introduce corrections between cs2 and dln(E/N)/dlnN that depend on the system's lifetime. We study analytically these deviations with the Gubser hydrodynamic solution, finding that, for ultrarelativistic bosons, they scale as the ratio of the freeze-out temperature TFO over the maximum initial temperature of the fluid T0; the nonthermodynamic aspect of these corrections is highlighted through their dependence on the system's initial conditions.

Published by the American Physical Society
2024
Exploring the mass spectrum and electromagnetic property of the
ΞccK(*)
and
ΞccK¯(*)
molecules
Authors: Sheng Li-Cheng , Huo Jin-Yu , Chen Rui , Wang Fu-Lai , Liu Xiang
Published: September 2024

Using the one-boson-exchange model, we investigate the interactions between the doubly charmed baryon Ξcc(3621) and the S wave (anti-)kaon accounting for the S−D wave mixing and coupled-channel effects. We find the coupled ΞccK/ΞccK* state with I(JP)=0(1/2−), the ΞccK* state with 0(1/2−), the ΞccK¯ state with 0(1/2−), and the ΞccK¯* states with 0(1/2−,3/2−) can be recommended as good doubly charmed molecular candidates with strangeness |S|=1. We further examine their M1 radiative decay behaviors and magnetic moments within the constituent quark model framework. This information can enhance our understanding of their inner structures, including the distribution of electric charge and the orientation of the constituent quarks’ spins.

Published by the American Physical Society
2024
Nc
-insensitivity of
QCD2A
Authors: Trittmann Uwe
Published: September 2024

The spectrum of two-dimensional adjoint QCD is surprisingly insensitive to the number of colors Nc of its gauge group. It is argued that the cancellation of finite Nc terms is rather natural and ultimately a consequence of the singularity structure of the theory. In short, there are no finite Nc terms, hence effectively there cannot be any finite Nc singular terms, since the former are necessary to guarantee well-behaved principal value integrals. We evaluate and categorize the matrix elements of the theory’s light-cone Hamiltonian to show how terms emerging from finite Nc contributions to the anticommutator cancel against contributions from the purely finite Nc term of the Hamiltonian. The cancellation is not complete; finite terms survive and modify the spectrum, as is known from numerical work. Additionally we show that several parton-number changing finite Nc matrix elements vanish independently of finiteness requirements. In particular, there is only one trace-diagonal finite Nc correction. It seems therefore that considering matrix elements rather than individual contributions can provide substantial simplifications when computing the spectrum of a theory with a large symmetry group.

Published by the American Physical Society
2024