bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse social media experiences and adolescents’ depressive symptoms: the moderating role of neurobiological responsivity to rejected peers
Authors: Trekels Jolien , Maza Maria T , Capella Jimmy , Jorgensen Nathan A , Kwon Seh-Joo , Lindquist Kristen A , Prinstein Mitchell J , Telzer Eva H
Published: October 2024

Adolescents’ experiences with social media are complex and can impact their mental well-being differently. Our study aimed to understand how neurobiological sensitivities may moderate the association between different social media experiences and depressive symptoms. In a multiwave study, 80 adolescents (Mage = 13.06, SD = 0.58) took part in an functional magnetic resonance imaging task designed to gauge the neural responses when viewing accepted and rejected peers within their own social networks (Wave 1). We also collected self-reported measures of positive (digital social connection) and negative (digital pressure) experiences on social media and depressive symptoms (Waves 2 and 3). Our findings revealed that there were no significant associations between digital social connection, digital pressure, and depressive symptoms 1 year later. However, the association between digital social connection and depressive symptoms was moderated by neural responsivity. Specifically, for adolescents with reduced sensitivity to their rejected peers in the ventral striatum, right temporoparietal junction, and ventromedial prefrontal cortex, digital social connection was associated with reduced depressive symptoms 1 year later. These results emphasize the importance of individual differences in how adolescents’ brains respond to rejected peers in shaping the impact of online experiences on their mental well-being.
Group empathy for pain is stronger than individual empathy for pain in the auditory modality
Authors: Shao Min , Qiu Yulan , Zhang Yudie , Qian Huiling , Wei Zilong , Hong Mingyu , Liu Shuqin , Meng Jing
Published: October 2024

Humans live in collective groups and are highly sensitive to perceived emotions of a group, including the pain of a group. However, previous research on empathy for pain mainly focused on the suffering of a single individual (“individual empathy for pain”), with limited understanding of empathy for pain to a group (“group empathy for pain”). Thus, the present study aimed to investigate the cognitive neural mechanisms of group empathy for pain in the auditory modality. The study produced group painful voices to simulate the painful voices made by a group, and recruited 34 participants to explore differences between their responses to group painful voices and individual painful voices using the event-related potential (ERP) techniques. The results revealed that group painful voices were rated with higher pain intensity, more negative affective valence, and larger P2 amplitudes than individual painful voices. Furthermore, trait affective empathy scores of the participants were positively correlated with their P2 amplitudes of group painful voices. The results suggested that the group empathy for pain may facilitate affective empathetic processing in auditory modality.
Association of mechanical power and postoperative pulmonary complications among young children undergoing video-assisted thoracic surgery
Authors: Zhu Change , Zhang Rufang , Li Jia , Ren Lulu , Gu Zhiqing , Wei Rong , Zhang Mazhong
Published: October 2024

BACKGROUND

Previous studies have discussed the correlation between mechanical power (MP) and lung injury. However, evidence regarding the relationship between MP and postoperative pulmonary complications (PPCs) in children remains limited, specifically during one-lung ventilation (OLV).

OBJECTIVES

Propensity score matching was employed to generate low MP and high MP groups to verify the relationship between MP and PPCs. Multivariable logistic regression was performed to identify risk factors of PPCs in young children undergoing video-assisted thoracic surgery (VATS).

DESIGN

A retrospective study.

SETTING

Single-site tertiary children's hospital.

PATIENTS

Children aged ≤2 years who underwent VATS between January 2018 and February 2023.

INTERVENTIONS

None.

MAIN OUTCOME MEASURES

The incidence of PPCs.

RESULTS

Overall, 581 (median age, 6 months [interquartile range: 5–9.24 months]) children were enrolled. The median [interquartile range] MP during OLV were 2.17 [1.84 to 2.64) J min−1. One hundred and nine (18.76%) children developed PPCs. MP decreased modestly during the study period (2.63 to 1.99 J min−1; P < 0.0001). In the propensity score matched cohort for MP (221 matched pairs), MP (median MP 2.63 vs. 1.84 J min−1) was not associated with a reduction in PPCs (adjusted odds ratio, 1.43; 95% CI, 0.87 to 2.37; P = 0.16). In the propensity score matched cohort for dynamic components of MP (139 matched pairs), dynamic components (mean 2.848 vs. 4.162 J min−1) was not associated with a reduction in PPCs (adjusted odds ratio, 1.62; 95% CI, 0.85 to 3.10; P 
= 0.15).

The multiple logistic analysis revealed PPCs within 7 days of surgery were associated with male gender, OLV duration >90 min, less surgeon's experience and lower positive end-expiratory pressure (PEEP) value.

CONCLUSIONS

MP and dynamic components were not associated with PPCs in young children undergoing VATS, whereas PPCs were associated with male gender, OLV duration >90 min, lesser surgeon's experience and lower PEEP value.

TRIAL REGISTRATION

ChiCTR2300074649.
Spatial mapping of the HCC landscape identifies unique intratumoral perivascular-immune neighborhoods
Authors: Marsh-Wakefield Felix , Santhakumar Cositha , Ferguson Angela L. , Ashhurst Thomas M. , Shin Joo-Shik , Guan Fiona H.X. , Shields Nicholas J. , Platt Barry J. , Putri Givanna H. , Gupta Ruta , Crawford Michael , Pulitano Carlo , Sandroussi Charbel , Laurence Jerome M. , Liu Ken , McCaughan Geoffrey W. , Palendira Umaimainthan
Published: October 2024

Background:

HCC develops in the context of chronic inflammation; however, the opposing roles the immune system plays in both the development and control of tumors are not fully understood. Mapping immune cell interactions across the distinct tissue regions could provide greater insight into the role individual immune populations have within tumors.

Methods:

A 39-parameter imaging mass cytometry panel was optimized with markers targeting immune cells, stromal cells, endothelial cells, hepatocytes, and tumor cells. We mapped the immune landscape of tumor, invasive margin, and adjacent nontumor regions across 16 resected tumors comprising 144 regions of interest. X-shift clustering and manual gating were used to characterize cell subsets, and Spectre quantified the spatial environment to identify cellular neighborhoods. Ligand-receptor communication was quantified on 2 single-cell RNA-sequencing data sets and 1 spatial transcriptomic data set.

Results:

We show immune cell densities remain largely consistent across these 3 regions, except for subsets of monocyte-derived macrophages, which are enriched within the tumors. Mapping cellular interactions across these regions in an unbiased manner identifies immune neighborhoods comprised of tissue-resident T cells, dendritic cells, and various macrophage populations around perivascular spaces. Importantly, we identify multiple immune cells within these neighborhoods interacting with VEGFA+ perivascular macrophages. VEGFA was further identified as a ligand for communication between perivascular macrophages and CD34+ endothelial cells.

Conclusions:

Immune cell neighborhood interactions, but not cell densities, differ between intratumoral and adjacent nontumor regions in HCC. Unique intratumoral immune neighborhoods around the perivascular space point to an altered landscape within tumors. Enrichment of VEGFA+ perivascular macrophages within these tumors could play a key role in angiogenesis and vascular permeability.
Post-translational modifications drive the effects of HMGB1 in alcohol-associated liver disease
Authors: Ge Xiaodong , Subramaniyam Nithyananthan , Song Zhuolun , Desert Romain , Han Hui , Das Sukanta , Komakula Sai Santosh Babu , Wang Chao , Lantvit Daniel , Ge Zhiyan , Hoshida Yujin , Nieto Natalia
Published: October 2024

Background:

We previously identified that high-mobility group box-1 (HMGB1) is increased and undergoes post-translational modifications (PTMs) in response to alcohol consumption. Here, we hypothesized that specific PTMs, occurring mostly in hepatocytes and myeloid cells, could contribute to the pathogenesis of alcohol-associated liver disease (AALD).

Methods:

We used the Lieber-DeCarli (LD) model of early alcohol-induced liver injury, combined with engineered viral vectors and genetic approaches to regulate the expression of HMGB1, its PTMs (reduced [H], oxidized [O], acetylated [Ac], both [O + Ac]), and its receptors (RAGE, TLR4) in a cell-specific manner (hepatocytes and/or myeloid cells).

Results:

Hmgb1 ablation in hepatocytes or myeloid cells partially protected, while ablation in both prevented steatosis, inflammation, IL1B production, and alcohol-induced liver injury. Hepatocytes were a major source of [H], [O], and [Ac] HMGB1, whereas myeloid cells produced only [H] and [Ac] HMGB1. Neutralization of HMGB1 prevented, whereas injection of [H] HMGB1 increased AALD, which was worsened by injection of [O] HMGB1. While [O] HMGB1 induced liver injury, [Ac] HMGB1 protected and counteracted the effects of [O] HMGB1 in AALD. [O] HMGB1 stimulated macrophage (MF) migration, activation, IL1B production, and secretion. Ethanol-fed Rage
ΔMye but not Tlr4
ΔMye, Rage
ΔHep, or Tlr4
ΔHep mice were protected from AALD, indicating a crucial role of RAGE in myeloid cells for AALD. [O] HMGB1 recruited and activated myeloid cells through RAGE and contributed to steatosis, inflammation, and IL1B production in AALD.

Conclusions:

These results provide evidence for targeting [O] HMGB1 of hepatocyte origin as a ligand for RAGE signaling in myeloid cells and a driver of steatosis, inflammatory cell infiltration, and IL1B production in AALD. Importantly, we reveal that [Ac] HMGB1 offsets the noxious effects of [O] HMGB1 in AALD.
Impact of the COVID-19 Pandemic on Pediatric Bacterial Community–acquired Pneumonia: A Multicenter Retrospective Study in Madrid, Spain
Authors: Aguilera-Alonso David , Sánchez-Cañete Juan , Ventura McArdle Leyre , del Rosal Teresa , Sanz Santaeufemia Francisco José , Soto Beatriz , Saavedra-Lozano Jesús , Prieto Tato Luis , Martínez Álvarez Francisco José , Bassy Navarro Sofía , Cercenado Emilia , Marín Mercedes , Rivas Gonzalo , Cendejas Bueno Emilio , González Abad María José , Molina Arana David , Yuste José , Baquero-Artigao Fernando , Calvo Cristina
Published: October 2024

This study conducted in Madrid, Spain between 2018 and 2023 shows a significant decrease in the pediatric bacterial community–acquired pneumonia cases during the COVID-19 pandemic, followed by a notable postpandemic increase surpassing prepandemic incidence. Streptococcus pneumoniae remains predominant, with an increasing prevalence of serotype 3, while Streptococcus pyogenes was the second most common pathogen.
Individuals Who Had a Lifetime History of Suicide Attempts and Their Relationships With Inflammation, Severity of Depressive Symptoms, and Childhood Maltreatments
Authors: Bellinello Gisele de Souza Teixeira , Urbano Mariana , Vargas Heber Odebrecht , Verri Waldiceu , Rossaneis Ana Carolina , Odebrecht Vargas Nunes Sandra
Published: October 2024

Lifetime history of suicide attempts is associated with inflammatory mechanisms, severity of depressive symptoms, and childhood trauma. This cross-sectional study enrolled 54 suicide attempters and 154 nonsuicide attempters. All individuals were assessed through a questionnaire, a structured clinical interview, scales, anthropometric measures, and laboratory biomarkers. Individuals with a history of lifetime suicide attempts showed significant positive correlations regarding soluble tumor necrosis factor receptor 1 and severity of depressive symptoms (p = 0.013), interleukin-1 receptor antagonist and severity of depressive symptoms (p = 0.04), and absenteeism from work and childhood physical abuse (p = 0.012). Suicide attempters also experienced more childhood trauma (sexual abuse, physical abuse, emotional abuse, emotional neglect, and physical neglect) compared with nonsuicide attempters. IL-4 levels were significantly lower in individuals who attempted suicide than in nonsuicidal individuals. Lifetime suicide attempts in major affective disorders were associated with childhood trauma and proinflammatory and anti-inflammatory cytokines.
Alexithymia—A Neglected Factor Influencing Educational Satisfaction and Psychological Wellbeing in Medical Students
Authors: Simic Katarina , Latas Milan , Pantovic Stefanovic Maja , Nesic Milica
Published: October 2024

Alexithymia presents a reduced ability to identify, express, and describe one's own emotions. In medical professionals, alexithymia is associated with increased burnout and substance use, as well as reduced altruistic behavior. Our aim was to examine the association between alexithymia and different sociodemographic, psychological, and somatic parameters among medical students. Participants included 186 third- and sixth-year students of the Faculty of Medicine in Belgrade, Serbia. Data were collected through an online survey, composed of 1) a general questionnaire (sociodemographic data, education satisfaction, grade point average, presence of psychological and somatic disorders), 2) Twenty-Item Toronto Alexithymia Scale, 3) Patient Health Questionnaire-9, and 4) Beck Anxiety Inventory. Third-year students had significantly higher rates of alexithymia compared with sixth-year students. Negative correlation was found between alexithymia and educational satisfaction (r = −0.276**) and alexithymia and grade point average (r = −0.186*). A positive correlation was found between alexithymia and depression (r = 0.424**) and alexithymia and anxiety (r = 0.338**). The negative impact of alexithymia on educational satisfaction and psychological health is pronounced in the population of medical students, indicating a need for preventive programs aimed in medical schools.
Evaluating the Evidence Base for TikTok Videos on Strategies for Becoming Pregnant
Authors: Jahnke Hannah , Henrich Natalie , Salem Wael , Shah Neel
Published: October 2024

The top 100 TikTok videos under the hashtag “#ttc” (trying to conceive) that featured strategies to improve the chances of becoming pregnant without treatment were assessed for medical accuracy. Videos were also characterized by creators’ professional qualifications and each video’s potential for profit through marketing links. Descriptive statistics and χ2 tests were used to examine relationships among these domains. More than half (57.0%) of the videos highlighted strategies that do not have a scientific evidence base. Health care professionals were less likely to promote misinformation than non–health care professionals (P<.001), but the majority of top content was created by nonprofessionals (62.0%). Non–evidence-based information was featured in 72.2% of for-profit videos. This study demonstrates high exposure and engagement with misinformation among people who are trying to become pregnant.
Demoralization as a specifier for adjustment disorders
Authors: Kissane David
Published: October 2024

Adjustment disorder (AD) is the most common psychiatric diagnosis yet carries the most loosely defined diagnostic criteria. The phenomenology of demoralization (hopelessness, pointlessness, discouragement, and entrapment) enriches criteria for AD substantially. Moreover, demoralization mediates the suicidality that can follow from maladaptive coping. The focus of treatment seeks to restore morale, hope, and meaning as clear therapeutic targets. Use of demoralization as a “specifier” for AD introduces a subtype that will enhance understanding of and communication about a patient, while providing optimal treatment targets.
Large-cell Basaloid Adenocarcinoma of the Lung
Authors: Suster David , Mejbel Haider A. , Mackinnon Alexander Craig , Suster Saul
Published: October 2024

A distinctive form of lung adenocarcinoma that closely mimics large-cell neuroendocrine carcinoma is described. The tumors arose in 6 women and 6 men aged 46–86 years (mean=58.4). They presented as peripheral subpleural masses measuring 2–12 cm (mean=6.5 cm). Histologically they were characterized by islands or anastomosing and serpiginous strands of large, atypical cells showing striking peripheral palisading of nuclei, with high mitotic activity and prominent comedo-like areas of necrosis. Because of the striking resemblance to neuroendocrine tumors, some of the cases were initially diagnosed as large-cell neuroendocrine carcinoma despite the absence of neuroendocrine markers. Immunohistochemistry showed positivity of the tumor cells for TTF1 and napsin-A, and negative staining for p40. The tumors were also uniformly negative for multiple neuroendocrine markers, including chromogranin, synaptophysin, CD56, and INSM1. Electron microscopy performed in 2 cases was negative for membrane-bound dense core neurosecretory granules. Pathogenic alterations were detected in 5 of 8 tumors tested by next-generation sequencing. Point mutations in KRAS and TP53 were identified in 5 patients. Low-level amplification of GNAS, KIT, and FGFR1 was present in 2 patients. No RB1 mutations were identified. Clinical follow-up in 10 cases showed that 2 patients died of their tumors, 2 experienced distant metastases, and 6 were alive and well from 1 to 13 years after diagnosis (median=7.1 y). Large-cell basaloid adenocarcinoma is an unusual variant of lung cancer that is easily confused with large-cell neuroendocrine carcinoma. Awareness of this unusual variant of lung adenocarcinoma is important for treatment and prognosis and for avoiding misdiagnosis.
Highlights From the 2023 Revision of Pediatric Tactical Emergency Casualty Care Guidelines
Authors: Garrett Andrew L. , Elsherbiny Amina , Shapiro Geoffrey L.
Published: October 2024

In 2023 the Committee for Tactical Emergency Casualty Care (C-TECC) issued updated Pediatric Tactical Emergency Casualty Care (TECC) Guidelines (Guidelines) that focus on the delivery of stabilizing care of children who are the victims of high-threat incidents such as an active shooter event. The Guidelines provide evidence-based and best practice recommendations to those individuals and departments that specifically provide operational medical support to law enforcement agencies caring for children in this uniquely dangerous environment where traditional resources may not be available. This article highlights key takeaway points from the Guidelines, including several updates since the first version was released in 2013.

The evidence base for the care of children in this environment is lacking, and medical care delivered in the high-threat environment is inconsistent and often not optimized for the care of infants and children. The Guidelines are supported from the existing literature base where possible, and where it is not, by consensus as to the current best practices as determined by iterative deliberations among the diverse and experienced group of stakeholders who are members of C-TECC. The Guidelines provide patient assessment and management information specific to the care of children in the following 3 dynamic phases of the high-threat environment: Direct Threat, Indirect Threat, and Evacuation. The phases represent a continuum of risk to the patient and the responder ranging from extreme (such as ongoing gunfire) to minimal (during movement toward definitive medical care).

The high-threat environment is dynamic and there is competing safety, tactical/operational, and patient care priorities for responders when infants and children are injured. The Guidelines provide recommendations on the type of medical and psychological care that should be considered under each phase of threat and establishes the context for how and why to deliver (or potentially defer) certain interventions under some circumstances in order the maximize the opportunity for a good outcome for an injured pediatric patient. The Guidelines also emphasize the importance of synergizing hospital-based pediatric trauma care with those law enforcement and fire/emergency medical services that may provide field care to children under high-threat circumstances.
Does Early Continuous Passive Motion Improves Effectiveness of Physical Therapy After Arthroscopic Release of Elbow Contracture: A Prospective Randomized Trial
Authors: Lihua Huang M.M. , Wang Yanmao , Ma Yanhong , Ding Jian , Lu Shengdi
Published: October 2024

Objective

To investigate the effectiveness of early continuous passive motion combined with physical therapy compared to physical therapy alone as the rehabilitation protocol after the release of elbow contracture.

Design

In this randomized controlled trial, 61 patients were randomly assigned to two groups (31 in the early continuous passive motion with physical therapy group vs. 30 in the physical therapy group). The patients received rehabilitation with or without early continuous passive motion for 4 weeks and were followed up for 6 months. The outcome measures were the range of motion and Mayo Elbow Performance Score.

Results

The early continuous passive motion with physical therapy group demonstrated statistically significant improvements in range of motion and the Mayo Elbow Performance Score compared with the physical therapy group at 6 weeks, 3 months, and 6 months postoperatively. These differences were not observed in the stability subscale of the Mayo Elbow Performance Score at any of the assessed time points, nor in its pain subscale at 6 months.

Conclusion

Compared with physical therapy alone, early continuous passive motion combined with physical therapy enabled a quicker recovery of functional elbow motion and early pain control within the 6-month follow-up after arthroscopic release of elbow contracture.
Characteristics, Impact, and Trends of Healthcare Simulation in Latin America and the Caribbean
Authors: Velásquez-Rimachi Victor , Cabanillas-Lazo Miguel , Prialé-Zevallos Alvaro , Dubreuil-Wakeham Solange , Samaniego-Lara Daniela , Runzer-Colmenares Fernando M. , Mayta-Tristán Percy
Published: October 2024

Summary Statement

This study highlights the growing significance of healthcare simulation in enhancing the quality and safety of patient care across Latin America and the Caribbean, by analyzing bibliometric trends and the impact of publications on simulation-based clinical training between 2012 and 2022. Leveraging the Scopus database and VOSviewer software for thesaurus interaction analysis, the research identified 610 documents, accumulating 4681 citations, thereby indicating a burgeoning interest in this field with notable publication spikes in 2017 and 2020. Brazil and the United States emerged as leading contributors, with a primary focus on “simulation training,” “clinical competence,” “medical education,” and “education.” The study observed an uptick in international collaboration, mirroring the increase in document count and citations. This bibliometric review underscores the emphasis on evaluating technical skills and clinical practices as prevailing areas of interest, highlighting Brazil's significant academic contributions, and suggesting a promising future for the implementation of clinical simulation in the region. The study advocates for continued scholarly output to align with global advancements in medical simulation, aiming to optimize patient outcomes.
Functional study ofPhaeodactylum tricornutumSeipin homolog highlights unique features of lipid droplets biogenesis in diatoms
Authors: Moigne Damien Le , Richard Fabien , Albrieux Catherine , Mahieu Mégane , Arrighi Matteo , Si-Larbi Grégory , Jouneau Pierre-Henri , Gros Valérie , Louwagie Mathilde , Roy Sylvaine , Amari Chems , Carletti Marta , Bonnarde Rachel , Gong Yangmin , Pan Yufang , Hu Hanhua , Bastien Olivier , Jouhet Juliette , Amato Alberto , Maréchal Eric , Salvaing Juliette
Published: October 2024

Diatoms are a major phylum of microalgae, playing crucial ecological roles. They derive from secondary endosymbiosis of a red alga by an unknown heterotrophic eukaryote, leading to a complex intracellular organization. In response to unfavorable conditions (stress), diatoms store oil in lipid droplets (LD), raising interest for applications, in particular biofuels. In spite of numerous investigations aiming to increase their oil content, LD biogenesis mechanisms in these organisms remain poorly understood. In this study, we functionally characterized the homolog of Seipin, a major actor of LD biogenesis, in the diatomPhaeodactylum tricornutum.PtSeipin shares conserved structural features with other Seipins, yet presents unique characteristics, that appear common to diatoms and more broadly Stramenopiles. We provide evidence that Stramenopiles Seipins were inherited from the host during secondary endosymbiosis. The localization of PtSeipin highlights that LD biogenesis can arise simultaneously from the endoplasmic reticulum (ER) and the plastid’s most external membrane. Finally, the knock-out of PtSeipin leads to a strong increase of TAG accumulation, a feature that is not observed in other organisms and is greatly enhanced following high light exposure. Our results suggest a redirection of lipid fluxes towards TAG synthesis, reduced TAG recycling or a combination of both.
Three cytochrome P450 enzymes catalyse the formation of furanoclerodane precursors in Salvia spp
Authors: Lin Ruoxi , Li Haixiu , Xiao Yiren , Wang Zhuo , Liu Licheng , Saalbach Gerhard , Martins Carlo , Martin Cathie , Tatsis Evangelos C.
Published: October 2024

Salvia species native to the Americas are rich in valuable bioactive furanoclerodanes, like the psychoactive salvinorin A found inSalvia divinorum, which is used in treatment of opioid addiction. However, there is relatively little known about their biosynthesis. To address this, we investigated the biosynthesis of salviarin, the simplest furanoclerodane structure in the ornamental sageSalvia splendens. Using a self-organizing map and mutual rank analysis of RNA-seq co-expression data, we identified three cytochrome P450 enzymes responsible for converting kolavenol into salviarin precursors, consecutively: annonene, hardwickiic acid and hautriwaic acid. As annonene and hardwickiic acid have also been proposed as intermediates in the biosynthesis of salvinorin A, and to examine our hypothesis for common evolutionary origin of the furanoclerodane pathway between the two Salvia species, we searched for homologous genes in available data forS. divinorum. The enzymes encoded by orthologous genes fromS. divinorumdisplayed kolavenol synthase (SdKLS), annonene synthase (SdANS), and hardwickiic acid synthase (SdHDAS) activity respectively, supporting the view that these are intermediate steps in the biosynthesis of salvinorin A. We investigated the origin of annonene synthase and the role of gene duplication in the evolution of this specific activity. Our work shows howS. splendenscan serve as a model species for studying furanoclerodanes biosynthesis in Salvia species, contributes to understanding the evolution of specialized metabolism in plants, and provides new tools to produce salvinorin A in biotechnological chassis.
Analysis of exome sequencing data implicates rare coding variants inSTAG1andZNF136in schizophrenia
Authors: Chick Sophie L , Holmans Peter , Grozeva Detelina , Sims Rebecca , Williams Julie , Owen Michael J , O’Donovan Michael C , Walters James T R , Rees Elliott
Published: October 2024

Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance. To increase power for gene discovery, we analysed exome-sequencing data for rare coding variants in a new sample of 4,650 schizophrenia cases and 5,719 controls, and combined these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3,444 proband-parent trios. Novel associations were identified forSTAG1andZNF136at exome-wide significance and for six additional genes at a false discovery rate of 5%. Among these genes,SLC6A1andKLC1are associated with damaging missense variants alone. Four of the eight novel genes are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover,STAG1andKLC1have fine-mapped common variant signals in schizophrenia. These findings provide novel insights into the neurobiology of schizophrenia, including an aetiological role for disrupted chromatin organisation.
Expanding and improving analyses of nucleotide recoding RNA-seq experiments with the EZbakR suite
Authors: Vock Isaac W. , Mabin Justin W. , Machyna Martin , Zhang Alexandra , Hogg J. Robert , Simon Matthew D.
Published: October 2024

Nucleotide recoding RNA sequencing methods (NR-seq; TimeLapse-seq, SLAM-seq, TUC-seq, etc.) are powerful approaches for assaying transcript population dynamics. In addition, these methods have been extended to probe a host of regulated steps in the RNA life cycle. Current bioinformatic tools significantly constrain analyses of NR-seq data. To address this limitation, we developed EZbakR, an R package to facilitate a more comprehensive set of NR-seq analyses, and fastq2EZbakR, a Snakemake pipeline for flexible preprocessing of NR-seq datasets, collectively referred to as the EZbakR suite. Together, these tools generalize many aspects of the NR-seq analysis workflow. The fastq2EZbakR pipeline can assign reads to a diverse set of genomic features (e.g., genes, exons, splice junctions, etc.), and EZbakR can perform analyses on any combination of these features. EZbakR extends standard NR-seq mutational modeling to support multi-label analyses (e.g., s4U and s6G dual labeling), and implements an improved hierarchical model to better account for transcript-to-transcript variance in metabolic label incorporation. EZbakR also generalizes dynamical systems modeling of NR-seq data to support analyses of premature mRNA processing and flow between subcellular compartments. Finally, EZbakR implements flexible and well-powered comparative analyses of all estimated parameters via design matrix-specified generalized linear modeling. The EZbakR suite will thus allow researchers to make full, effective use of NR-seq data.
Bayesian Inference of Pathogen Phylogeography using the Structured Coalescent Model
Authors: Roberts Ian , Everitt Richard G. , Koskela Jere , Didelot Xavier
Published: October 2024

Over the past decade, pathogen genome sequencing has become well established as a powerful approach to study infectious disease epidemiology. In particular, when multiple genomes are available from several geographical locations, comparing them is informative about the relative size of the local pathogen populations as well as past migration rates and events between locations. The structured coalescent model has a long history of being used as the underlying process for such phylogeographic analysis. However, the computational cost of using this model does not scale well to the large number of genomes frequently analysed in pathogen genomic epidemiology studies. Several approximations of the structured coalescent model have been proposed, but their effects are difficult to predict. Here we show how the exact structured coalescent model can be used to analyse a precomputed dated phylogeny, in order to perform Bayesian inference on the past migration history, the effective population sizes in each location, and the directed migration rates from any location to another. We describe an efficient reversible jump Markov Chain Monte Carlo scheme which is implemented in a new R package. We use simulations to demonstrate the scalability and correctness of our method and to compare it with existing comparable software. We also applied our new method to several state-of-the-art datasets on the population structure of real pathogens to showcase the relevance of our method to current data scales and research questions.
Synthesis and characterization of chloroquine-modified albumin-binding siRNA-lipid conjugates for improved intracellular delivery and gene silencing in cancer cells
Authors: Lo Justin H. , Gbur Eva F. , Francini Nora , Ma Jinqi , Sorets Alexander G. , Fletcher R. Brock , Yu Fang , D’Arcy Richard , Oltman Connor G. , Uddin Md. Jashim , Duvall Craig L.
Published: October 2024

siRNA therapeutics have considerable potential as molecularly-targeted therapeutics in malignant disease, but identification of effective delivery strategies that mediate rapid intracellular delivery while minimizing toxicity has been challenging. Our group recently developed and optimized an siRNA conjugate platform termed “siRNA-L2,” which harnesses non-covalent association with endogenous circulating albumin to extend circulation half-life and achieve tumor-selective delivery without the use of traditional cationic lipids or polymers for transfection. To improve intracellular delivery and particularly the endosomal escape properties of siRNA-L2towards more efficient gene silencing, we report synthesis of siRNA-CQ-L2conjugates, in which chloroquine (CQ), an endosomolytic quinoline alkaloid, is covalently incorporated into the branching lipid tail structure. We accomplished this via synthesis of a novel CQ phosphoramidite, which can be incorporated into a modular siRNA-L2backbone using on-column solid-phase synthesis through use of asymmetric branchers with levulinyl-protected hydroxide groups that allow covalent addition of pendant CQ repeats. We demonstrate that siRNA-CQ-L2maintains the ability to non-covalently bind albumin, and with multiple copies of CQ, siRNA-CQ-L2mediates higher endosomal disruption, cellular uptake/retention, and reporter gene knockdown in cancer cells. Further, in mice, the addition of CQ did not significantly affect circulation kinetics nor organ biodistribution and did not produce hematologic or organ-level toxicity. Thus, controlled, multivalent conjugation of albumin-binding siRNA-L2to endosomolytic small molecule compounds holds promise in improving siRNA-L2knockdown potency while maintaining albumin-binding properties and overall safety.
Biochemical and Phytochemical Efficacy of DefattedMoringa oleiferaSeeds in Alleviating Protein-Energy Malnutrition
Authors: Jegede Raphael Eneji , Ayeni Gideon , Abaniwo Rose Mafo , Audu Godwin Amoka , Haruna Abdullahi
Published: October 2024

Protein-energy malnutrition (PEM) is a severe health condition affecting millions, especially in developing regions. This study investigates the potential ofMoringa oleiferaseeds as a low-cost protein source to address protein energy malnutrition.Moringa oleiferaseeds were defatted using different solvents (n-hexane, acetone, and a mixture of n-hexane and acetone) and used in formulating diets for PEM-induced Wistar rats. The study analyzed the seeds’ phytochemical constituents, proximate composition, amino acid profiles, and bioactive compounds through Gas Chromatograph-Mass Spectroscopy (GC-MS). Twenty (2) wistar Rats were randomly assigned to four groups: Group A, control group, B= PEM-induced group, Group C, malnourished rats treated with 15% soya bean based-diet and group D, malnourished rats treated with 15% defattedMoringa oleiferaseed-based diet. The results show that defatting increased protein content and reduced anti-nutritional factors like oxalates, saponins, and tannins, enhancing nutrient bioavailability. DefattedMoringa oleiferaseed-based diets improved liver and kidney functions, lipid profiles, and protein digestibility in protein energy malnutrition-induced rats. Additionally, the seeds contained essential bioactive compounds with potential antioxidant, antimicrobial, and anti-inflammatory properties. These findings suggest thatMoringa oleiferaseeds could be a promising alternative protein source for combating protein energy malnutrition.
Depleting trafficking regulator CASK promotes intercalated disc organization and ventricular function
Authors: Blandin Camille , Dilanian Gilles , Fontaine Vincent , Mougenot Nathalie , Gravez Basile , Bobin Pierre , Duboscq-Bidot Laetitia , Farhi Dounia , Chardonnet Solenne , Nadaud Sophie , Sanchez-Alonzo Jose L. , Shevchuk Andriy , Gorelik Julia , Gandjbakhch Estelle , Hatem Stéphane , Villard Eric , Balse Elise
Published: October 2024

Background

The intercalated disc (ID) electromechanically couples adjacent cardiomyocytes. Alteration of this structure plays a central role in cardiac arrhythmias, notably arrhythmogenic cardiomyopathy (ACM), an inherited genetic disorder of desmosomes. Calcium/Calmodulin-Dependent Serine Protein Kinase (CASK), a costameric component of the lateral membrane, regulates cardiomyocyte protein trafficking. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts. Here, we investigated CASK regulation of the organization of ID components in normal and pathological contexts.

Methods

We studied the outcomes of CASK depletion in neonatal rat hearts using a cardiac-specific adeno-associated virus strategy. We used conventional and strain echocardiography, hemodynamics, electrocardiography, histology, and gene and protein expression studies to characterize adult rat hearts. We also studied the effects of CASK depletion in neonatal rat ventricular cardiomyocytes (NRVM), and control and ACM (PKP2+/-) IPS cell-derived CM (hIPS-CM) using proteomics, electron microscopy, high-resolution imaging, mechano-scanning ion conductance microscopy (mechano-SICM), and stress resistance tests. We studied cardiac CASK expression and localization in human ACM and non-transplantable control hearts.

Results

Depletion of CASK in our multiple experimental models revealed that CASK regulates cardiomyocyte IDs. In rats, CASK depletion improved contractile reserve and compliance. In cultured rat cardiomyocytes, CASK knockdown increased localization of connexin 43 (Cx43) and PKP2 at IDs, resulting in increased contact stiffness. InPKP2+/-hIPS-CMs, CASK expression was increased. CASK depletion in these cells promoted PKP2 accumulation at cell contacts, formation of desmosome-like structures, and stress resistance. In the right ventricles of ACM patients, CASK protein level was also increased and CASK abnormally localized at the ID.

Conclusion

CASK functions as a repressor of ID organization and tissue cohesion, suggesting novel mechanisms for regulating ID structure and function. These observations, along with CASK upregulation and mislocalization in ACM, open up new perspectives on understanding the pathophysiology of ACM and suggest innovative strategies for its treatment.
Circulation ofKlebsiella pneumoniaestrains between the termites, chimpanzees and humans
Authors: Houmenou Cheikh Tidiane , Sarr Habibou , Diene Seydina M. , Kacel Idir , Sokhna Cheikh , Fenollar Florence , Mediannikov Oleg
Published: October 2024

The emergence and multiplication of multi-resistant microbes is becoming a major concern in medicine and scientific research, requiring an integrated, global approach to prevent their spread and develop new therapeutic solutions. Klebsiella pneumoniaecan cause a variety of infections. It has several distinctive features, such as extended-spectrum beta-lactamase (ESBL) production and frequency in hospital-acquired infections, which set it apart from other bacteria asPseudomonas aeruginosaor staphylococci and make it of particular concern in the clinical setting. In this study, we worked on four strains of multidrug-resistantK. pneumoniaeisolated from different patients at Fann Hospital in Dakar, Senegal. Whole genomes were compared them with those of nineK. pneumoniaeisolates from chimpanzees (CHZ) and six from termites (T_NSC) from our previous study. The comparison revealed two major genetic groups: three human strains were virtually identical to those found in three chimpanzees and four genomes extracted from termites regularly consumed by chimpanzees were identical to fiveK. pneumoniaestrains from chimpanzees. In silico, we identified the resistance genes and their corresponding families from each isolate, then genotyped them before comparing them with other isolates stored in the Institute Pasteur database. These strains have never been previously identified in Senegal.

It has been shown here that multiresistantK. pneumoniaestrains circulate between chimpanzees and termites and between chimpanzees and humans. Furthermore, these strains, often associated with nosocomial infections, have been identified and genotyped outside Senegal. Although similar strains have been already identified in tropical countries and in different intensive care units throughout the world, we hypothesize that they may originate from termite-chimpanzee ecosystem.
Torsion is a Dynamic Regulator of DNA Replication Stalling and Reactivation
Authors: Jia Xiaomeng , Gao Xiang , Zhang Shuming , Inman James T. , Hong Yifeng , Singh Anupam , Patel Smita , Wang Michelle D.
Published: October 2024

The inherent helical structure of DNA dictates that a replisome must rotate relative to DNA during replication, presenting inevitable topological challenges to replication. However, little is known about how the replisome progresses against torsional stress. Here, we developed a label-free, high-resolution, real-time assay to monitor replisome movement under torsion. We visualized the replisome rotation of DNA and determined how the replisome slows down under torsion. We found that while helicase or DNA polymerase (DNAP) individually is a weak torsional motor, the replisome composed of both enzymes is the most powerful DNA torsional motor studied to date. It generates ∼ 22 pN·nm of torque before stalling, twice the stall torque ofE. coliRNA polymerase. Upon replisome stalling, the specific interaction between helicase and DNAP stabilizes the fork junction; without it, the fork can regress hundreds of base pairs. We also discovered that prolonged torsion-induced stalling inactivates the replisome. Surprisingly, DNAP exchange, mediated by the helicase, is highly effective in facilitating replication restart, but only if excess DNAP is present during stalling. Thus, helicase and DNA polymerase work synergistically as a powerful torsional motor, and their dynamic and fluid interactions are crucial for maintaining fork integrity under torsional stress. This work demonstrates that torsion is a strong regulator of DNA replication stalling and reactivation.
Altered Hormone and Bioactive Lipid Plasma Profile in Rodent Models of Polycystic Ovarian Syndrome Revealed by Targeted Mass Spectrometry
Authors: Scott Hannah C , Philpott Martin , Berridge Georgina , Yu Zhanru , O’Brien Darragh P , Becker Christian , Lindgren Cecilia , Oppermann Udo , Müller Jörg , Fritsch Martin , Pinto-Fernández Adán , Kessler Benedikt M
Published: October 2024

Polycystic ovarian syndrome (PCOS) symptoms include excessive body or facial hair, irregular periods, reduced fertility, and reoccurring pregnancy loss. Hyperandrogenism and chronic inflammation are hallmarks of PCOS, which is diagnosed by analysing steroid hormones in the blood. Studies suggest that bioactive lipids are contributing to chronic inflammation. To research PCOS, animal models, such as letrozole- and dihydrotestosterone-treated rats, are used. They display similar ovarian and metabolic characteristics, although plasma lipid profiles have not been determined. Therefore, in order to validate the use of these models for PCOS, we have optimised a mass spectrometry based targeted lipidomics workflow which increases the sensitivity of measuring these lipids in rat plasma. Our analysis shows that letrozole caused a significant elevation of 5α-androstene-3,17-dione and testosterone. Dihydrotestosterone treatment resulted in increased dehydroepiandrosterone-sulphate and allopregnanolone but a reduction in testosterone, progesterone, pregnenolone, and D-sphingosine. In both models 25-hydroxycholesterol and leukotriene C4were significantly diminished and 4-cholesten-3-one was significantly increased, and these particular metabolites are not known to be changed in human PCOS. These results suggest that the plasma lipids of these rodent models have some changes akin to human PCOS and other changes that are not.
How the microbiome liberates iron from heme
Authors: Nath Arnab Kumar , da Silva Ronivaldo Rodrigues , Gauvin Colin C. , Akpoto Emmanuel , Adedoyin Victoria , Dlakić Mensur , Lawrence C. Martin , DuBois Jennifer L.
Published: October 2024

The microbiome is a hidden organ system with diverse metabolic roles. UsingBacteroides thetaiotaomicron(B theta) as a model, we asked how microbiome species process iron, the quintessential biometal supporting respiration and life as we know it, when iron is provided in complex with protoporphyrin IX (PPIX) asheme. An intestinal transporter for heme has not been unequivocally identified. Canonical pathways for reclaiming heme iron from host cells or the diet require O2, which is unavailable in the GI tract and many pathological microenvironments. HmuS, a homolog of cobalamine-(vitamin B12) and chlorophyll-building chelatases, is widespread in anaerobic microbial ecosystems. In this work, we provide direct physiological, biochemical, and structural evidence for the anaerobic removal of iron from heme by HmuS, a de-chelatase that deconstructs heme to PPIX and Fe(II). We show that heme can be used as a sole iron source byB theta, yielding PPIX, and thathmuSinactivation under these conditions is lethal. Iron removal from heme depends on theB thetamembrane fraction, NADH, and O2exclusion. Absorbance spectra indicate that heterologously expressed HmuS is isolated with a non-substrate heme bound and can accommodate multiple heme equivalents under saturating conditions. Solution of the cryoEM structure reveals heme and two cations at sites that are conserved across the HmuS family and the chelatase superfamily, respectively. The proposed structure-based mechanism for iron removal further links biosynthetic and biodegradative pathways for heme, chlorophyll, and vitamin B12, three ancient and biologically crucial metallocofactors.

Significance Statement

Iron in its heme and non-heme forms is essential for nearly all life. This work defines a microbial mechanism for metabolizing heme that is widespread in gastrointestinal and other anaerobic ecosystems. To date, an intestinal cellular transporter for heme has not been unequivocally identified. However, heme, abundant in both red meat diets and animal cells, is converted by the bacterial HmuS enzyme into a non-heme form from which the iron can be repurposed. HmuS enzymes form a distinct de-chelatase subset of a superfamily of chelatases that catalyze metal insertion into chlorophyll and vitamin B12, indicating convergence of metabolic pathways for biosynthesis and degradation of three of life’s essential metallocofactors. Understanding HmuS function supports engineered approaches to directing microbiome-host metabolism and offsetting heme-associated pathologies including anemia, inflammation, and cancer.
Highly expressed cell wall genes contribute to robustness of sepal size
Authors: Hartasánchez Diego A. , Dumond Mathilde , Dubrulle Nelly , Monéger Françoise , Boudaoud Arezki
Published: October 2024

Reproducibility in organ size and shape is a fascinating trait of living organisms. The mechanisms underlying such robustness remain, however, to be elucidated. Taking the sepal of Arabidopsis as a model, we investigated whether variability of gene expression plays a role in variation of organ size and shape. Previous work from our team identified cell-wall related genes as being enriched among the genes whose expression is highly variable. We then hypothesized that the variation of measured morphological parameters in cell-wall related single knockout mutants could be correlated with the variation in gene expression of the corresponding gene (the knocked-out gene) in wild-type plants. We analyzed sepal size and shape from 16 cell-wall mutants and found that sepal size variability correlates positively, not with gene expression variation, but with mean gene expression of the corresponding gene in wild type. These findings support a contribution of cell-wall related genes to the robustness of sepal size.