bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal fibrosis associated with inflammatory bowel disease: Known and unknown
Authors: Zhang Yao , Zhuang Haiming , Chen Kai , Zhao Yizhou , Wang Danshu , Ran Taojing , Zou Duowu
Published: February 2025

Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), leading to a high incidence of surgical interventions and significant disability. Despite its clinical relevance, no targeted pharmacological therapies are currently available. This review aims to explore the underlying mechanisms driving intestinal fibrosis and address unresolved scientific questions, offering insights into potential future therapeutic strategies. We conducted a literature review using data from PubMed up to October 2024, focusing on studies related to IBD and fibrosis. Intestinal fibrosis results from a complex network involving stromal cells, immune cells, epithelial cells, and the gut microbiota. Chronic inflammation, driven by factors such as dysbiosis, epithelial injury, and immune activation, leads to the production of cytokines like interleukin (IL)-1β, IL-17, and transforming growth factor (TGF)-β. These mediators activate various stromal cell populations, including fibroblasts, pericytes, and smooth muscle cells. The activated stromal cells secrete excessive extracellular matrix components, thereby promoting fibrosis. Additionally, stromal cells influence the immune microenvironment through cytokine production. Future research would focus on elucidating the temporal and spatial relationships between immune cell-driven inflammation and stromal cell-mediated fibrosis. Additionally, investigations are needed to clarify the differentiation origins of excessive extracellular matrix-producing cells, particularly fibroblast activation protein (FAP)+ fibroblasts, in the context of intestinal fibrosis. In conclusion, aberrant stromal cell activation, triggered by upstream immune signals, is a key mechanism underlying intestinal fibrosis. Further investigations into immune–stromal cell interactions and stromal cell activation are essential for the development of therapeutic strategies to prevent, alleviate, and potentially reverse fibrosis.
Targeting apolipoprotein C-III: a game changer for pancreatitis prevention in severe hypertriglyceridemia
Authors: Weijs Bram M. , Oostveen Reindert F. , Kraaijenhof Jordan M. , Stroes Erik S.G.
Published: February 2025

Purpose of review

The aim of this review is to examine recent advancements in RNA-targeted therapies for the management of severe hypertriglyceridemia (sHTG) and prevention of sHTG-associated acute pancreatitis.

Recent findings

Recent developments in RNA-targeted therapies, aimed at inhibiting apolipoprotein C-III (apoC-III), have demonstrated substantial and sustained reductions in triglyceride levels. Novel therapies, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), such as volanesorsen, olezarsen, and plozasiran, have shown promising results in recent trials. These therapies not only effectively lower plasma triglyceride levels but also significantly reduce the incidence of acute pancreatitis.

SHTG is a high-burden metabolic disorder that is associated with a significantly increased incidence and severity of acute pancreatitis. Traditional lifestyle interventions and conventional therapies, including fibrates and n-3 fatty acids, often provide only modest reductions in triglycerides and fail to prevent sHTG-associated acute pancreatitis. The emergence of novel and targeted RNA-therapies represents a potential breakthrough in the management of sHTG and acute pancreatitis prevention.
Taking a Closer Look at Incivility in Prelicensure Nursing Education
Authors: Weaver Rebecca , Evans Michael , Hrabovsky Sharilee , Loeb Susan
Published: February 2025

Background:

Incivility in undergraduate nursing education is a complex, multifaceted issue. Student-to-faculty incivility can be characterized by behaviors that negatively impact the faculty’s ability to perform and enjoy their job.

Purpose:

To synthesize current research in undergraduate nursing education about student-to-faculty incivility in the classroom setting.

Methods:

A narrative review was performed on literature from 5 databases and retrieved articles’ reference lists. Relevant articles from 2018 through January 2, 2025, were reviewed.

Results:

Thematic analysis of 16 articles identified 4 key themes: (1) types of incivility, (2) causes of and influences on incivility, (3) consequences of incivility, and (4) strategies for addressing and mitigating incivility.

Conclusion:

Student-to-faculty incivility contributes to many negative consequences in academia including decreased faculty retention and continuance of incivility into practice. Targeted interventions and institutional strategies should be developed to mitigate these behaviors.
Ten-Year Trends in How Early-Stage Sepsis Start-Ups Receive Investment
Authors: Younger John G , Jordan Jacob , Kaido Shintaro
Published: February 2025

Often initiated with small governmental or philanthropic grants, nearly all improvements in the detection and care of sepsis require many years and many millions of dollars of financing before becoming generally clinically available. As early-stage healthcare investors are free to pursue a wide variety of new enterprises, innovations in sepsis care must compete in the early investment marketplace by offering both a path to clinical benefit and a path to commercial viability upon commercialization. In this note, we consider the investment environment for sepsis-related technologies including pharmaceuticals and biologicals, diagnostic and therapeutic devices, and health care information technologies and place a decade of investment trends into a broader economic context. Our hope is to better familiarize basic, translational, and clinical scientists with greater insight into how their inventions will be supported as they make their way to the bedside.
Resonant capture of Saturn’s arcs
Authors: El Moutamid M. , Sicardy B. , Renner S. , Souami D.
Published: February 2025

Obtained images from the Cassini spacecraft have unveiled several small satellites in the vicinity of Mimas’ orbit: Aegaeon, Methone and Anthe. Methone and Anthe are situated within arcs of material, while Aegaeon orbits within an arc near the inner edge of Saturn’s G ring. The presence of these arcs and moons is consistent with their confinement by corotation eccentric resonance (CER) with Mimas. Aegaeon is captured in an inner 7 : 6 mean motion resonance with Mimas, while Methone and Anthe are, respectively, captured in outer 14 : 15 and 10 : 11 resonances with Mimas. Here, we estimate the probabilities of capturing these small satellites into their respective CERs with Mimas as the orbit of the latter evolves through tidal effects. We will discuss the potential implications of this work, in particular the constraints it may provide on Mimas’ orbital evolution.

This article is part of the theme issue ‘Major advances in planetary sciences thanks to stellar occultations’.
Centaur 29P/Schwassmann–Wachmann 1 and its near-nucleus environment from a stellar occultation
Authors: Pereira C. L. , Braga-Ribas F. , Sicardy B. , Morgado B. E. , Ortiz J. L. , Assafin M. , Miles R. , Desmars J. , Camargo J. I. B. , Benedetti-Rossi G. , Kretlow M. , Vieira-Martins R.
Published: February 2025

Comets offer valuable insights into the early Solar System’s conditions and processes. Stellar occultations enable detailed study of cometary nuclei typically hidden by their coma. Observing the star’s light passing through the coma helps infer dust’s optical depth near the nucleus and determine dust opacity detection limits. 29P/Schwassmann–Wachmann 1, a Centaur with a diameter of approximately 60 km, lies in a region transitioning from Centaurs to Jupiter-family comets. Our study presents the first-ever observed occultation by 29P, allowing in the future for a more refined orbit and thus better predictions for other occultations. The light curve reveals a solid-body detection lasting

3.65
±

0.05

s, corresponding to a chord length of approximately 54 km. This provides a lower limit for the object’s radius, measured at

27.0
±

0.7

km. We identified features on both sides of the main-body occultation around 1700 km from the nucleus in the sky plane for which upper limits on apparent opacity and equivalent width were determined. Gradual dimming within 23 km of the nucleus during ingress only is interpreted as a localized dust cloud/jet above the surface with an optical depth of approximately

τ
=

0.18

.

This article is part of the theme issue ‘Major advances in planetary sciences thanks to stellar occultations’.
Investigating the formation of small Solar System objects using stellar occultations by satellites: present, future and its use to update satellite orbits
Authors: Braga-Ribas F. , Vachier F. , Desmars J. , Margoti G. , Sicardy B.
Published: February 2025

The history of the outer solar system is intrinsically related to the Giant Planets migration. A massive disk of material within a radius of 30 au was scattered during the planetary migration, creating different dynamic populations in the Transneptunian region. They were formed in a collisional environment when massive collisions allowed them to grow and form much smaller moons than the primary body. The dynamical group, known as the Cold Classicals, was formed in a sparse disk from 42 to about 47 au and did not suffer much from planet migration. Observations show that many of Cold Classical are binary, consistent with the streaming instability process. The stellar occultation technique, with a spatial resolution of a few kilometres, can be used to search for binaries where other techniques are unable to do so, and to characterize the known satellites of Trans-Neptunian Objects (TNO), constraining their formation scenarios. We review here the first stellar occultations by TNO’s satellites (besides Charon), and discuss the methods used to detect these events. We also fit new orbital elements and system mass for Vanth (Orcus/1) and Weywot (Quaoar/1), finding reasonable solutions for pure Keplerian orbits. Finally, we discuss the prospects regarding the stellar occultations by TNO binaries and their implications for the study of the history of the Solar System.

This article is part of the theme issue ‘Major advances in planetary sciences thanks to stellar occultations’.
Clinical metagenomics: ethical issues
Authors: Johnson Tess , Jamrozik Euzebiusz , Ramachandran Prashanth , Johnson Stephanie
Published: February 2025

Metagenomics is increasingly used for diagnosis in hospital settings. It is useful particularly in cases of unknown aetiology, where novel or difficult-to-diagnose pathogens are suspected, and/or following unexplained disease outbreaks. In this paper, we present three use cases that draw on existing reports: one involving a patient in intensive care with encephalitis of unknown aetiology; a second case with likely infection with drug-resistant Klebsiella pneumoniae and an incidental finding of unknown relevance; and a third case situated in an unexplained outbreak of acute hepatitis in children, with severe outcomes due to co-infection. We examine each case in turn, highlighting ethical questions arising in relation to clinical issues including: disclosure to patients of untreatable disease, cost-effectiveness, the value of resistance testing, sensitivity and specificity, uncertain or unexpected findings, patient consent and data sharing. We conclude by proposing recommendations for further research and developing particular pieces of guidance to improve clinical uses of metagenomics for diagnosis.
Hypoxia responses in arginase 2 deficient mice enhance cardiovascular health
Authors: XU WEILING , Asosingh Kewal , Janocha Allison J , Madden Evan , Wanner Nicholas , Trotter Dylan , Novotny Michael V , Mulya Anny , Farha Samar , Erzurum Serpil C
Published: February 2025

RATIONALE: Physiological responses to hypoxia involve adaptations in the hematopoietic and cardiovascular systems, which work together to ensure adequate oxygen delivery to tissues for energy production. The arginine/nitric oxide (NO) pathway regulates both systems through its effects on erythropoiesis and vasodilation. In Tibetan populations native to high-altitude hypoxia, increased NO production from arginine and decreased arginine metabolism by arginase contribute to these adaptive mechanisms. These metabolic changes enhance tissue oxygen delivery and reduce the risk of hypoxic pulmonary hypertension. Here, we hypothesize that genetic deletion of mitochondrial arginase 2 (Arg2) in mice will enhance cardiovascular effects and mitigate hypoxia-induced pulmonary hypertension. METHODS: Complete blood counts, bone marrow erythroid differentiation, plasma arginine and NO (measured as nitrite), right ventricular systolic pressure (RVSP), heart rate, heart weight, and blood pressure were measured in wild-type (WT) andArg2knockout (Arg2KO) mice exposed to short-term (6, 12, 48, or 72 hours) or long-term (3 weeks) hypoxia. RESULTS: Under normoxic conditions,Arg2KO and WT mice exhibit similar RBC counts, hemoglobin levels, hematocrit, heart rate, systolic and diastolic blood pressures, and heart weight (allP> 0.05). WT mice increase erythropoiesis at 12 hours of hypoxia, including proerythroblasts (stage I,P= 0.004), polychromatic erythroblasts (stage III,P= 0.0004), and orthochromatic erythroblasts (stage IV,P= 0.03), butArg2KO mice do not increase erythropoiesis. After 48 hours of hypoxia,Arg2KO mice increase proerythroblasts (stage I,P= 0.0008), but levels remain significantly lower than in WT mice. Plasma arginine and NO levels increase under hypoxia. NO levels peak at 12 hours of hypoxia in WT mice, then decline rapidly. In contrast, NO levels inArg2KO mice are higher than in WT mice, with sustained elevations at 48 hours of hypoxia (P= 0.03).Arg2KO mice have significantly higher plasma arginine levels than WT at 6, 12, and 72 hours of hypoxia (allP< 0.05). Under chronic hypoxia,Arg2KO and WT mice show similar RBC counts, hemoglobin levels, hematocrit, and NO levels. Unlike WT,Arg2KO mice do not increase RVSP (P= 0.4) and have lower mean arterial (P= 0.03) and diastolic blood pressures (P= 0.01), as well as much lower heart rates (P< 0.0001). Additionally, small blood vessels increase in lungs ofArg2KO mice (CD31,P= 0.02; vWF,P= 0.6). CONCLUSIONS: Arginine metabolism in the mitochondria plays a key role in modulating adaptive responses to hypoxia. Deletion ofArg2results in delayed erythropoiesis under acute hypoxia, but better cardiovascular health, as indicated by higher levels of nitrite and arginine, and lower RVSP, blood pressure, and heart rate with chronic hypoxia.
Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid
Authors: Snieckute Ruta , Sulskis Darius , Jocyte Arune , Venclovaite Urte , Tamulyte Rimgaile , Ziaunys Mantas , Smirnovas Vytautas , Sakalauskas Andrius
Published: February 2025

α-Synuclein (aSyn) is an intrinsically disordered protein involved in neurotransmission and synaptic plasticity. The pathological aggregation of this protein is a hallmark of synucleinopathies such as Parkinson's disease (PD) or Multiple System Atrophy (MSA). Misfolded aSyn, which primarily originates in cell cytosol, transmits between neurons, promoting a prion-like propagation. However, the extracellular environments such as interstitial and cerebrospinal fluids (ISF & CSF) play a major role in its clearance and pathological transformation. The molecular components of CSF, including proteins, glycosaminoglycans, and metal ions may influence the aggregate morphology, structure and cytotoxicity to cells. To better understand how extracellular composition affects aggregates and their formation, we employed artificial cerebrospinal fluid (aCSF) to mimic potential aggregation processes occurring in CSF. We observed distinct aCSF-specific aSyn fibrils that exhibited low stability outside aCSF, and the removal of key CSF components led to its structural alterations. Cryo-electron microscopy revealed that these fibrils possess an electron density pocket coordinated with polar basic AAs (K43, K45, H50) that is also observed in aggregates obtained from MSA patients. Our findings illustrate the importance of physiologically relevant conditions in studying aSyn aggregation and may explain why disease-related fibril structure replication in vitro has not yet been successful.
Data-driven inference of digital twins for high-throughput phenotyping of motile and light-responsive microorganisms
Authors: Giusti Andrea , Salzano Davide , di Bernardo Mario , Gorochowski Thomas E
Published: February 2025

Light can affect the movement of microorganisms. These responses can drive collective behaviours like photoaccumulation and photodispersion, which play a key role in broader biological functions like photosynthesis. Our understanding of these emergent phenomena is severely limited by difficulties in obtaining data needed to establish accurate models that can serve as a basis for multi-scale analyses. Here, we address this issue by developing an integrated experimental and computational platform to collect large temporal imaging datasets that allow for the inference of 'digital twins' - mathematically precise computational models that accurately mirror the behavior of individual microorganisms - and show that they can replicate the light response of diverse microorganisms in silico. We show that a generalised phenomenological model of movement can be effectively parameterised from experimental data to capture key behavioural traits of two commonly studied photo-responsive microorganisms (Euglena gracilis and Volvox aureus) and demonstrate our model's ability to accurate reproduce patterns of movement for individuals and populations in response to dynamic and spatially varying light patterns. This work takes steps towards the automated phenotyping of multi-scale behaviours in biology and complements high-throughput genome sequencing efforts by allowing for more comprehensive and quantitative genotype-to-phenotype mappings. It also unlocks new opportunities for the design of spatial control algorithms to guide collective microorganism behaviour.
Blocky proline/glutamine patterns in the SFPQ intrinsically disordered region dictate paraspeckle formation as a distinct membraneless organelle
Authors: Takakuwa Hiro , Yoda Takao , Yamazaki Tomohiro , Hirose Tetsuro
Published: February 2025

Membraneless organelles (MLOs) formed through phase separation play crucial roles in various cellular processes. Many MLOs remain spatially compartmentalized, avoiding fusion or engulfment with one another. MLOs are formed by dynamic multivalent interactions among biomolecules, exemplified by proteins with intrinsically disordered regions (IDRs). However, the molecular principles behind how IDRs maintain MLO independence remain poorly understood. Here, we investigated the proline/glutamine (P/Q)-rich IDR of SFPQ, a protein identified as a key factor in segregating paraspeckles from nuclear speckles, to uncover the principles underlying this process. Paraspeckle segregation analyses, using MS2 tethering of SFPQ mutants onto NEAT1 long noncoding RNA, revealed that P/Q residues within the SFPQ IDR, whose enrichment is conserved from humans to zebrafish, play a crucial role in its segregation activity. In addition to the amino acid composition, the blocky patterns of P/Q residues are required for the segregation from nuclear speckles. Among human IDRs exhibiting PQ-block patterns, BRD4 IDR shows strong sequence similarity to the SFPQ IDR, and its IDR exhibits segregation activity at a level comparable to that of SFPQ. Furthermore, our molecular dynamics simulation suggests that the PQ-blocky patterns required for the paraspeckle segregation do not correlate with the IDR characteristics necessary for self-assembly. Thus, these data suggest that the PQ-blocky patterns in IDRs represent a previously uncharacterized property, which plays a role in maintaining the independence of MLOs, possibly through a mechanism distinct from the conventional phase separation-promoting function of IDRs.
Prevalence and Risks factors of the different forms of Domestic Violence Among Pregnant Women Attending Antenatal Clinics in the Buea Health District of Cameroon
Authors: Tanue Elvis Asangbeng , Chifen Henrietta Nchang , Njouendou Abdel Jélil , Nyuydzedze Stanley Sunjo , Laban Mildred Nje , Nsagha Dickson Shey
Published: February 2025

Background Domestic violence during pregnancy is a global public health problem which is linked with adverse maternal and fetal outcomes. Despite its significant impact on maternal and child health, the issue remains underexplored and underreported in Cameroon. This study therefore aimed at assess the various forms of domestic violence, their prevalences and associated factors among pregnant women attending antenatal care services in public and private hospitals in the Buea Health District of Cameroon. Materials and Methods This was a hospital-based cross-sectional study conducted between the months of April to June 2021. A consecutive sampling technique was used to select the participants and a, WHO instrument on domestic violence in low-income countries was used to assess violence against pregnant women. Data collected was cleaned and analysed using SPSS version 26.0. Multiple logistic regression analysis was used to determine the relationship between the dependent variable (domestic violence) and independent variables at a 95% confidence interval (CI) for types of domestic violence while adjusting for confounding factors. Results Of the 346 pregnant women who participated in this study, 303 (87.57%) were identified as experiencing at least one form of domestic violence. The most common form of domestic violence was psychological aggression (82.7%), followed by controlling behavior (78.0%), then physical (42.2%), economic deprivation (42.2%) and sexual (34.4%) violence. Women with monthly income below 50,000 XAF (AOR=4.31, 95% CI 1.23-15.08; p=0.022), and consuming alcohol (AOR=6.00, 95% CI 2.41-14.93; p<0.001) were more likely to experience psychological violence. Physical violence was associated with women with less than tertiary education (AOR=8.26, 95% CI 2.84-24.00; p=0.001) and having partners who gamble (AOR=8.11, 95% CI 3.34-19.69; p=0.001). Controlling behavior, was associated with partners who consumed alcohol (AOR 4.31; 95% CI 1.94-9.60; p=0.001) and to women with a monthly income below 25,000 XAF (AOR=3.53, 95% CI 1.26-9.89; p=0.016). Partners chosen by family (AOR=5.62, 95% CI 1.58-19.95; p=0.008), being housewives (AOR=9.55, 95% CI 2.36-38.57; p=0.002) and partners who smoked (AOR=3.22, 95% CI 1.32-7.84; p=0.010) were significantly associated to economic deprivation. Women who choose their partners (AOR=0.09, 95% CI 0.02-0.52; p=0.007) were less likely to experience sexual violence. Conclusion More than three quarters of the pregnant women in the study experience at least one type of domestic violence. This high proportion highlights the need for policy to address the problem of violence against pregnant women.
Genome-wide association study provides novel insight into the genetic architecture of severe obesity
Authors: Krishnan Mohanraj , Anwar Mohammad Yaser , Justice Anne E , Chittoor Geetha , Chen Hung-Hsin , Roshani Rashedeh , Smit Roelof A.J , Preuss Michael H , Chami Nathalie , Hadad Benjamin S , Parra Esteban J , Cruz Miguel , Hui Qin , Wilson Peter W.F , Sun Yan V , Zhang Xiaoyu , Linchangco Gregorio V , Kardia Sharon L.R , Faul Jessica D , Weir David R , Bielak Lawrence F , Highland Heather M , Young Kristin L , Qi Baiyu , Wang Yujie , Fornage Myriam , Haiman Christopher , Cheng Iona , Peters Ulrike , Kooperberg Charles , Buyske Steven , McCormick Joseph B , Fisher-Hoch Susan P , Lona-Durazo Frida , Peralta Jesus , Gomez-Zamudio Jamie , Rich Stephen S , Ferrier Kendra R , Lange Ethan M , Gignoux Christopher G , Kenny Eimear E , Wojcik Genevieve L , Cho Kelly , Gaziano Michael J , Djousse Luc , Liu Shuwei , Vaidya Dhananjay , de Mutsert Renée , Josyula Navya S , Bauer Christopher R , Zhao Wei , Walker Ryan W , Smith Jennifer A , Lange Leslie A , Meyer Mariah C , Liu Ching-Ti , Yanek Lisa R , Lee Miryoung , Raffield Laura M , Loos Ruth J.F , Gordon-Larsen Penny , Below Jennifer E , North Kari E , Graff Mariaelisa
Published: February 2025

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95thpercentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥40 kg/m2and Obesity Class IV BMI ≥50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated one novel signal in an unknown locus [BHLHE40-AS1] and three novel signals in known loci of BMI [TENM2,PLCL2,ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.
Co-occurrence of Seizures and Gastrointestinal Symptoms in Children with ASD
Authors: Tagliavia Alessandro , Vyshedskiy Andrey
Published: February 2025

The goal of this cluster analysis of comorbidities in children with Autism Spectrum Disorder (ASD) was to find potential co-occurrence between health symptoms that would not otherwise be investigated. We analyzed parent-reported data from 130,985 users of a free language-learning application. The initial cohort was stratified by ASD severity and age group to explore patterns within these subpopulations. Across these cohorts and subgroups, we observed a consistent co-occurrence of gastrointestinal symptoms, such as diarrhea and constipation, with seizures and lethargy. These results suggest that a common underlying mechanism may be driving both gastrointestinal disturbances and seizure activity in children with ASD.
Distinct metastatic organotropism shapes prognosis in lung adenocarcinoma with brain metastasis
Authors: Sayin Sama I. , Eklund Ella A. , Ali Kevin X. , Dzanan Jozefina J. , Xylander Moe , Dankis Martin , Lindahl Per , Sayin Volkan I. , Hallqvist Andreas , Wiel Clotilde
Published: February 2025

Background: Metastatic organotropism in lung cancer significantly influences prognosis, yet current treatment and clinical management guidelines are largely generalized for metastatic disease, regardless of organ site involvement. Notably, up to 30% of non-small cell lung cancer (NSCLC) patients present with brain metastases (BM) at diagnosis, underscoring the need for a more nuanced understanding of metastatic patterns. However, real-world clinical data on metastatic organotropism in well-characterized patient cohorts remain surprisingly scarce. Here, we evaluate patterns of metastasis, clinical characteristics and survival outcomes in patients with lung adenocarcinoma (LUAD), the major histological NSCLC subtype. Methods: We performed a multi-center retrospective study including 913 stage IV LUAD patients, diagnosed and molecularly assessed in western Sweden between 2016 and 2021. Our primary study outcome was the distribution of specific metastatic sites and its impact on Overall Survival (OS). Results: Out of 913 stage IV LUAD patients, 23.4% had BM. These patients exhibited markedly different metastatic patterns compared to those without BM, and median survival was significantly shorter (6 months) than those without BM (7.8 months) (p = 0.021). In addition, more than one metastatic tumor in the brain coincided with worse OS, compared to those with no, or with only one metastatic tumor in the brain. Importantly, OS was also influenced by metastasis in specific extracranial organs, like the pleura and lungs. Conclusions: Our study highlights the distinct metastatic patterns and survival outcomes associated with BM in stage IV LUAD. These findings emphasize the need for site-specific approaches in managing metastatic disease due to the impact of BM on survival.
Basic-Leucine-Zipper Transcription Factors Regulate Selective Molecular Phenotypes in Regulatory T Cells During IL-2-Induced Activation
Authors: Tse Joyce , Liu Xuan , Eres Ittai , Yamawaki Tracy , Kanke Matt , Killian Marisela , Amrute Junedh , Chaudhry Ashutosh , Sahoo Anupama , Liu Wen-Jun , Kao Cheng-Yuan , Luo Xin , Lu Jiamiao , Lu Daniel , Wang Songli , Martin Scott , Li Chi-Ming
Published: February 2025

Regulatory T (Treg) cells have long been recognized as modulators of immunological tolerance and homeostasis. Previously, we used scRNA-seq to reveal significant Treg heterogeneity in response to IL-2-induced activation. Herein, we leveraged enrichment analyses, as well as bulk and single nucleus multi-omics in splenic and lung Tregs, to uncover and confirm the importance of transcription factors (TFs) and chromatin remodeling in Treg activation. Multiple bZIP TF motifs showed increased chromatin accessibility post IL-2 treatment, with correlated transcriptional changes resembling Th1 and Th2 molecular phenotypes, further confirmed by spatial ATAC-seq. By combining gene perturbation and CUT&RUN assays before and after Treg stimulation, we show that bZIP TFs, such as BATF and BACH1, are critical to IL-2-induced Treg activation, coordinating epigenetic and transcriptional changes that selectively drive T-helper phenotypes and metabolic pathways.
Bivalent ligands as a new universal chemotype of BCL6 degrader by inducing aggregation
Authors: Hu Rong , Hu Xia-Tong , Yang Ying-Yue , Luo Peng , Li Cai-Hua , Liu Zhi-Hao , Yu Luo-Ting , Wang Ning-Yu
Published: February 2025

BCL6 naturally exists as a homodimer to exert its transcriptional repressive function. Previous studies shown that molecular glue BI3802 can induce BCL6 dimer polymerization and thus degradation by ubiquitin-proteasome system. In this study we proposed a new strategy to degrade BCL6 by its homo-bivalent ligands, which can be rationally designed by assemble two BCL6 BTB ligands via linker. These homo-bivalent degraders (HBiDs) can induce polymerization of BCL6 dimer through chain assembly and ultimately lead to its ubiquitination and degradation. Since HBiD does not require a fragment to interact with components of protein degradation system, it could exhibit better target selectivity than traditional protein degraders while avoid drug resistance caused by mutations in protein degradation components. Here we will provide the proof-of-concept evidences for HBiD as BCL6 degrader. Most HBiDs synthesized in this study could degrade BCL6 with extraordinary selectivity, regardless of the chemotype of BCL6 ligands. The degradation of BCL6 depends on the aggregation of BCL6 dimer induced by HBiD and the recruitment of SIAH1, the natural E3 ligase of BCL6. As protein dimerization is a common phenomenon in cells, HBiD may provide us with a powerful strategy for designing protein degraders as drug candidates or molecular probes.
Mid-aged mice rapidly normalize dysglycemia but aggravate obesity-induced hypothalamic and microglial changes upon dietary obesity reversal
Authors: Zemer Alon , Haim Yulia , Tsitrina Alexandra , Chalifa-Caspi Vered , Muallem Habib , Pincu Yair , Yoel Uri , Monsonego Alon , Rudich Assaf
Published: February 2025

Objective: Obesity-induced-dysglycemia and hypothalamic-microgliosis coincide, but whether they remain linked upon obesity reversal, and what is the effect of age, remain unclear. Here we hypothesized that rapid normalization of dysglycemia upon obesity-reversal remains linked to microgliosis resolution, but differs between young and mid-aged mice. Methods: Young (7w) and mid-aged (1y) mice were fed normal chow (NC) or high-fat diet (HFD,8w), then switched to NC (Rev,2w). Results: Compared to young mice, NC-fed mid-aged mice were heavier and weight-stable, gained weight with HFD comparably, and lost less weight in Rev. HFD-induced dysglycemia was less severe in mid-aged compared to young mice, but similarly normalized by obesity-reversal. However, whole-hypothalamus RNA sequencing revealed 2,419 differentially expressed genes (DEGs) in mid-aged mice, ~4-times more than in young mice, and in both age-groups ~80% of DEGs obesity-induced changes were aggravated in Rev. Furthermore, compared with young mice, middle-aged mice showed greater obesity-induced microglial cyto-morphological changes in the arcuate nucleus (ARC), which associated with increased p-NFκB-(p-p65) nuclear staining. Only in middle-aged mice obesity-induced microglial changes were aggravated by obesity reversal, with cell volume correlating (Rho(ρ)=0.691, p=0.001) with adipose tissue crown-like-structures. Conclusions: In conclusion, rapid dysglycemia normalization is uncoupled to the resolution of hypothalamic microgliosis, more-so in mid-age.
Abdominal symptoms of invasive meningococcal disease are associated with the induction of plasminogen activator inhibitor in omental adipocytes
Authors: Taha Muhamed-Kkeir , Oliveira Damien , Gros Marion , Aouiti-Trabelsi Myriam , Deghmane Ala-Eddine
Published: February 2025

Abdominal symptoms are increasingly reported in invasive meningococcal disease (IMD), but the underlying mechanisms remain unclear. We aimed to explore the pathophysiology of these presentations using an animal model. We utilized a collection of 20 meningococcal isolates that were either associated or not associated with abdominal presentations, which were injected intraperitoneally into transgenic mice expressing human transferrin. We employed histological examination, RNA sequencing (RNAseq) transcriptomic analysis, and reverse transcriptase real-time PCR to analyze tissue preparations of the mice's omentum. The 20 tested isolates induced similar levels of bacteremia in mice. However, isolates associated with abdominal presentations (mainly serogroup W isolates of clonal complex 11) caused thrombotic lesions in the blood vessels of the omentum, and they also induced a higher inflammatory response in the omentum with elevated levels of IL-6, TNF-alpha, and KC. Furthermore, these isolates induced higher expression of several genes, some of which are involved in coagulopathy, such as plasminogen activator inhibitor 1 (PAI-1). We also demonstrated that the PAI-1 encoding gene is overexpressed in adipocyte cells of the omentum. Lipopolysaccharide from the isolates associated with abdominal presentations, instead of whole bacteria, induced similar pathological findings. During IMD, thrombosis formation in the omentum's blood vessels is associated with a local induction of an inflammatory response and overexpression of the plasminogen activator inhibitor 1 encoding gene. These lesions can lead to thrombosis and hypoperfusion in the omentum, resulting in clinical abdominal presentations
c-Jun regulates postpartum β-cell apoptosis and survival downstream of prolactin signaling
Authors: Chung Jin-Yong , Ruiz-Otero Nelmari , Banerjee Ronadip R
Published: February 2025

Objective: Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets at different time points from late gestation to early postpartum to identify regulators of β-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues and cells. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. Methods: To examine regulation of c-Jun within β-cells we used a mouse genetic model lacking β-cell prolactin receptor (PRLR) and stimulation of cultured islets with recombinant prolactin. We used chemical inhibitors of signal transduction pathways to examine signaling downstream of PRLR. TUNEL was used to detect endogenous or dexamethasone-induced apoptosis. Q-PCR, Western blotting, and immunostaining were used to assess gene and protein expression. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA. We examined both murine and human islets and tissues. Results: We found that expression of c-Jun transcript in murine β-cells is temporally restricted to late gestation and early postpartum and requires prolactin signaling. Moreover, c-Jun protein expression was mutually exclusive with apoptotic β-cells identified by TUNEL staining. In both murine and human islets, prolactin treatment is sufficient to induce c-Jun expression and downstream MAPK/ERK signaling. Pharmacologic inhibition of c-Jun blocks prolactin-mediated survival of β-cells following pro-apoptotic stress, including failure to upregulate pro-survival factors Bcl2l1 (Bcl-xL) and Birc5 (Survivin). Finally, human islets during pregnancy also exhibit increased c-Jun expression in β-cells, but c-Jun induction is absent in β-cells from pregnant donors with gestational diabetes (GDM). Conclusions: c-Jun contributes to pro-survival effects of lactogens downstream of PRLR / MAPK signaling in β-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.
Analysis of SFTS pathogenesis based on single-cell RNA sequencing of monocytes
Authors: Zhang Yin , Xu Yuanhong
Published: February 2025

Backgroud Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified tick-borne viral disease with a high mortality rate. Monocytes are known to play an important role in the pathogenesis of SFTS, but the distinct subpopulations of monocytes associated with the disease progression and their roles in inflammatory responses remain unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to explore the specific monocyte subpopulations correlated with the progression of SFTS and their involvement in inflammatory processes. Methods scRNA-seq analysis was conducted on isolated monocytes from seven SFTS patients, validated by cell identification through flow cytometry. Comparative analyses were performed using three normal monocyte samples from public databases. Bioinformatic tools including Cell Ranger, Seurat, Monocle 2, GSEA, and SCENIC were utilized to identify distinct cell populations and transcriptional patterns. Results Our results indicate that severe SFTS patients in the ICU exhibited a reduced proportion of circulating HLA-DR+CD14+ monocytes compared to non-severe hospitalized SFTS patients, indicating a dysfunctional immune response. Increased numbers of CD163+CD14+ monocytes in acute SFTS patients correlated with disease severity. CD163+CD14+ monocytes were identified as potential target cells for SFTSV infection. SFTSV infection could drive monocyte differentiation into the M2 phenotype, promoting virus persistence and disease advancement. Conclusion Our studies in SFTS patients have shown that monocytes are target cells for SFTSV. Notably, an expansion of CD163+CD14+ monocytes in SFTS has been shown to be associated with severe clinical disease. In addition, activated IL-6/JAK/STAT3 signaling in SFTS patients induced CD163+CD14+ monocyte expansion, which was recovered by tofacitinib treatment.
A Machine Learning Approach Elucidates Spatial Patterns of Environmental Properties Driving Microbial Composition Over Santos Basin, South Atlantic
Authors: Moreira Julio Cezar Fornazier , Modolon Fluvio , Bergo Natascha M , Vieira Danilo C , Fonseca Gustavo , Peres Francielli V , Lizarraga Rebeca GM , Duque-Castano Diana C , Emilio Alice M , Amendola Augusto M , Romano Renato Gamba , Chuqui Mateus Gustavo , Paula Fabiana S , Moreira Daniel Leite , Jonck Celio Roberto , Bendia Amanda G , Brandini Frederico Pereira , Pellizari Vivian Helena
Published: February 2025

Microbial communities in marine ecosystems play a pivotal role in global biogeochemical cycles, with particular relevance in ecologically and industrially significant regions such as the Santos Basin (SB), Brazil's largest marine sedimentary basin and a hub for oil and gas exploration. Yet, our capacity of predicting the microbial community structure and function remains limited for marine ecosystems. This study investigated the structure of microbial communities across different depths in the SB, using amplicon sequencing data and quantitative cell counts obtained via flow cytometry. Using a hybrid machine learning framework combining Self-Organizing Maps and Random Forest, we identified five distinct microbial assemblages (named microbial associations) in the SB predicted with 86% accuracy. These associations were primarily driven by temperature, water density, salinity, and nutrients such as phosphate and nitrate. Our findings showed a clear stratification of microbial communities across pelagic zones, with temperature as the main factor driving the structure in epipelagic and mesopelagic layers, while salinity and density exerted greater influence in the deeper bathypelagic communities. Temporal and spatial variations, particularly between 2019 and 2021, in regions influenced by the Cabo Frio upwelling and Rio de la Plata plume, further highlighted the impact of regional and local oceanographic processes on community dynamics. The associations from deeper waters harbored more diverse microbial assemblages, and shallow waters, on the other hand, possess higher absolute abundance of microbial cells, suggesting niche specialization across depths. This study underscores the importance of environmental gradients as well as local oceanographic processes in shaping microbial diversity, providing valuable insights into the ecological dynamics of the SB, which are essential for understanding the potential impacts of human activities, such as oil and gas exploration and production, on these critical marine ecosystems.
Critical Period Plasticity is Associated with Resilience to Short Unpredictable Stress
Authors: Williams Robert , van den Oord Charlie , Lee Erica , Fedde Samuel , Oscherwitz Gia , Ribic Adema
Published: February 2025

Exposure to stress can increase the risk of depression in susceptible individuals, but not in resilient ones. Resilience to stress decreases with age, parallel to drastic changes in the quality of brain plasticity from juvenile to old age, suggesting that the type of plasticity found in the maturing brain promotes resilience. To indirectly test this, we administered short unpredictable stress to adult male and female mice, as well as to adolescent mice and mice that lack SynCAM 1 and display extended adolescent-like, critical period plasticity in the brain. We found that short unpredictable stress robustly increased core body temperature in all groups of mice, indicative of stress-induced hyperthermia (SIH) and confirming the efficacy of the stress paradigm. However, depressive-like behavior as measured though tail suspension test was increased in adult mice only, supporting that the type of plasticity found in the maturing brain promotes resilience to stress. All three groups of mice showed a mild increase in locomotor activity after stress, suggesting that the quality of plasticity does not correlate with resilience to anxiety-like phenotypes. Our study hence provides further evidence for the protective role of developmental plasticity during stress and points to new mechanisms that promote resilience to stress-induced depression.
Subleading logarithmic behavior in the parquet formalism
Authors: Gievers Marcel , Schmidt Richard , von Delft Jan , Kugler Fabian B.
Published: February 2025

The Fermi-edge singularity in x-ray absorption spectra of metals is a paradigmatic case of a logarithmically divergent perturbation series. Prior work has thoroughly analyzed the leading logarithmic terms. Here, we investigate the perturbation theory beyond leading logarithms and formulate self-consistent equations to incorporate all leading and next-to-leading logarithmic terms. This parquet solution of the Fermi-edge singularity goes beyond the previous first-order parquet solution and sheds new light on the parquet formalism regarding logarithmic behavior. We present numerical results in the Matsubara formalism and discuss the characteristic power laws. We also show that, within the single-boson exchange framework, multi-boson exchange diagrams are needed already at the leading logarithmic level.

Published by the American Physical Society
2025
Fully charmed P-wave tetraquark resonant states in the quark model
Authors: Wu Wei-Lin , Zhu Shi-Lin
Published: February 2025

We conduct the first comprehensive P-wave four-body dynamical calculations of the fully charmed tetraquark systems within the quark potential model. We apply the Gaussian expansion method to solve the four-body Schrödinger equation, incorporating both dimeson and diquark-antidiquark spatial configurations. The matrix elements of P-wave states are calculated analytically using the infinitesimally shifted Gaussian basis functions. With the complex scaling method, we obtain several fully charmed P-wave resonant states with compact tetraquark configuration in the mass region of (7.0, 7.2) GeV, including states with exotic quantum numbers JPC=0−−,1−+. However, we find no resonant states with the mass M<7  GeV and width Γ<200  MeV. Combining the present investigation with our previous results on S-wave fully charmed tetraquark systems [, ], we find no candidates for the experimental states X(6400) and X(6600) in the quark model.

Published by the American Physical Society
2025
How fast can protons decay?
Authors: Davoudiasl Hooman , Denton Peter B.
Published: February 2025

Current laboratory bounds imply that protons are extremely long-lived. However, this conclusion may not hold for all time and in all of space. We find that the proton lifetime can be ∼15 orders of magnitude shorter in the relatively recent past on Earth or at the present time elsewhere in the Milky Way. A number of terrestrial and astrophysical constraints are examined and potential signals are outlined. We also sketch possible models that could lead to spatial or temporal variations in the proton lifetime. A positive signal could be compelling evidence for a new long range force of nature, with important implications for the limitations of fundamental inferences based solely on laboratory measurements.

Published by the American Physical Society
2025