bluuebunny/crossref_metadata_2025 huggingface dataset:
Local nucleolar surveillance mechanisms maintain rDNA stability
Authors: Liu Ruofei , Xuan Jiachen , Pan Junqi , Chelliah Shalini Sundramurthi , Dmello Rhynelle , Cowley Karla J. , Mendez Shannon , Zhang Yangyi , Gitareja Kezia , Wakefield Matthew , Deans Andrew , Scott Clare , Chan Keefe T. , Simpson Kaylene J. , Kang Jian , Sanij Elaine
Published: January 2025

The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. The highly repetitive and transcribed nature of the rRNA genes (rDNA) by RNA polymerase I (Pol I) poses a challenge for DNA repair and replication machineries. Here, we profile the nucleolar proteome and the chromatin landscape of stalled replication sites upon rDNA damage to characterize the early steps of nucleolar DNA damage response (nDDR). We observed early dynamics in nucleolar-nucleoplasmic proteome localization and identified nucleolar replication stress signatures involving chromatin remodeling networks, transcription-replication conflicts and DNA repair. Our findings define localized surveillance mechanisms that activate the nDDR. Further, we identified that upon rDNA damage, nucleolar RNA Polymerase (Pol) II binds to intergenic rDNA sequences and generates R-loops (DNA:RNA hybrid structures) that are essential for recruiting nDDR factors. Using a boutique CRISPR-Cas9 synthetic lethal screen of DNA repair factors with inhibitors of RNA Pol I transcription, we identified an unexpected protective role for the DNA translocase RAD54L in nDDR. Loss of Rad54L increases nucleolar R-loops and rDNA damage leading to defects in nucleolar structure and enhanced sensitivity to PARP and RNA Pol I inhibitors. Altogether, our study uncovers localized surveillance networks within the nucleolus that respond to rDNA damage. These insights expand our understanding of the molecular mechanisms governing nDDR and opens new avenues for developing nDDR-targeting therapies.
Autism-Associated Genes and Neighboring lncRNAs Converge on Key Gene Regulatory Networks
Authors: Andersen Rebecca E. , Talukdar Maya , Sakamoto Tyler , Song Janet H.T. , Qian Xuyu , Lee Seungil , Delgado Ryan N. , Zhao Sijing , Eichfeld Gwenyth , Harms Julia , Walsh Christopher A.
Published: January 2025

The diversity of genes implicated in autism spectrum disorder (ASD) creates challenges for identifying core pathophysiological mechanisms. Aggregation of seven different classes of genetic variants implicated in ASD, in a database we callConsensus-ASD, reveals shared features across distinct types of ASD variants. Functional interrogation of 19 ASD genes and 9 neighboring long non-coding RNAs (lncRNAs) using CRISPR-Cas13 strikingly revealed differential gene expression profiles that were significantly enriched for other ASD genes. Furthermore, construction of a gene regulatory network (GRN) enabled the identification of central regulators that exhibit convergently altered activity upon ASD gene disruption. Thus, this study reveals how perturbing distinct ASD-associated genes can lead to shared, broad dysregulation of GRNs with critical relevance to ASD. This provides a crucial framework for understanding how diverse genes, including lncRNAs, can play convergent roles in key neurodevelopmental processes and ultimately contribute to ASD.
Retinal and Optic Nerve Lesions Correspond to Amyloid in Autosomal Dominant Alzheimer’s Disease
Authors: Kashani Amir H , Koronyo-Hamaoui Maya , Koronyo Yosef , Shi Haoshen , Alluwimi Muhammed , Singer Maxwell , Sagare Abhay , Hawes Debra , Tang Anna , Jiang Xuejuan , Collazo Martinez Ana , Ross-Cisneros Fred N. , Sadun Alfredo A. , Ringman John M.
Published: January 2025

Autosomal dominant Alzheimer’s disease (ADAD) is a rare form of Alzheimer’s disease (AD) in which the biology of the disease can be explored during the presymptomatic phase of the illness. The retina is an outgrowth of the central nervous system and therefore provides the opportunity for direct observation of neural tissue and its vasculature during life. Retinal thinning measuredin vivohas been previously described in persons carrying ADAD mutations through fundoscopy but its pathologic correlates have not been reported.

We describe retinal lesions detected using fundoscopyin vivoin a patient homozygous for the A431E mutation inPSEN1and its pathological correlates. Retinal lesions seen with fundoscopy during life corresponded to intraretinal and prelaminar optic nerve head amyloid β42-protein that were surrounded by perivascular anti-11A50-B10-Aβ40and gliosis. We then performed a cross-sectional, observational study of forty-one Latinos in three cohorts consisting of (1) persons with ADAD causing mutations, (2) at 50% risk for, but testing negative for ADAD mutations, and (3) elderly subjects not at-risk for ADAD.

Clinical exam demonstrated novel, yellow, intraretinal lesions in Cohort 1 in absence of drusen. Fifty-six percent of Cohort 1 subjects had >10 retinal lesions compared to 0% and 25% for Cohorts 2 and 3, respectively (P< 0.04). There has been some controversy as to the detectability of Aβ in the retina of persons with AD during life and our findings verify the presence of intraretinal, prelaminar, and perivascular amyloidosis detectable during life in a subset of AD patients.
Modelling the impact of changes to prescription medicine cost-sharing schemes among middle aged and older adults
Authors: Larkin James , Prendergast Ciaran , Murry Logan T. , Flood Michelle , Clyne Barbara , Burke Sara , Keegan Conor , Boland Fiona , Fahey Tom , Persaud Nav , Kenny Rose Anne , Moriarty Frank
Published: January 2025

Objective

To assess impacts of government changes to prescription medicine co-payments on individuals’ out-of-pocket prescription medicine expenditure.

Methods

Data from The Irish Longitudinal Study on Ageing were used. Participants were community-dwelling adults aged ≥56 years. Ireland has two prescription cost-sharing schemes: the General Medical Services (GMS) scheme (primarily for low-income populations), involving a low monthly payment cap and low co-payments, and the Drugs Payment Scheme (DPS) (for others), with a higher cap and no co-payment limit. We modelled changes to these schemes implemented between 2016-2022 using 2016 data, assessing impacts on out-of-pocket prescription medicine expenditure across participant characteristics.

Results

Among 4,155 participants with out-of-pocket prescription medicine expenditure, estimated mean annual prescription medicine expenditure for GMS-eligible participants reduced from €117 (95%CI=€114-120) to €55 (95%CI=€54-€56) due to post-2016 scheme changes. For DPS-eligible participants it reduced from €719 (95%CI=€694-€744) to €555 (95%CI=€541-€569). Those on more medicines had greater savings, with similar savings across income groups.

Conclusions

Co-payment changes led to average savings of €62 for GMS-eligible participants and €174 for DPS-eligible participants. Although absolute savings were smaller for GMS participants, these were likely more impactful for this low-income population. Further reductions in monthly caps and co-payment charges, particularly for low-income populations, warrant consideration.
Impact of the COVID-19 pandemic on regional and national uptake of HIV testing services in Sierra Leone: a descriptive analysis
Authors: Sheriff Hannah , Egesimba Ginika , Molleh Bailah , Tucker Jarieu , Younge Gerald , Tamba Francis K. , Lakoh Sulaiman , Chan Adrienne K. , Mishra Sharmistha , Sevalie Stephen
Published: January 2025

Background

A key milestone in the reduction of the global HIV burden is reaching the UNAIDS 95-95-95 target by 2025. The COVID-19 pandemic may have affected the ability of countries to achieve this target, but data to describe this impact is limited. This study assessed national HIV testing service uptake in Sierra Leone during three periods of the COVID-19 pandemic.

Methods

We conducted a retrospective cross-sectional study using secondary program data of all patients tested for HIV in all 16 districts of Sierra Leone. Data from March 2019 to February 2020 (pre-COVID-19); March 2020 to February 2021 (during COVID-19); and March 2021 to February 2022 (post-COVID-19) were extracted from DHIS-2 and descriptive analyses were performed using Stata (15.1, StataCorp LLC, College Station, TX).

Results

The median number of HIV tests was 58,588 (IQR 54,232 to 62,077) in the pre-COVID phase, 55,141 (IQR 52,975 to 57,689) during the COVID-19 phase, and 74,954 (IQR 72,166 to 76,250) in the post-COVID phase. This shows that HIV testing rate decreased by 6.3% during the COVID-19 period and increased substantially by 36.0% in the post-COVID-19 period. Twice more women than men were tested for HIV across all periods—pre-COVID-19 (38,825 vs. 19,789), during COVID-19 (36,923 vs. 17,755), and post-COVID-19 (49,205 vs. 25,472) phases.

Conclusion

Our study shows that HIV testing was significantly disrupted during the COVID-19 pandemic but recovered quickly after the pandemic. These findings highlight that lessons learned from previous epidemics may influence adaptive strategies to maintain essential health services during public health emergencies.
Baseline associations between exposure to metals and systolic and diastolic blood pressure among women in the Household Air Pollution Intervention Network Trial
Authors: Karakwende Patrick , Barr Dana Boyd , Checkley William , Clasen Thomas , Lovvorn Amy , Contreras Carmen Lucía , Diaz Anaite A. , Dusabimana Ephrem , Las Fuentes Lisa De , Jabbarzadeh Shirin , Johnson Michael , Kalisa Egide , Kirby Miles , McCracken John P. , Ndagijimana Florien , Ndikubwimana Adolphe , Ntakirutimana Theoneste , de Dieu Ntivuguruzwa Jean , Jennifer L , Peel Ajay Pillarisetti , Davila-Roman Victor G. , Rosa Ghislaine , Waller Lance A. , Wang Jiantong , Thompson Lisa , Clark Maggie L. , Young Bonnie N.
Published: January 2025

Lead (Pb) and cadmium (Cd) are metals that occur naturally in the environment and are present in biomass fuels, such as wood. When these fuels are burned, they can release Pb and Cd into the air, leading to exposure through inhalation. Studies of exposure to metals and health outcomes suggest harmful impacts, including cardiovascular diseases. We assessed baseline associations between Pb and Cd concentrations in dried blood spots with systolic and diastolic blood pressure (SBP, DBP) among women in the Household Air Pollution Intervention Network (HAPIN) trial. We analyzed data from three of the four HAPIN randomized controlled trial sites (Guatemala, Peru, and Rwanda), focusing on women aged 40 to 79 years living in households reliant on biomass cooking. Dried blood spots were collected, processed, and analyzed for Pb and Cd exposure; SBP and DBP were measured following international guidelines. Demographic, socioeconomic, and dietary variables were collected via standardized questionnaires administered by local field staff. Statistical analyses included multivariable linear regression to examine associations between Pb and Cd, separately, and BP, adjusting for covariates informed by a Directed Acyclic Graph. Additional analyses assessed effect modification by age and research site. There was regional variation in BP levels among women, with median SBP and DBP values higher in Rwanda (116.3 mmHg, 73.0 mmHg) and Guatemala (113.3 mmHg, 68.3 mmHg) compared to Peru (106.0 mmHg, 63.3 mmHg). Pb exposure showed positive associations with both SBP and DBP. For each log-unit increase in Pb concentration, we observed increases of 2.36 mmHg SBP (95% CI 0.51, 4.20) and 1.42 mmHg DBP (95% CI 0.16, 2.67). Cd was not associated with SBP or DBP in this analysis. Pb exposure may be an important risk factor for increased SBP and DBP, markers of cardiovascular disease risk.
Applying an Intersectional Approach to Examine the Associations between Sexual Minority Stressors, Resilience, and Substance Misuse Disparities among a National Sample of Sexual Minority Populations
Authors: Zhang Chen , Qiao Shan , Chang Wonkyung , Liu Yu
Published: January 2025

Objectives

Our study aims to investigate the associations between sexual minority stressors, resilience factors, and substance misuse outcomes, using an intersectional framework to examine heterogeneities across sexual minority populations (SMPs). The study hypothesized that resilience factors would mitigate the adverse effects of minority stressors on alcohol and drug misuse risks.

Design

The current study employed a secondary data analysis strategy to analyze a cross-sectional data using Bayesian hierarchical modeling and Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA).

Setting

Data were obtained from the Generation Study (Wave 1), a nationally representative cohort of SMPs in the United States.

Participants

The study included 1,518 participants aged 18–59. Combinations of education, birth sex, sexual orientation, income, and race/ethnicity defined intersectional strata. Participants were selected based on self-reported demographic and behavioral data.

Primary and Secondary Outcome Measures

Primary outcomes were the risks of alcohol use disorder (AUD) and drug use disorder (DUD), measured using validated scales (AUDIT and DUDIT). Explanatory variables included resilience factors (social support, life satisfaction, social well-being, community connectedness) and sexual minority stressors (everyday discrimination, perceived stigma, healthcare stereotype threat, internalized homophobia).

Results

Bayesian modeling identified everyday discrimination as the strongest predictor of AUD (Estimate = 0.10, 95% CI [0.01, 0.18]) and DUD (Estimate = 0.23, 95% CI [0.15, 0.32]). Perceived stigma was negatively associated with AUD risk (Estimate = –0.06, 95% CI [-0.12, 0.00]), and social well-being was inversely associated with DUD risk (Estimate = –0.17, 95% CI [-0.23, –0.10]). MAIHDA revealed that intersectional strata contributed to 1.61% of the variance in AUDIT scores and 1.88% in DUDIT scores. Including resilience and stressors in the model explained 93.6% of the strata-level variance for AUDIT and 34.45% for DUDIT, underscoring the significant impact of these factors on substance misuse disparities.

Conclusions

The findings highlight the complex interplay between resilience, stressors, and intersectional identities in substance use behaviors among SMPs. Using an intersectional framework and MAIHDA can enhance understanding of heterogeneities in substance misuse across strata and inform targeted, equity-focused interventions to reduce disparities. Further research should explore longitudinal effects and intervention development.
Real world data analysis of venous thromboembolism, adverse major cardiovascular events, neoplasia and serious infections in ulcerative colitis patients
Authors: de la Oliva Víctor , Esteban-Medina Alberto , Fernández del Valle Patricia , Sánchez Ana , Susin M. Belen , Dopazo Joaquín , Loucera Carlos , Leo-Carnerero Eduardo
Published: January 2025

Venous thromboembolism (VTE), major adverse cardiovascular events (MACE), neoplasia, and serious infections are significant complications associated with Immune-mediated inflammatory diseases. Actually, the occurrence of such complications in these patients has been observed to be higher than that anticipated from classical risk factors alone. Additionally, the administration of anti-inflammatory treatments, such as corticosteroids, associated to inflammatory diseases is recognized to further elevate this risk. In Spain, data on the prevalence of risk of cardiovascular events, neoplasia or serious infections, particularly among individuals with ulcerative colitis are scarce. This study leverages real-world data from the Andalusian Health Population Database (BPS) to analyze the incidence and risk factors of these complications among ulcerative colitis patients. A cohort of 23,518 patients, aged 18 years or older, with an ulcerative colitis diagnosis between 2010 and 2019, was used in the study. The objective was to assess the incidence of VTE, MACE, neoplasms, and serious infections and to evaluate the impact of age and other factors related to ulcerative colitis on these outcomes.

The study revealed a notably higher incidence of VTE and MACE in ulcerative colitis patients compared to the incidence described for the general population, particularly among those over 60 years of age. Specifically, the incidence of VTE was significantly elevated post-diagnosis, with deep vein thrombosis (DVT) and pulmonary embolism, being the most common manifestations. MACE, including myocardial infarction and stroke, also presented a higher risk, especially in older patients. Also, a significant portion of patients developed various malignancies. Also remarkable is the significant higher incidence of VTE, malignancies and serious infections as the severity of ulcerative colitis increases. The use of immunosuppressive therapies was associated with an increased risk of infections, and likely with VTE and malignancies, further complicating the management of these patients.

The findings of this study underscore the need for heightened vigilance in the management of ulcerative colitis patients, particularly those at advanced ages. Preventive strategies, such as thromboprophylaxis during hospitalization and regular monitoring for cardiovascular and neoplastic complications, are essential. The study contributes valuable insights into the burden of comorbidities in ulcerative colitis and highlights the importance of tailored treatment and monitoring strategies to improve patient outcomes.
Host environment shapes filarial parasite fitness andWolbachiaendosymbionts dynamics
Authors: Fercoq Frédéric , Cormerais Clément , Remion Estelle , Gal Joséphine , Plisson Julien , Fall Arame , Alonso Joy , Lhermitte-Vallarino Nathaly , Hübner Marc P. , Kohl Linda , Landmann Frédéric , Martin Coralie
Published: January 2025

Filarial nematodes, responsible for diseases like lymphatic filariasis and onchocerciasis, depend on symbioticWolbachiabacteria for reproduction and development. Using theLitomosoides sigmodontisrodent model, we investigated how host type-2 immunity influencesWolbachiadynamics and parasite development. Type-2 immune environments selectively reduce germlineWolbachiain female filariae from wild-type mice, a change associated with disrupted oogenesis, embryogenesis, and microfilarial production, while somaticWolbachiaremain unaffected. Antibiotic treatments achieving systemicWolbachiaclearance result in similar reproductive impairments. Notably,Wolbachia-free microfilariae are observed shortly afterWolbachiadepletion, suggesting that early-stage embryogenesis can proceed temporarily before progressive germline dysfunction ensues.Wolbachia-free microfilariae develop into infective larvae in the vector, but stall beyond the L4 stage in vertebrate hosts, showing arrested growth and reproductive organ maturation defects in both male and female larvae. These findings highlight the variable dependency onWolbachiaacross life stages and provide insights into host-parasite-endosymbiont interactions shaped by environmental pressures.

Graphical abstract.
Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions
Authors: Mao Suifang , Song Rui , Jin Shibo , Pang Song , Jovanovic Aleksandra , Zimmerman Adam , Li Peng , Wu Xinying , Wendland Michael F. , Lin Kerry , Chen Wei-Chi , Choksi Semil P. , Chen Gang , Holtzman Michael J. , Reiter Jeremy F. , Wan Ying , Xuan Zhenyu , Xiang Yang K. , Xu C Shan , Upadhyayula Srigokul , Hess Harald F. , He Lin
Published: January 2025

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by Smo/Gαi/cAMP pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in developing choroid plexus, a derepression of Aqp1 and Atp1a2, and ultimately, an increased CSF production. Hence, developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.
Atom-level Machine Learning of Protein-glycan Interactions and Cross-chiral Recognition in Glycobiology
Authors: Carpenter Eric J. , Peng Chuanhao , Wang Sheng-Kai , Greiner Russell , Derda Ratmir
Published: January 2025

Cross-chiral recognition in glycobiology is the interactions between biologically conventional proteins and the enantiomers of biological glycans (e.g., L-proteins binding with L-hexoses) from organisms across all kingdoms of life. By symmetry, it also describes the interactions of chirally mirrored proteins with normal D-glycans. Knowledge of cross-chiral recognition is critical to understanding the potential interactions of existing life forms with artificial mirror-life forms, but currently known rules of protein-glycan interaction are insufficient. To build a methodology for learning such interactions, we constructed machine learning models that predict binding strength between proteins and glycans represented as graphs of atoms, rather than monosaccharides. Atomic q-gram and Morgan fingerprint (MF) based representation of glycans made it possible to train ML models that predict lectin binding properties of glycans, glycomimetic compounds, and enantiomers of all natural glycans. Critical to this training was merging disparate data—some with relative fluorescence units (RFU) from glycan microarrays and others with Kd values from ITC—using a universal "fraction bound" parameter f at a specific lectin concentration. A fully-connected neural network architecture, MCNet takes a MF and concentration (C) as inputs and returns f for 147 lectins. Performance of MCNet is comparable to the GlyNet models, and by proxy to other state-of-the art models that predict strength of protein-glycan interactions. MCNet effectively predicts binding of glycomimetic compounds to Galectins 1, 3, and 7. Breaking from a monosaccharide-based description makes it possible for MCNet to predict cross-chiral recognition. We employed a Liquid Glycan Array to validate some predictions, such as the lack of interactions of L-mannose with D-mannose binding lectins, purified ConA, and DC-SIGN displayed on cells, and weak binding of L-Man to galactose-binding lectins. MCNet's atom-level input makes it possible to agglomerate protein-glycan data from diverse glycans across all kingdoms of life and non-glycan structures (e.g. glycomimetic compounds). The universal fraction bound parameter makes it possible to unify disparate quantitative observations (Kd/IC50, RFU, chromatographic retention times, etc.). We believe that such an approach will facilitate a merger of knowledge from diverse glycobiology datasets and predict protein interactions with uncommon/unnatural glycans not attainable from current ML models.
Single-cell spatial transcriptome reveals pathological features of human hippocampus with sclerosis
Authors: Wang Lifang , Li Xingjie , Liu Yuyang , Jin Bufan , Wei Yanrong , He Youzhe , Ma Yaru , Wu Zihan , Gong Xue , An Yanru , Kong Xueying , Xing Yanan , Ye Ruixi , Tao Quyuan , Li Aiqing , Chang Mingkai , Pu Li , Li Jinmei , Pang Li , Zhou Dong , Song Cai , Liu Shiping , Xu Xun , Liu Longqi , Han Lei , Hong Zhen
Published: January 2025

More than half of epileptic patients ultimately turned to intractable epilepsy. Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), the most common type of intractable epilepsies, whose pathological mechanism remains elusive. Here, using 42 human hippocampal samples from surgical donors of MTLE (32 with and 10 without HS) through single-cell resolution Stereo-seq and histologcial experiments, we revealed spatially pathological changes of gene expression and cell type composition with HS systematically. After precise parcellation of hippocampal subregions and differentially expressed gene (DEG) analysis between each region with and without sclerosis, we found Cornu Ammonis (CA) subregions with higher number of DEGs were vulnerable to sclerosis, especially CA1 and CA3. Within CA1, we found that CA1-superficial and proximal areas were more vulnerable than CA1-deep and distal areas in sclerosis. Meanwhile, after analyzing 350,795 segmented cells from Stereo-seq, we found dramatically increasing density of astrocyte accompanied with significantly decreasing density of excitatory neurons in CA1, especially superficial and proximal CA1, and CA3 in sclerosis. In these two vulnerable subregions, proliferative astrocyte (P_astrocyte) and reactive astrocyte (R_astrocyte) were found to be enriched whereas apoptotic subtype of astrocyte (A_astrocyte), related with apoptotic pathway, was mainly located in alveus, which strengthened cell communication with reactive microglia (R_microglia) in HS, revealing the novel pathological feature in our work. The pseudotime analysis indicated that CA excitatory neurons underwent synaptic impairment, energy dysfunction, aging, and finally losing cell identity until death through autophagy or apoptosis. Besides, we also found a resilient subtype, EX_CA2-4.3, highly expressed extracellular matrix related genes includingPDYN, and was increasing the interaction of BDNF-NTRK, NFASC-CNTN1 to withstand the damage from sclerosis. Together, our study provided a reference of human hippocampus with and without HS caused by MTLE, and highlighted the potential pathological mechanism on molecular and cellular level of MTLE-HS.
Peptide Design through Binding Interface Mimicry
Authors: Kong Xiangzhe , Jiao Rui , Lin Haowei , Guo Ruihan , Huang Wenbing , Ma Wei-Ying , Wang Zihua , Liu Yang , Ma Jianzhu
Published: January 2025

Peptides offer distinct advantages for targeted therapy, including oral bioavailability, cellular permeability, and high specificity, which set them apart from conventional small molecules and biologics. In this work, we developed an AI algorithm, named PepMimic, to transform a known protein receptor or an existing antibody of a target into a short peptide drug by mimicking the binding interfaces between targets and known binders. The structural root mean square deviation and interface DockQ with reference binders were 61% and 75% better than the best existing methods on the PepBench datasets. We then applied this novel peptide-design methodology to five drug targets: PD-L1, CD38, BCMA, HER2, and CD4. SPRi results show that 8% of the peptides exhibited dissociation constant (KD) values at the 10-8M level, and 26 peptides achieving KDvalues as low as 10-9M. This success rate was 20,000 times higher than that observed in a random library screening conducted under identical conditions. PepMimic was applied to target proteins lacking available binders by first utilizing AI algorithms to design protein binders, followed by the generation of peptides through simulation of these artificial interfaces. The top-ranked peptides underwent extensive cellular validation andin vivotesting through tail vein injections in breast, myeloma, and lung tumor mouse models. Experimental results demonstrated effective membrane binding and highlighted the strong potential of these peptides for clinical diagnostic imaging and targeted therapeutic applications.
Characterising ongoing brain aging from cross-sectional data
Authors: Smith Stephen M. , Miller Karla L. , Nichols Thomas E.
Published: January 2025

“Brain age delta” is the difference between age estimated from brain imaging data and actual age. Positive delta in adults is normally interpreted as implying that an individual is aging (or has aged) faster than the population norm, an indicator of unhealthy aging. Unfortunately, from cross-sectional (single timepoint) imaging data, it is impossible to know whether a single individual’s positive delta reflects a state of faster ongoing aging, or an unvarying trait (in other words, a “historical baseline effect” in the context of the population being studied). However, for a cross-sectional dataset comprising many individuals, one could attempt to disambiguate the overall relative contributions of varying aging rates vs. fixed baseline effects. We present a method for doing this, and show that for the most common approaches, which estimate a single delta per subject, baseline effects are likely to dominate. If instead one estimates multiple biologically distinct modes of brain aging, we find that some modes do reflect aging rates varying strongly across subjects. We demonstrate this, and verify our modelling, using longitudinal (two timepoint) data from 4,400 participants in UK Biobank. In addition, whereas previous work found incompatibility between cross-sectional and longitudinal brain aging, we show that careful data processing does show consistency between cross-sectional and longitudinal results.
Defining the cell and molecular origins of the primate ovarian reserve
Authors: Wamaitha Sissy E. , Rojas Ernesto J. , Monticolo Francesco , Hsu Fei-man , Sosa Enrique , Mackie Amanda M. , Oyama Kiana , Custer Maggie , Murphy Melinda , Laird Diana J. , Shu Jian , Hennebold Jon D. , Clark Amander T.
Published: January 2025

The primate ovarian reserve is established during late fetal development and consists of quiescent primordial follicles in the ovarian cortex, each composed of granulosa cells surrounding an oocyte in dictate. As late stages of fetal development are not routinely accessible for study with human tissue, we exploited the evolutionary proximity of the rhesus macaque to investigate primate follicle formation. Similar to human prenatal ovaries, the rhesus also develops multiple types of pre-granulosa (PG) cells, with the majority of primordial follicles derived from PG2 with small variable contributions from PG1. We observed that activated medullary follicles recruit fetal theca cells to establish a two-cell system for sex-steroid hormone production prior to birth, providing a cell-based explanation for mini puberty.
Meta all the way down: An overview of neuroimaging meta-analyses
Authors: Oudyk Kendra , Dockès Jérôme , Peraza Julio , Kent James , Torabi Mohammad , Wang Michelle , McPherson Brent , Mirhakimi Niusha , de la Vega Alejandro , Laird Angela R. , Poline JB
Published: January 2025

Meta-analyses are invaluable tools for navigating the rapidly expanding scientific literature. Given their high value, ensuring the quality of meta-analyses is paramount. We conducted a multifaceted overview, examining each step in a manual neuroimaging meta-analysis on a large scale. We used four novel datasets comprising over 14,000 papers, including fMRI meta-analyses, fMRI studies, studies included in meta-analyses, and studies associated with image data on NeuroVault.

Regarding successes, two-thirds of meta-analyses stated that they followed PRISMA guidelines, and 65% included a flowchart describing their inclusion process.

We point out several areas for improvement. Pre-registration was fairly rare (20%), and only half listed their exact search strategy. There could be a location bias in which papers are included, and many did not include enough studies to be robust against publication bias (68% of meta analyses have less than 30 studies included).

We also offer ideas for future directions. As image based meta-analysis is the gold standard, we have indicated which topics have the most image data available. The potential redundancy of topics can be visualized in our paper, and we recommend future meta-analyses be in conversation with past ones by citing and discussing previous similar work. By addressing these findings, the neuroimaging community can collectively improve the field of neuroimaging meta-analyses.
Cholinergic dynamics in the septo-hippocampal system provide phasic multiplexed signals for spatial novelty and correlate with behavioral states
Authors: Moghadam Fatemeh Farokhi , Guzman Blanca E. Gutierrez , Zheng Xihui , Parsa Mina , Hozyen Lojy M. , Dannenberg Holger
Published: January 2025

In the hippocampal formation, cholinergic modulation from the medial septum/diagonal band of Broca (MSDB) is known to correlate with the speed of an animal’s movements at sub-second timescales and also supports spatial memory formation. Yet, the extent to which sub-second cholinergic dynamics, if at all, align with transient behavioral and cognitive states supporting the encoding of novel spatial information remains unknown. In this study, we used fiber photometry to record the temporal dynamics in the population activity of septo-hippocampal cholinergic neurons at sub-second resolution during a hippocampus-dependent object location memory task using ChAT-Cre mice. Using a general linear model, we quantified the extent to which cholinergic dynamics were explained by changes in movement speed, behavioral states such as locomotion, grooming, and rearing, and hippocampus-dependent cognitive states such as recognizing a novel location of a familiar object. The data show that cholinergic dynamics contain a multiplexed code of fast and slow signals i) coding for the logarithm of movement speed at sub-second timescales, ii) providing a phasic spatial novelty signal during the brief periods of exploring a novel object location, and iii) coding for environmental novelty at a seconds-long timescale. Furthermore, behavioral event-related phasic cholinergic activity around the onset and offset of the behavior demonstrates that fast cholinergic transients help facilitate a switch in cognitive and behavioral state before and during the onset of behavior. These findings enhance understanding of the mechanisms by which cholinergic modulation contributes to the coding of movement speed and encoding of novel spatial information.
Working memory shapes neural geometry in human EEG over learning
Authors: Wójcik Michał J. , Li Amy , Wasmuht Dante , Stroud Jake P. , Stokes Mark G. , Myers Nicholas E. , Hunt Laurence T.
Published: January 2025

Working memory has been traditionally studied as a passive storage for information. However, recent advances have suggested that working memory is prospective rather than retrospective, meaning that its content undergoes transformations that will support future behaviour. One perspective that underscores this notion conceptualises memory processes as a computational resource that can be used to reduce the complexity of computation at decision time. Here, we explore this perspective by examining whether the process of maintenance shapes neural geometry and leads to low-dimensional representations during storage and later decision time. We recorded EEG in 25 human participants who learnt to solve a XOR task. We hypothesised that separating task features by a working memory delay would result in participants temporally decomposing the XOR computation, by prospectively processing one of the task features early in trial time. In line with our predictions, participants transformed the first feature from a sensory to an abstract format and maintained this pre-processed information throughout the delay. This process was related to the low-dimensional representation required at decision time early in learning, a representation that has recently been shown to support later cross-generalisation. These results demonstrate that low-dimensional representations, elsewhere associated with slow learning, might also provide a mechanism for maintenance processes in working memory.
Exploiting Endogenous Cas9-Based Genome Editing ofLacticaseibacillus rhamnosusGG (LGG) for Precision Food Fermentation and Live Biotherapeutics
Authors: Xie Zifan , Jin Yong-Su , Miller Michael J.
Published: January 2025

Lacticaseibacillus rhamnosusGG (LGG) is one of the most studied probiotic strains and is widely used in both food and therapeutic industries. With its safe and health-beneficial properties, LGG is an ideal candidate for genome modification to enhance its functionalities for food, industrial and pharmaceutical applications. However, precise and efficient genome engineering tools for LGG are unavailable. In this study, we developed a novel genome engineering tool for LGG based on its endogenous type II-A CRISPR-Cas9 system. By employing a validated protospacer adjacent motif (PAM), a customized single guide RNA (sgRNA) expression cassette and a homologous repair template, we successfully reprogrammed the native CRISPR-Cas9 system for targeted genome modifications. Using this method, we successfully constructed a fucose-negative LGG incapable of growing on L-fucose and a lactose-positive LGG. The lactose-positive LGG exhibited significantly improved growth in milk compared to its parental strain LGG, which is unable to ferment lactose, attributed to its ability to metabolize lactose efficiently. Moreover, this strain showed robust growth during yogurt fermentation and maintained viability during cold storage for at least three weeks. These findings highlight the potential of the lactose-positive LGG as an improved culture for dairy industry and a functional probiotic for food and therapeutic applications.

Importance

A precise and efficient genome editing tool is essential for unlocking the full potential ofLacticaseibacillus rhamnosusGG (LGG), the most extensively studied probiotic strain. This study established the first high-efficiency genome editing platform for LGG by harnessing the endogenous type II-A CRISPR-Cas9 system. Using this tool, we achieved targeted gene modifications, without introducing scars, heterologous DNA, or antibiotic resistance genes. The engineered lactose-positive LGG strain demonstrated improved growth in lactose-containing dairy products and robust performance during yogurt fermentation, highlighting its industrial and therapeutic value. This platform not only advances the development of enhanced probiotic strains but also establishes LGG as a versatile vehicle for synthetic biology and biotechnological applications.
Population-level encoding of somatosensation in mouse sensorimotor cortex
Authors: Park Seungbin , Lipton Megan H. , Dadarlat Maria C.
Published: January 2025

1

Dexterous limb movements rely on somatosensation (touch and proprioception), which provides the sense of the body’s posture, movement, and interaction with objects. The heterogeneous responses of single neurons in sensorimotor cortex to somatosensation have led to disparate views of the computa-tional role of this brain area in somatosensory processing. Here, we use population-level analyses of neural activity recorded during active and passive limb movements to assess the structure and sum-marize the properties of neural encoding in sensorimotor cortex. We used 2-photon imaging to record the activity of thousands of neurons in these brain areas from eight anesthetized mice during passive deflections of each limb. We additionally analyzed neural responses to passive limb movements in eight awake mice, sourced from an open dataset [1], and neural responses to spontaneous limb movements in eight mice, collected during a previous study [2]. To conduct the population-level analyses, we found the principal components of the time-varying neural population activity matrix in each set of experi-ments. Across all three datasets and behavioral conditions, a small fraction of principal components explained a large fraction of variance in the neural responses. These low-dimensional representations of single and multi-limb movements were well conserved across animals, including orthogonal represen-tations of ipsilateral and contralateral limbs. This organization of somatosensory information mirrors the well-known structure of neural encoding of motor commands. Furthermore, while the activity of in-dividual neurons and small populations best encoded intrinsic variables, larger populations of neurons additionally encode extrinsic variables — a representational structure that is commonly associated with higher-level brain areas. Together, these analyses demonstrate that population-level encoding of somatosensory information in mouse sensorimotor cortex is structured to facilitate sensorimotor integration across the brain.
Paraspeckle Protein NONO Regulates Active Chromatin by Allosterically Stimulating NSD1
Authors: Hsu Chen-I , Mei Shenglin , Demmerle Justin , Ruttenberg Sarah , Sahn Mahnue , Yu Jia-Ray
Published: January 2025

NSD1 is a key lysine methyltransferase for di-methylation of lysine 36 of histone H3 (H3K36me2) essential for the establishment of active chromatin domains. While the loss of NSD1 catalytic activity halts embryonic development and a gain of that drives oncogenesis in leukemia and glioma, the regulatory mechanisms that control NSD1 activity in these processes remain poorly understood. Here, we uncover that NSD1 requires allosteric activation through the aromatic pocket of its PWWP2 domain. Surprisingly, we identify that NSD1-PWWP2 binds to a non-canonical target, nuclear paraspeckle protein NONO, and this protein-protein interaction allosterically stimulates the catalytic activity of NSD1. Mouse embryonic stem cells (mESC) engineered with mutations in the aromatic pocket of NSD1-PWWP2 cannot differentiate into neural progenitor cells (NPC), and genetic depletion of NONO partially phenocopied this defect at cellular and transcriptional levels, potentially explaining the neurodevelopmental disorder phenotypes in NSD1- or NONO-deficient patients. Our work revealed a novel mechanism driving active chromatin domain formation and has critical implications in the interplay between nuclear paraspeckles and active chromatin, and a vulnerability of NSD1 for therapeutic interventions.

GRAPHIC ABSTRACT

HIGHLIGHTS

The catalytic activity of NSD1 requires the aromatic pocket of its PWWP2 domain

The aromatic pocket of NSD1-PWWP2 binds to a non-canonical target, paraspeckle protein NONO, which allosterically stimulates NSD1

Disruption of the assemblies of paraspeckles dampens global H3K36me2 levels

NONO deficiency partially phenocopies the defects of neural differentiation in NSD1-knockout embryonic stem cells
Novel antimicrobial activity of photoactive compounds originally synthesized for industrial applications
Authors: Ezquerra-Aznárez José Manuel , Alonso-Román Raquel , Lucía Ainhoa , Andreu Raquel , Franco Santiago , Aínsa José A. , Ramón-García Santiago
Published: January 2025

The emergence of antimicrobial resistance threatens advances achieved by medicine in the last century. This situation has been aggravated by the suboptimal outcome of screening campaigns to provide novel antibiotics. In this study, we took an alternative approach to discover new chemical scaffolds with antimicrobial activity. We screened a collection of photoactive compounds originally synthesized for industrial purposes and found that 4H-pyran-4-ylidenes are active against Gram-positive bacteria. Compounds belonging to this family displayed dose-dependent bactericidal activity against wild-typeStaphylococcus aureusand Methicillin ResistantS. aureus(MRSA). Importantly, they were not cytotoxic to hepatic cell lines at the concentrations at which antimicrobial activity was observed. Resistance to 4H-pyran-4-ylidenes inS. aureuswas achieved via mutations in thernylocus, likely via changes in mRNA levels of genes critical for their activity. Overall, we demonstrate that chemical libraries not originally intended for drug discovery can be a fruitful source of chemical diversity for the development of novel antimicrobials.
The patient-specific mouse model withFoxg1frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome
Authors: Jeon Shin , Park Jaein , Moon Ji Hwan , Shin Dongjun , Li Liwen , O’Shea Holly , Hwang Seon Ung , Lee Hyo-Jong , Brimble Elise , Lee Jae W. , Clark Stewart , Lee Soo-Kyung
Published: January 2025

Abstracts

Single allelic mutations in the forebrain-specific transcription factor geneFOXG1lead to FOXG1 syndrome (FS). To decipher the disease mechanisms of FS, which vary depending on FOXG1 mutation types, patient-specific animal models are critical. Here, we report the first patient-specific FS mouse model,Q84Pfsheterozygous (Q84Pfs-Het) mice, which emulates one of the most predominant FS variants. Remarkably, Q84Pfs-Het mice recapitulate various human FS phenotypes across cellular, brain structural, and behavioral levels, such as microcephaly, corpus callosum agenesis, movement disorders, repetitive behaviors, and anxiety. Q84Pfs-Het cortex showed dysregulations of genes controlling cell proliferation, neuronal projection and migration, synaptic assembly, and synaptic vesicle transport. Interestingly, the FS-causingQ84Pfsallele produced the N-terminal fragment of FOXG1, denoted as Q84Pfs protein, in Q84Pfs-Het mouse brains. Q84Pfs fragment forms intracellular speckles, interacts with FOXG1 full-length protein, and triggers the sequestration of FOXG1 to distinct subcellular domains. Q84Pfs protein also promotes the radial glial cell identity and suppresses neuronal migration in the cortex. Together, our study uncovered the role of the FOXG1 fragment derived from FS-causingFOXG1variants and identified the genes involved in FS-like cellular and behavioral phenotypes, providing essential insights into the pathophysiology of FS.
Chronic social instability stress differentially affects the behavior and the transcriptome of the anterodorsal bed nucleus of the stria terminalis between male and female mice
Authors: Degroat Thomas J. , Paladino Sarah E. , Denney Katherine , Moran Kevin M. , Samuels Benjamin A. , Roepke Troy A.
Published: January 2025

Stress can be broken down into systemic and processive stressors with processive stressors requiring higher limbic processing. These are also often called social stressors as they require an understanding of social dynamics as opposed to physical based stressors. This differing of processing necessitates we study both phenomena. Additionally, sex is an important aspect of stress research as men and women show differing responses to stress and mood disorder development. To study this, we used a chronic social instability stress (CSIS) paradigm to stress male and female mice. This paradigm is approximately 7-weeks long and involves changing the cage mates of a mouse every 3 days so stable social dynamics cannot form. Afterwards, one cohort was used for avoidance behavior testing using the open field test, the elevated plus maze, the light/dark box emergence test, and the novelty suppressed feeding test. A second cohort was used for bulk RNA-Sequencing of the anterodorsal bed nucleus of the stria terminalis which is a limbic structure known to be related to chronic stress signaling. In the behavior assays, CSIS caused the females to be less avoidant, while the males became more avoidant. Additionally, we found that a low estrogen state in the females caused them to be less avoidant than in a high estrogen state. In the transcriptome, we found major differences between the males and females with the males expressing more genes related to transcription whereas the females expressed more genes related to synaptic transmission. We also found that the transcriptome in the males is more sensitive to the stress than the females. In summary, we have found how social stress is differentially regulated between males and females and how this may be related to the development of stress-related behavioral changes.