bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 Vaccine Safety Studies among Vulnerable Populations: A Systematic Review and Meta-analysis of 120 Observational Studies and Randomized Clinical Trials
Authors: Mohammadi Sima , Sisay Malede Mequanent , Saraswati Putri Widi , Osman Alhadi Khogali , Zuithoff Nicolaas.P.A , Weibel Daniel , Sturkenboom Miriam , Ahmadizar Fariba
Published: December 2024

BACKGROUND

The COVID-19 vaccines were rapidly developed and tested, but concerns about vaccine-related adverse events remain, especially in vulnerable groups like pregnant women, children, and those with certain health conditions. This review aims to summarize rates of such adverse events in individuals often not included in randomized clinical trials (RCT).

METHOD

From December 2019 to February 2022, we searched Embase and Medline for observational studies and RCTs on adverse events post-COVID-19 vaccination in vulnerable groups. We examined serious and non-serious events in individuals with specific medical conditions, infants, children, pregnant individuals, and socioeconomically disadvantaged individuals. Cumulative risks for all events were calculated. The Incidence rate (IR) and 95% confidence intervals were reported for those studies that met the follow-up period criteria based on the referenced literature. For events with data on exposed and unexposed groups, we calculated the odds ratio. Pooled incidence rates were calculated per 1000 person-days using a random-effects model. Sub-group analyses were conducted based on vaccine types and doses, with heterogeneity assessed using I2.

FINDINGS

Of the 4,254 papers, 235 met eligibility criteria, including 120 studies with 171,073 participants (113 observational, eight RCTs. We examined 17 severe and 7 non-severe adverse event categories. Lymphadenopathy (IR: 1.95[1.20;3.19]), autoimmune disease and multiple sclerosis flare-up (1.13 [0.47;2.68]), and cardiac symptoms (0.26[0.00;10.58]) were the most severe events. Allergic reactions were more common among autoimmune (7.03[4.10;12.06]) and cancer (4.87[2.21;10.76]) groups. vaccinees who received the second dose of vaccine had higher proportions of disease flare-ups (39.27 [18.08;85.31] vs 22.13 [10.22; 47.93]); cardiac symptoms (6.11[2.05-18.22] vs 3.78[2.53-5.65]); and cardiac events (5.34[1.69;16.90] vs 5.05[1.40,18.19]) in observational studies.

INTERPRETATION

This review highlights COVID-19 vaccine safety in vulnerable populations, enhancing vaccination strategies. Further real-world research is needed to validate and extend our findings, especially in addressing safety gaps among vulnerable groups.
Biomolecular Condensates can Induce Local Membrane Potentials
Authors: Gurunian Anthony , Lasker Keren , Deniz Ashok A.
Published: December 2024

Biomolecular condensates are a ubiquitous component of cells, known for their ability to selectively partition and compartmentalize biomolecules without the need for a lipid membrane. Nevertheless, condensates have been shown to interact with lipid membranes in diverse biological processes, such as autophagy and T-cell activation. Since many condensates are known to have a net surface charge density and associated electric potential(s), we hypothesized that they can induce a local membrane potential. Using an electrochromic dye, we demonstrate that poly-lysine/ATP condensates induce a localized membrane potential in Giant Unilamellar Vesicles. This effect diminishes with increasing salt concentration and higher ATP-to-poly-lysine ratios, underscoring the key role of condensate charge. Numerical modeling of the condensate-membrane interface using an electro-thermodynamic framework supports our experimental findings and highlights parameters expected to play a key role in the effect. These results have broad implications for biological processes regulated by membrane potential, particularly in contexts such as neuronal signaling, where condensate interactions with membranes may play a previously unrecognized regulatory role.
Cellular Function of a Biomolecular Condensate Is Determined by Its Ultrastructure
Authors: Scholl Daniel , Boyd Tumara , Latham Andrew P. , Salazar Alexandra , Khan Asma , Boeynaems Steven , Holehouse Alex S. , Lander Gabriel C. , Sali Andrej , Park Donghyun , Deniz Ashok A. , Lasker Keren
Published: December 2024

Biomolecular condensates play key roles in the spatiotemporal regulation of cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ) as a model system, revealing how its material properties and cellular function depend on its ultrastructure. We revealed PopZ’s hierarchical assembly into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques, and molecular dynamics simulations. The helical domain drives filamentation and condensation, while the disordered domain inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client binding sites in the dense phase. These findings establish a multiscale framework that links molecular interactions and condensate ultrastructure to macroscopic material properties that drive cellular function.
Impaired axon regeneration and heightened synaptic dynamics in the injured aged mammalian cortex
Authors: Bass Cher , Bharath Anil A , Paola Vincenzo De
Published: December 2024

How aging affects axon regeneration and synaptic repair in the brain is poorly understood. To study age-related changes in neural circuits, we developed a model of axonal injury in the aged (>2 years) mouse somatosensory cortex. By directly tracking fluorescently labelled injured axons by multiphoton imaging, we find that while axon degeneration in the aged brain is comparable to the young adult brain, axon regeneration is impaired. We further examine changes in the most common type of cortical synapses, En Passant Boutons (EPBs), and observe a transient and significant increase in the number and size of boutons 6 hours post-lesion. Using a computational model of a recurrent neural network, we examined the functional consequences of these synaptic increases on memory, comparing results to models of the young adult brain. The results suggest that increased synaptic dynamics might enable partial recovery from injury via synaptic re-wiring in the aged brain.

Highlights

Impaired axon regeneration in the aged brain is not due to slowed degeneration.

Synaptic reorganization occurs following axon injury in the aged brain.

Synaptic reorganization may serve as a compensatory mechanism after injury.
Keratin 16 spatially inhibits type I interferon responses in stressed skin
Authors: Cohen Erez , Xu Yang , Orosco Amanda , Wang Dajia , Johnson Craig N. , Steen Kaylee , Sarkar Mrinal K. , Özlü Nurhan , Tsoi Lam C , Gudjonsson Johann E. , Parent Carole A. , Coulombe Pierre A.
Published: December 2024

The stress-induced keratin intermediate filament gene/proteinKRT16(K16) is spatially restricted to the suprabasal compartment of the epidermis and extensively used as a biomarker for psoriasis, hidradenitis suppurativa, atopic dermatitis and other inflammatory disorders. However, its role in these conditions remains poorly defined. Here we show that K16 negatively regulates type-I interferon (IFN) signaling and innate immune responses. In mouse skinin vivo,loss ofKrt16leads to exacerbation of imiquimod-induced psoriasiform disease and heightened recruitment of neutrophils in a phorbol ester-induced model of acute sterile inflammation. InKRT16null human keratinocytes, loss of K16 amplifies IFN signaling including phospho-IRF7 and ISG15 after treatment with synthetic dsRNA poly(I:C). Mechanistically, K16 interacts with effectors of the RIG-I-like receptor (RLR) pathway, including 14-3-3ɛ, and inhibits the 14-3-3ɛ:RIG-I interaction upstream of IFN activationin vivoandex vivo. These findings uncover a new paradigm for keratin-dependent regulation of innate immunity, with significant implications for our understanding of inflammatory skin diseases.
CAZyme3D: a database of 3D structures for carbohydrate-active enzymes
Authors: Shanmugam N.R. Siva , Yin Yanbin
Published: December 2024

CAZymes (CarbohydrateActive EnZymes) degrade, synthesize, and modify all complex carbohydrates on Earth. CAZymes are extremely important to research in human health, nutrition, gut microbiome, bioenergy, plant disease, and global carbon recycling. Current CAZyme annotation tools are all based on sequence similarity. A more powerful approach is to detect protein structural similarity between query proteins and known CAZymes indicative of distant homology. Here, we developed CAZyme3D (https://pro.unl.edu/CAZyme3D/) to fill the research gap that no dedicated 3D structure databases are currently available for CAZymes. CAZyme3D contains a total of 870,740 AlphaFold predicted 3D structures (named Whole dataset). A subset of CAZymes 3D structures from 188,574 nonredundant sequences (named ID50 dataset) were subject to structural similarity-based clustering analyses. Such clustering allowed us to organize all CAZyme structures using a hierarchical classification, which includes existing levels defined by the CAZy database (class, clan, family, subfamily) and newly defined levels (subclasses, structural cluster [SC] groups, and SCs). The inter-family structural clustering successfully grouped CAZy families and clans with the same structural folds in the same subclasses. The intra-family structural clustering classified structurally similar CAZymes into SCs, which were further classified into SC groups. SCs and SC groups differed from sequence similarity-based CAZy subfamilies. With CAZyme structures as the search database, we created job submission pages, where users can submit query protein sequences or PDB structures for a structural similarity search. CAZyme3D will be a useful new tool to assist the discovery of novel CAZymes by providing a comprehensive database of CAZyme 3D structures.
Optic Disc and Vessel Segmentation from Fundus Image using Miniunet Architecture
Authors: Jana Subrata
Published: December 2024

The segmentation of the retinal blood vessels significantly impacts the early diagnosis of conditions that affect the eyes, such as diabetes and glaucoma. This work uses fundus pictures to segment retinal blood vessels using mini-Unet algorithms. Many thousands of gloss training samples are required for effective deep network training, which is highly permissible. Mini-Unet starts with a spatial concentration element that multiplies the concentration map by the input feature for adaptive element enhancement and deduces the concentration map in addition to the spatial measurement. Mini-unit architecture creates a structure of a constricting path that enables a particular position. We design three types of primal action, such as Unet_Gatting, AttnGating Block, and convolution, for image segmentation. The mini_unet model is a modified version of the unet model. In Figure 1.1, mention where to modify my techniques. The success of the planned network structure was verified by two segmentation responsibilities: retina vessel segmentation and lung segmentation. Our technique used segmentation of existing DRIVE and STARE datasets. In fundus images using deep learning-based convolutional neural networks. In our technique, accuracy is .95337.
Diazepam modulates anterior cingulate glutamate levels in people at clinical high-risk for psychosis
Authors: Kiemes A. , Livingston N. R. , Lukow P. B. , Knight S. , Jelen L. A. , Reilly T.J. , Dima A. , Nettis M. A. , Lythgoe D.J. , Casetta C. , Egerton A. , Spencer T. , De Micheli A. , Fusar-Poli P. , Grace A. A. , Williams S. C. R. , McGuire P. , Davies C. , Stone J. M. , Modinos G.
Published: December 2024

Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABAAreceptors, can prevent the emergence of behavioural and neurobiological alterations relevant to psychosis in adulthood. Here, we examined this neurochemical mechanism in individuals at clinical high-risk for psychosis (CHRp) in a randomised, double-blind, placebo-controlled crossover study. Twenty-four individuals aged 18-35 were scanned twice using proton magnetic resonance spectroscopy (1H-MRS) to measure anterior cingulate cortex (ACC) Glx (glutamate and glutamine) levels, once after a single dose of diazepam (5 mg), and once after placebo. Mixed-effects model analyses revealed that diazepam reduced ACC Glx levels compared to placebo (t(20.8) = −2.14,p= 0.04). The effect of diazepam on Glx levels was greater in older CHRp individuals (t(12) = −4.36,p= 0.001). These findings suggest that pharmacological modulation of GABAAreceptors can alter glutamatergic changes in psychosis.
Perceived Safety and Mental Health among Asian American Women: Exploring the Moderating Role of Loneliness and Resilience
Authors: Cao Jiepin , Shevrin Sarah , An Linh M. , Wong Jennifer A. , Choi Sugy , Yi Stella S. , Trinh-Shevrin Chau , Lim Sahnah
Published: December 2024

Asian American women are an understudied population facing substantial mental health burden, largely driven by the increasing rates of gender- and race-based violence and discrimination. Perceived safety, a key factor influencing mental health, has been underexplored. This study aimed to 1) examine the relationship between perceived safety with mental health outcomes (i.e., depression and anxiety); 2) examine the link between behavioral changes due to safety concerns and mental health outcomes; and 3) explore the moderating effects of loneliness and resilience on these relationships, drawing from a community sample of n=345 Asian American women. Perceived safety was defined as feeling safe in public spaces, transportation and neighborhoods. In our study, 28.7%, 56.2% and 20.6% of women reported feeling unsafe in public spaces, transportation and neighborhoods, respectively. Feeling unsafe in public spaces was associated with higher odds of depression (aOR=2.37, 95%CI: 1.40, 4.02) and anxiety (aOR=2.61, 95%CI: 1.56, 4.37). Avoiding public spaces, leaving home or transportation were linked to increased odds of depression (aOR=2.05, 95%CI: 1.23, 3.40; aOR=2.26, 95%CI: 1.37, 3.74; aOR=2.03, 95%CI: 1.16, 3.57, respectively) while only avoiding leaving home was associated with anxiety (aOR=2.04, 95%CI: 1.24, 3.36). Loneliness moderated the association between avoiding public spaces and anxiety: women were not lonely who avoided public spaces had significantly higher odds of anxiety (aOR=4.77, 95% CI: 1.24, 18.34), whereas no moderating effect was observed amongst women who were lonely (aOR=0.93, 95% CI: 0.53, 1.64). Resilience did not moderate these relationships (allP>0.050). Our findings highlight the mental health impacts associated with reduced perceptions of safety and avoidance behaviors in this group, highlighting the pervasive fear experienced by Asian American women in their day-to-day lives, and emphasizing the need for targeted interventions to address the unique safety challenges faced by Asian American women.
A Bioinformatics-Driven ceRNA Network in Stomach Adenocarcinoma: Identification of Novel Prognostic mRNA-miRNA-lncRNA Interactions
Authors: Kamal Ebtihal , Omar Zainab Mohammed Mahmoud , Geddawy Ayman , Omer Ahmad AA
Published: December 2024

Stomach adenocarcinoma is a major contributor to worldwide mortality and poses a substantial challenge to improving life expectancy. The main objective of the current work was to identify diagnostic and prognostic biomarkers in stomach adenocarcinoma in order to advance translational medicine and patient outcomes. By accomplishing this objective, the research seeks to provide significant insights into the field of translational medicine. Seven novel unfavourable prognosis-associated genes (NALCN, CALCR, CPT1C, ELAVL3, FLJ16779, MYOZ3, and TPST1) were first identified. Additionally, 41 potential miRNAs were predicted. ELAVL3-hsa-mir-29a-3p and CALCR-hsa-mir-29a-3p axes were identified as two critical pathways in the carcinogenesis of stomach adenocarcinoma via a bioinformatics analysis. Following that, lncRNAs binding to hsa-mir-29a-3p were predicted via starBase and miRNet databases for predicting lncRNA binding sites. After conducting both expression and survival analyses for these predicted lncRNAs, we found that only one lncRNA (KCNQ1OT1) was markedly overexpressed in stomach adenocarcinoma, and its elevated expression was associated with an unfavourable prognosis. Next, we established a comprehensive mRNA-miRNA-lncRNA triple ceRNA network linked to the prognosis of patients with stomach adenocarcinoma. In summary, the current study provides an extensive ceRNA network that highlights novel diagnostic and prognostic biomarkers for stomach adenocarcinoma.
Chromosome end protection by RAP1-mediated inhibition of DNA-PK
Authors: Eickhoff Patrik , Sonmez Ceylan , Fisher Charlotte E.L. , Inian Oviya , Roumeliotis Theodoros I. , dello Stritto Angela , Mansfeld Jörg , Choudhary Jyoti S. , Guettler Sebastian , Lottersberger Francisca , Douglas Max E.
Published: December 2024

During classical non-homologous end joining (cNHEJ), DNA-dependent protein kinase (DNA-PK) encapsulates free DNA ends, forming a recruitment platform for downstream end-joining factors including Ligase 4 (LIG4)1. DNA-PK can also bind telomeres and regulate their resection2–4, but does not initiate cNHEJ at this position. How the end joining process is regulated in this context-specific manner is currently unclear. Here we show that the shelterin components TRF2 and RAP1 form a complex with DNA-PK that directly represses its end joining function at telomeres. Biochemical experiments and cryo-electron microscopy reveal that when bound to TRF2, RAP1 establishes a network of interactions with KU and DNA that prevents DNA-PK from recruiting LIG4. In mouse and human cells, RAP1 is redundant with the Apollo nuclease in repressing cNHEJ at chromosome ends, demonstrating that the inhibition of DNA-PK prevents telomere fusions in parallel with overhang-dependent mechanisms. Our experiments show that the end joining function of DNA-PK is directly and specifically repressed at telomeres, establishing a molecular mechanism for how individual linear chromosomes are maintained in mammalian cells.
Suppression of PCBP1 Enhances PPARγ via TAK1 Modulation to Improve Glycemic and Lipid Metabolism Disorders in Gestational Diabetes Mellitus
Authors: Xia Xuemei , Chen Yan
Published: December 2024

Gestational diabetes mellitus (GDM) affects the health of pregnant women and their fetuses. Poly(C)-binding protein 1 (PCBP1), a multifunctional RNA-binding protein, is pivotal in maintaining cytosolic iron homeostasis. This study sheds light on the role and mechanism of PCBP1 in glucose and lipid metabolism dysregulation in GDM via a high-fat diet-induced GDM mouse model and a palmitic acid (PA)-triggered insulin resistance(IR) model in HepG2 cells. Glucose tolerance and insulin tolerance tests were performed in GDM mice, with lipid metabolism evaluated via hematoxylin-eosin (HE) staining, Oil Red O staining, as well as biochemical assay kits. Glucose content was quantified using the glucose oxidase method, while cell viability was evaluated trough the CCK-8 assay. Apoptotic activity was examined through TUNEL staining, and the expression levels of key proteins, including phosphorylated AKT (p-AKT), phosphorylated IRS1 (p-IRS1), PCBP1, TAK1, and PPARγ, were analyzed through Western blotting. The results demonstrated that GDM mice exhibited profound glucose and lipid metabolism disorders, characterized by significant lipid droplet accumulation in hepatic cells and disrupted insulin signaling pathways. Furthermore, hepatic expression of PCBP1 and TAK1 was notably upregulated, whereas PPARγ expression was significantly reduced. In vitro experiments revealed that silencing PCBP1 alleviated glucose and lipid metabolism abnormalities and improved insulin signaling in PA-induced insulin-resistant HepG2 (IR-HepG2) cells. This intervention also enhanced cell viability and suppressed apoptosis. Further mechanistic studies indicated that inhibition of TAK1 expression facilitated PPARγ upregulation, while TAK1 overexpression negated these effects. Additionally, silencing PPARγ in TAK1-silenced cells reversed the metabolic improvements in IR-HepG2 cells, whereas overexpression of PPARγ mitigated the adverse effects of PCBP1 overexpression. The foregoing findings demonstrate that PCBP1 exerts its effects on glucose and lipid metabolism in GDM via the TAK1/PPARγ signaling axis. Our study highlights the important function of the PCBP1/TAK1/PPARγ signaling pathway in mediating glucose and lipid metabolism in GDM, providing valuable insights into possible therapeutic targets for GDM treatment.
The Impact of Menopause on Hypercholesterolemia and Comorbidities: A Population-Based Study.
Authors: Esteban-Medina Alberto , de la Oliva Victor , Fernandez del Valle Patricia , Sanchez Ana , Susin M. Belen , Loucera Carlos , Dopazo Joaquin , Antinolo Guillermo
Published: December 2024

Background: Hormones play a pivotal role in women's health. Estrogen, for example, not only regulates reproduction but also protects against several chronic conditions, such as heart disease and osteoporosis. As women age, the transition to menopause, a period characterized by a significant drop in estrogen levels, triggers physiological changes that can affect their overall health and quality of life. These changes extend beyond typical menopausal symptoms like hot flashes and vaginal dryness, potentially leading to increased cardiovascular risk, cognitive decline, and bone density loss. Hypercholesterolemia is a critical risk factor for atherosclerotic cardiovascular disease and is associated with significant comorbidities, particularly in postmenopausal women. Understanding the sex-specific differences in the progression and impact of hypercholesterolemia is essential for improving patient outcomes. Objective: This study explores the implications of hormonal transition, particularly menopause, on women's health and highlights the potential of real-world data (RWD) to address these gaps. By integrating sex and gender considerations into clinical decision-making. To achieve so, sex-based differences in the prevalence, progression, and comorbidity patterns of hypercholesterolemia are analyzed at region-wide level, using real-world data (RWD) from the Andalusian Population Health Database (BPS). Methods: A retrospective cohort of 557,034 patients diagnosed with hypercholesterolemia between 2016 and 2022 was analyzed. Patients were stratified by sex and age groups (<50 and ≥50 years). A comparative analysis was performed to assess differences in the prevalence of hypercholesterolemia and associated comorbidities. Results: Women were diagnosed later than men, with an average age of 59.1 years compared to 56.0 years for men. Postmenopausal women exhibited a sharp rise in hypercholesterolemia prevalence, surpassing men in older age groups. Women also displayed higher rates of comorbidities, including osteoporosis, anxiety disorders, and hypertension, particularly during the menopausal transition. The analysis revealed a significant influence of estrogen decline on lipid profiles and comorbidities risk in women. Conversely, men had higher hypercholesterolemia prevalence in younger age groups, likely due to lifestyle and genetic factors. Conclusions: This study demonstrates that menopause is a critical period influencing the progression of hypercholesterolemia and associated comorbidities in women. These findings underscore the importance of sex-specific approaches in the prevention and management of hypercholesterolemia. The use of RWD allowed for a comprehensive evaluation of sex and age disparities, providing actionable insights for clinical practice.
The Way Home: A Scoping Review of Public Health Strategies to Increase the Utilization of Home Dialysis in Chronic Kidney Disease Patients
Authors: Yongphiphatwong Natcha , Teerawattananon Yot , Supapol Pitsinee , Pandejpong Denla , Chuanchaiyakul Tanainan , Sutawong Jiratorn , Gandhi Naline , Kiatkrissada Nutthawongse , Dabak Saudamini Vishwanath , Anothaisintawee Thunyarat
Published: December 2024

Introduction

Home dialysis (HoD) remains underutilized, despite evidence showing it provides comparable mortality rates to in-center hemodialysis (ICHD) while offering advantages such as improved quality of life and lower overall costs. This scoping review comprehensively evaluates the impact of public health interventions on increasing the use of HoD, including both Peritoneal Dialysis (PD) and Home Hemodialysis (HHD).

Methods

Relevant studies were searched in the Web of Science, Medline, Embase, Scopus, EBSCOhost, and EconLit databases from their inception through May 2024. Studies were eligible for review if they assessed the effectiveness of public health interventions in terms of utilization and retention rates for general HoD, PD, and HHD.

Results

Forty-three studies were included, with interventions categorized into three main types: educational programs, service provision improvements, and modifications to payment structures. Our findings indicate that educational interventions—aimed at enhancing knowledge about dialysis options and promoting shared decision-making among patients, families, and healthcare providers—and service provision improvements, such as assisted PD and nephrologist-performed catheter insertions, could significantly increase the initiation, utilization, and retention rates of HoD. However, the impact of payment interventions on HoD outcomes differed across different contexts.

Conclusion

Education and service provision enhancements may represent the most effective public health interventions for increasing initiation, utilization, and retention rates of HoD in dialysis requiring patients. However, these findings are predominantly based on evidence from observational studies; further experimental studies with rigorous methodology are warranted to validate the effectiveness of these interventions in promoting HoD utilization.

PLAIN TEXT SUMMARY

Kidney dialysis is a life-sustaining therapy that can be offered both at home and in medical centres, however, home dialysis is underutilised globally. This scoping review gathers evidence from around the world to identify and assess the effectiveness of public health interventions to improve home dialysis utilization. The interventions we found were mainly related to improving patient knowledge, redesigning service provision, or adjusting payment/reimbursement conditions. Our results suggest that educating patients about their dialysis options to support shared decision-making before they require dialysis and offering assisted peritoneal dialysis at home can help increase the number of patients starting and staying on home dialysis. However, adjusting payment and reimbursement policies showed mixed results.
MentalQLM: A lightweight large language model for mental healthcare based on instruction tuning and dual LoRA modules
Authors: Shi Jiayu , Wang Zexiao , Zhou Jiandong , Liu Chengyu , Sun Poly Z.H. , Zhao Erying , Lu Lei
Published: December 2024

Mental disorders present significant challenges to healthcare systems and carry profound social consequences. The rapid development of large language model (LLM) has opened new avenues for enhancing mental healthcare. However, existing approaches primarily rely on instruction tuning and few-shot in-context learning with massive datasets and large-scale backbone models, resulting in significant computational costs. To address these challenges, we propose MentalQLM, a novel lightweight LLM by developing a new dual Low-rank Adaptation (LoRA) approach. The development of MentalQLM consists of two key stages. Firstly, datasets are pruned based on perplexity and diversity analysis to reduce computational requirements. The first LoRA module is instruction-tuned to adapt the LLM for downstream mental health classification tasks. Secondly, a dense layer augmented with a second LoRA module is fine-tuned to enhance performance on complex multi-class classification tasks. Extensive experiments validate the effectiveness of the proposed MentalQLM on five benchmark datasets. Despite having only 0.5B parameters, the model outperforms or demonstrates comparable performance to larger counterparts in both classification and reasoning tasks. This establishes MentalQLM as a promising solution for lightweight and efficient deployment in realworld mental healthcare applications. All the code will be released athttps://github.com/tortorish/MentalQLM.
Transcriptomic regulation of juvenile-to-adult vegetative phase transition in grapevine
Authors: Ferradás Yolanda , Royo Carolina , Martínez-Zapater José Miguel , Lijavetzky Diego
Published: December 2024

Plants go through two distinct stages in their vegetative phase, with the juvenile stage being characterized by a lack of maturity to respond to flowering induction stimuli and the adult stage marked by the presence of this capacity. Phase transition has been extensively analysed in herbaceous species such as Arabidopsis and maize, where the sequential activity of miR156 and miR172 in the control of the juvenile to adult phase transition has been determined. Contrarily, little is known about most woody perennial crops, where phase transition appears to be dissociated, with a first transition from juvenile to adult vegetative state in the first year and a subsequent induction to flower in later years under flowering-inductive environmental conditions. This significantly extended vegetative phase makes fruit production depend on the grafting of adult vegetative materials. A particular aspect of grapevine vegetative phase transition is that it is marked by the differentiation of tendrils, a modified sterile reproductive organ adapted to climbing, which is continuously generated with different patterns in differentVitisspecies. When the grapevine plant reaches flowering inductive condition in later years, it produces inflorescences in place of some tendrils. As a first step to understand the regulation of phase change in grapevine, we have performed a detailed gene expression analysis of the juvenile-to-adult phase transition during the development of grapevine plantlets grown from seeds. The RNA-seq analysis demonstrated that miR156 was significantly repressed in the grapevine’s adult phase, where the appearance of tendrils acts as a marker of the transition. Consistent with the results reported in other species, we observed the activation of severalSPLgenes, known to be targets of miR156, providing evidence for the conservation of the miR156-SPLs regulatory module in grapevine. However, no variation was detected in the expression of miR172 andTPSgenes were found downregulated, two key determinants in the transition to flowering in other species. This could be explained considering that grapevines do not flower during the first years of growth. Interestingly, we were able to observe the overexpression of several genes known to be involved in the establishment of flower meristem identity, which in the case of grape had also been detected along tendril development, consistent with the proposed common ontogenetic origin of tendrils and inflorescences in theVitaceaefamily.
Controlling reactogenicity while preserving immunogenicity from a self-amplifying RNA vaccine by modulating nucleocytoplasmic transport
Authors: Wojcechowskyj Jason A , Jong Robyn M , Mäger Imre , Flach Britta , Munson Paul V , Mukherjee Pragya , Mertins Barbara , Barcay Katherine R , Folliard Thomas
Published: December 2024

Self-amplifying RNA (saRNA)-based vaccines have emerged as a potent and durable RNA vaccine platform. However, RNA vaccine platforms trigger undesirable side effects at protective doses, underscoring the need for improved tolerability. To address this, we leveraged the Cardiovirus leader protein, which is well-characterized to dampen host innate signaling by modulating nucleocytoplasmic transport (NCT). Co-administration of a leader-protein-encoding mRNA (which we have named “RNAx”) delivered alongside vaccine cargo saRNA reduced interferon production while enhancing Influenza hemagglutinin (HA) expression in human primary cells and murine models. RNAx potently decreased serum biomarkers of reactogenicity after immunizations with an HA-expressing saRNA-LNP vaccine while maintaining the magnitude of the antibody and cellular response. RNAx also consistently enhanced binding antibody titers after a single injection and in some conditions enhanced binding antibody and neutralization titers post-boost. These findings support RNAx as a promising platform approach for improving tolerability of saRNA-LNP vaccines while preserving or enhancing immunogenicity.
Discovery of disease-associated cellular states using ResidPCA in single-cell RNA and ATAC sequencing data
Authors: Carver Shaye , Taraszka Kodi , Groha Stefan , Gusev Alexander
Published: December 2024

To enhance understanding of cellular heterogeneity and disease from single-cell sequencing data, we introduce ResidPCA, a robust method for cell state identification that models cell type heterogeneity. Simulations demonstrate ResidPCA’s efficacy, particularly in complex scenarios, with its accuracy more than four times higher than conventional Principal Component Analysis (PCA) and over three times higher than Non-negative Matrix Factorization (NMF)-based methods in identifying states expressed across multiple cell types. In scRNA-seq data from light-stimulated mouse visual cortex cells, ResidPCA captures stimulus-driven variability with an accuracy more than five times higher than NMF methods. In single nucleus data from an Alzheimer’s disease cohort, ResidPCA identified 44 snATAC-based and 42 snRNA-based states. 30 snATAC states were significantly enriched for Alzheimer’s disease heritability and were often more significantly enriched than established cell types such as microglia. The ResidPCA-based snATAC state most significantly enriched for Alzheimer’s disease heritability further elucidates a recently identified mechanism involving the neuron-ODC-microglial axis. This state links early amyloid production in neurons and oligodendrocytes with later-stage microglial activation and immune response, driving Alzheimer’s disease progression. These results demonstrate ResidPCA’s ability to reveal additional biological variation in single-cell data and uncover disease-relevant cell states.
Transcriptional Dosage of Oncogenic KRAS Drives Lung Adenocarcinoma Cell States, Progression and Metastasis
Authors: Serresi Michela , Cetin Ali Osman , Dramaretska Yuliia , Kertalli Sonia , Schmitt Matthias J. , Naumann Heike , Zschummel Maria , Liesse-Labat Marie , Maciel Lucas F. , Declercq Jeroen , Marine Jean-Christophe , Gargiulo Gaetano
Published: December 2024

Cancer cells display distinct, recurrent phenotypic cell states. Metastatic spreading correlates with tumor cell state evolution. However, the molecular mechanisms underlying metastasis remain elusive. Here, we demonstrate that the quantitative dosage of oncogenic KRAS drives lung adenocarcinoma progression and metastasis via the integration of external signaling and pioneer transcription factor dynamics into qualitative cell states. Combining mouse models, in vivo CRISPR activation screens, and fate mapping, we show that even mild transcriptional amplification of KRAS significantly fuels tumor progression and metastasis. Chromatin profiling and transcriptomics reveal that high and low KRAS dosages supersede and integrate inflammatory and TGFβ signaling to dictate mouse cancer cell states. Patient data show that KRAS dosages correlate with distinct survival outcomes, transcription factor activity, and cell states. Direct KRAS inhibition in xenografts limits the KRAS-high “proliferative” cell state but spares a minimal residual state mimicking the KRAS-low “ciliated-like” state. Thus, oncogenic KRAS dosage fuels tumor heterogeneity at the cell state level and drives a bimodal tumor evolution during metastasis, with implications for prognosis and treatment.
Comprehensive Assessment of a Fasting-Mimicking Diet: Salivary Metabolite Profiles, Weight Loss, and Biomarker Analysis
Authors: Hof Kevin Sebastiaan , Wall Christopher Tadhg
Published: December 2024

Fasting-mimicking diets (FMDs) have shown to result in various health benefits, including body weight reduction, body fat reduction, decreased blood pressure and longevity promoting effects through enhanced ketogenesis and reduced glycolysis. The direct impact of FMDs on metabolite fluctuations, however, remains elusive. Here, we explore the effects of FMDs on the human salivary metabolic profiles and weight in a single-arm case study. Specifically, we present a bio-energetic framework to estimate fat loss as a component of the sustained weight loss, the effects on metabolite quantities involved in energetic reprogramming and the effects on the abundance of metabolites originating from the gut microbiome. These findings highlight the importance of metabolic health tracking to further our understanding of the effects of fasting, personalized nutrition and effective preventive health measures.

In brief

Hof & Wall demonstrate that fasting-mimicking diets have short-term effects on the energy production, energetic reprogramming and gut microbiome output in humans by use of saliva metabolomics and nuclear magnetic resonance (NMR).

Highlights

45% of total sustained weight loss could be attributed to fat loss as calculated by bio-energetic calculation framework

Fasting-mimicking diets increase L-glutamine, L-glutamate and succinic acid indicating immediate effects on energy metabolism

Fasting-mimicking diets increase short-chain fatty acids i.e. acetate, butyrate and propionate. Other gut microbiome metabolites are increased as well i.e. acetoin, fucose and ethanol.
Direct and abscopal anti-tumor responses elicited by peripheral nerve schwannoma irradiation synergize with anti-PD1 treatment in vestibular schwannoma models
Authors: Yin Zhenzhen , Lu Simeng , Wu Limeng , Sun Yao , Blake David W. , Chen Jie , Landegger Lukas D. , Ho William , Xiu Bingyu , Jones Adam P. , Muzikansky Alona , Shih Helen A. , Stankovic Konstantina M. , Plotkin Scott R. , Xu Lei
Published: December 2024

NF2-related schwannomatosis (NF2-SWN) is a progressive and disabling disease requiring effective treatments. The hallmark ofNF2-SWN is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to permanent sensorineural hearing loss and severely impacting patients’ quality of life. Currently, there are no FDA-approved drugs for VS or the associated hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but have not yet been systematically investigated in non-malignant tumors such as VS. In our studies, we demonstrated that combining anti-PD1 (αPD1) treatment with radiation therapy (RT) provides three significant therapeutic benefits: i) Enhanced αPD1 efficacy and immune memory: RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) Reduced RT dose and associated tissue injury: The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) Elicited abscopal effects on cerebellopontine angle (CPA) schwannomas: RT to peripheral nerve tumor induces a systemic abscopal effect, which synergizes with αPD-1 to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. Together, our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS andNF2-SWN.
Fluence rate-dependent kinetics of light-triggered liposomal doxorubicin assessed by quantitative fluorescence-based endoscopic probe
Authors: Rohrbach Daniel J. , Carter Kevin A. , Luo Dandan , Shao Shuai , Aygun-Sunar Semra , Lovell Jonathan F. , Sunar Ulas
Published: December 2024

Liposomal doxorubicin (Dox), a treatment option for recurrent ovarian cancer, often suffers from suboptimal biodistribution and efficacy, which might be addressed with precision drug delivery systems. Here, we introduce a catheter-based endoscopic probe designed for multispectral, quantitative monitoring of light-triggered drug release. This tool utilizes red-light photosensitive porphyrin-phospholipid (PoP), which is encapsulated in liposome bilayers to enhance targeted drug delivery. By integrating diffuse reflectance and fluorescence spectroscopy, our approach not only corrects the effects of tissue optical properties but also ensures accurate drug delivery to deep-seated tumors. Pre-liminary results validate the probe effectiveness in controlled settings, highlighting its potential for future clinical adaptation. This study sets the stage for in vivo applications, enabling the exploration of next-generation treatment paradigms for the management of cancer by optimizing chemotherapy administration with precision and control.
Loss of SynDIG4/PRRT1 alters distribution of AMPA receptors in Rab4- and Rab11-positive endosomes and impairs basal AMPA receptor recycling
Authors: He Chun-Wei , Díaz Elva
Published: December 2024

The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synapse plasticity as well as hippocampal-dependent learning and memory. Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression. These findings suggest that SynDIG4 may play an important role in regulating AMPAR distribution through intracellular trafficking mechanisms; however, the precise roles by which SynDIG4 governs AMPAR distribution remain unclear. In this study, we characterized the endocytosis and recycling of GluA1-containing AMPARs under basal conditions. We did not observe any change in baseline endocytosis; however, we did observe a significant decrease in recycling of GluA1-containing AMPARs in cultured hippocampal neurons from mice lacking SynDIG4. This resulted in a significant increase in the levels of internal GluA1 and GluA2, along with greater colocalization of these subunits with Rab4-positive recycling endosomes in hippocampal neurons lacking SynDIG4. Notably, the overlap between Rab4- and Rab11-positive vesicles was elevated in hippocampal neurons lacking SynDIG4, suggesting an impairment in the trafficking between Rab4 and Rab11 compartments. Furthermore, our findings revealed a reduction in surface GluA1 within synaptic regions of hippocampal neurons lacking SynDIG4. Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions. This regulatory function of SynDIG4 may contribute to the deficits in GluA1-dependent synaptic plasticity and impairment of hippocampal-dependent learning and memory behaviors observed in SynDIG4 deficient mice.
Single-cell analysis reveals distinct immune characteristics of hepatocellular carcinoma in HBV-positive versus HBV-negative cases
Authors: Liu Ke , Chen Erbao , Liang Jiaming , Li Yanyan , Cheng Binghua , Shi Wenli , Zhou Zeyu , Zhou Wenjie , Tian Hui , Yang Dongye , Shao Ximing , Li Hongchang
Published: December 2024

Infection with the Hepatitis B virus (HBV) is a key risk factor for Hepatocellular carcinoma (HCC) development and progression. It is widely recognized that immunopathological mechanisms are pivotal in developing HBV-related HCC. Nevertheless, the specific mechanisms by which HBV-induced modifications within the tumor microenvironment (TME) contribute to HCC pathogenesis are still not well understood. Here, we utilized single-cell RNA sequencing to analyze and compare the immune landscapes between HBV-positive and HBV-negative HCC. We discovered that HBV infection significantly modifies the immune cell makeup and state, and leads to the suppression and exhaustion of T cells within the TME. Specifically, an increase in SLC4A10+ CD8+ T cells and IFITM3+ macrophages was observed, along with the upregulation of the gene SLC35F1 in various immune cell subtypes. These findings offer valuable insights into the alteration of the immunological microenvironment in HCC associated with HBV infection, suggesting possible targets for immunotherapeutic intervention.
The Basal Ciliary but not Cytosol PKA Specifically Regulates HH Pathway Downstream of Smoothened
Authors: Zhang Hongyu , Huang Zhuoya , Chen Shujing , Chen Guangxin , Ben Jin , Ingham Philip , Zhao Zhonghua
Published: December 2024

Effectors of the vertebrate Hedgehog (HH) signaling pathway are organized through primary cilia (PC) that grow and retract in lockstep with the cell cycle in response to extracellular signals. Protein kinase A (PKA), a kinase with ubiquitous distribution in most cells, functions as a specific negative regulator of the HH pathway. Its functional specificity in the HH pathway has been suggested to be controlled by cAMP in the PC. However, the regulation of PKA and its functions in PC is still poorly elucidated, partially due to the lack of observation of PKA localization in PC and inconsistency in the fluctuation of ciliary cAMP with HH pathway activity. Herein, we have developed an effective biosensor for monitoring real-time PKA activity in the PC of both cultured cells and zebrafish embryos, using a ciliary specific localized FRET-based A-kinase activity probe (Nphp3N-AKAR2-CR). Although the PKA catalytic subunit (PKA-C) was not observed in PC, ciliary PKA basal activity in cells was detected by Nphp3N-AKAR2-CR. Notably, its activity was modestly increased both by inhibition and activation of the HH pathway at the level of Smoothened (Smo). In addition, we have found that only ciliary-targeted PKA and not cytosolic PKA, can specifically modulate the HH pathway, even when the integrity of the PC is disrupted. Our results suggest that a basal level of PKA activity in the PC maintains the HH pathway in the OFF state and that PKA mediated inhibition is countered by changes in GLI concentration in the PC.