bluuebunny/crossref_metadata_2025 huggingface dataset:
Virally-Mediated Enhancement of Efferent Inhibition Reduces Acoustic Trauma in Wild Type Murine Cochleas
Authors: Slika Eleftheria , Fuchs Paul A. , Wood Megan Beers
Published: September 2024

Noise-induced hearing loss (NIHL) poses an emerging global health problem with only ear protection or sound avoidance as preventive strategies. In addition, however, the cochlea receives some protection from medial olivocochlear (MOC) efferent neurons, providing a potential target for therapeutic enhancement. Cholinergic efferents release ACh (Acetylycholine) to hyperpolarize and shunt the outer hair cells (OHCs), reducing sound-evoked activation. The (α9)2(α10)3nicotinic ACh receptor (nAChR) on the OHCs mediates this effect. Transgenic knock-in mice with a gain-of-function nAChR (α9L9’T) suffer less NIHL. α9 knockout mice are more vulnerable to NIHL but can be rescued by viral transduction of the α9L9’T subunit. In this study, an HA-tagged gain-of-function α9 isoform was expressed in wildtype mice in an attempt to reduce NIHL. Synaptic integration of the virally-expressed nAChR subunit was confirmed by HA-immunopuncta in the postsynaptic membrane of OHCs. After noise exposure, α9L9’T-HA injected mice had less hearing loss (auditory brainstem response (ABR) thresholds and threshold shifts) than did control mice. ABRs of α9L9’T-HA injected mice also had larger wave1 amplitudes and better recovery of wave one amplitudes post noise exposure. Thus, virally-expressed α9L9’T combines effectively with native α9 and α10 subunits to mitigate NIHL in wildtype cochleas.

One Sentence Summary

Viral transduction of a gain-of-function nAChR enhances the native cholinergic inhibition to protect the cochlea from noise-induced hearing loss.
Conditional Localization Pharmacology Manipulates the Cell Cycle with Spatiotemporal Precision
Authors: Deng Changfeng , Lan Yung-Chi , Chen Geng-Yuan , Ekeabu Chigozie S. , Chung Megan , Lampson Micheal A. , Chenoweth David M.
Published: September 2024

Traditional pharmacology has limited control of drug activity and localization in space and time. Herein, we described an approach for kinase regulation using conditional localization pharmacology (CLP), where an inactive caged inhibitor is localized to a site of interest in a dormant state using intracellular protein tethering. The activity of the inhibitor can be regulated with spatial and temporal precision in a live cellular environment using light. As a proof of concept, a photocaged MPS1 kinase inhibitor (reversine) bearing a Halo-tag ligand tether was designed to manipulate the cell cycle. We demonstrate that this new caged reversine halo probe (CRH) strategy is capable of efficient localization and exceptional spatiotemporal control over spindle assembly checkpoint (SAC) silencing and mitotic exit.
A structural MRI marker predicts individual differences in impulsivity and classifies patients with behavioral-variant frontotemporal dementia from matched controls
Authors: Godefroy Valérie , Durand Anaïs , Simon Marie-Christine , Weber Bernd , Kable Joseph , Lerman Caryn , Bergström Fredrik , Levy Richard , Batrancourt Bénédicte , Schmidt Liane , Plassmann Hilke , Koban Leonie
Published: September 2024

Impulsivity and higher preference for sooner over later rewards (i.e., delay discounting) are transdiagnostic markers of many psychiatric and neurodegenerative disorders. Yet, their neurobiological basis is still debated. Here, we aimed at 1) identifying a structural MRI signature of delay discounting in healthy adults, and 2) validating it in patients with behavioral variant frontotemporal dementia (bvFTD)—a neurodegenerative disease characterized by high impulsivity. We used a machine-learning algorithm to predict individual differences in delay discounting rates based on whole-brain grey matter density maps in healthy male adults (Study 1, N=117). This resulted in a cross-validated prediction-outcome correlation ofr=0.35 (p=0.0028). We tested the validity of this brain signature in an independent sample of 166 healthy adults (Study 2) and its clinical relevance in 24 bvFTD patients and 18 matched controls (Study 3). In Study 2, responses of the brain signature did not correlate significantly with discounting rates, but in both Studies 1 and 2, they correlated with psychometric measures of trait urgency—a measure of impulsivity. In Study 3, brain-based predictions correlated with discounting rates, separated bvFTD patients from controls with 81% accuracy, and were associated with the severity of disinhibition among patients. Our results suggest a new structural brain pattern—the Structural Impulsivity Signature (SIS)—which predicts individual differences in impulsivity from whole-brain structure, albeit with small-to-moderate effect sizes. It provides a new brain target that can be tested in future studies to assess its diagnostic value in bvFTD and other neurodegenerative and psychiatric conditions characterized by high impulsivity.
Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia
Authors: Ahrens Jessica , Ford Sabrina D. , Schaefer Betsy , Reese David , Khan Ali R. , Tibbo Philip , Rabin Rachel , Cassidy Clifford , Palaniyappan Lena
Published: September 2024

Importance

Despite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear.

Objective

To use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia.

Design, Setting, and Participants

This longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants.

Main Outcomes and Measures

Neuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures.

Results

We found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, pcorrected=0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t92=2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, pcorrected=0.094).

Conclusions and Relevance

These findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected ‘final common pathway’ for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover.

Key Points

Question

Is the same midbrain dopamine pathway impacted by cannabis as in psychosis?

Findings

Cannabis use disorder participants had elevated neuromelanin-MRI signal in a cluster of ventral substantia nigra voxels and in a subregion previously documented to have elevated signal in relation to untreated psychotic symptoms.

Meaning

Increased dopamine functioning in the ventral substantia nigra may contribute to the risk of psychosis in people with cannabis use disorders.
Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment
Authors: Chen Zhuoyao , Chi Gamma , Balo Timea , Chen Xiangrong , Montes Beatriz , Clifford Steven C , Szabo Timea , Kiss Arpad , Herner András , Kotschy András , Bullock Alex N
Published: September 2024

Neomorphic mutations and drugs can elicit unanticipated effects that hinder mechanistic understanding for clinical practice. Recurrent indel mutations in the Kelch domain of the KBTBD4 E3 ligase rewire epigenetic programs for stemness in medulloblastoma by recruiting LSD1-CoREST-HDAC1/2 complexes as neo-substrates for ubiquitination and degradation. Remarkably, UM171, an investigational drug for haematopoietic stem cell transplantation, was found to degrade LSD1-CoREST-HDAC1/2 complexes in a wild-type KBTBD4-dependent manner, suggesting a potential common mode of action. We identified that these neomorphic interactions were mediated by the HDAC deacetylase domain. Cryo-EM studies of both wild-type and mutant KBTBD4 captured 2:1 and 2:2 KBTBD4-HDAC2 complexes at resolutions spanning 2.7 Å to 3.1 Å. The mutant and drug-induced complexes adopted similar structural assemblies requiring both Kelch domains in the KBTBD4 dimer for each HDAC2 interaction. UM171 was identified as a bona fide molecular glue binding across the ternary interface. Most strikingly, the indel mutation reshaped the same surface of KBTBD4 providing the first example of a natural mimic of a molecular glue. Together, the structures provide mechanistic understanding of neomorphic KBTBD4 and help to explain the structure-activity relationships of UM171 derivatives for future drug design.
G-CSF and IL-6 drive myeloid dysregulation during severe viral infection
Authors: Kajihara Kimberly , Yan Donghong , Seim Gretchen L. , Little-Hooy Hannah , Kang Jing , Chen Cynthia , De Simone Marco , Delemarre Tim , Darmanis Spyros , Shivram Haridha , Bauer Rebecca N. , Rosenberger Carrie M. , Kapadia Sharookh B. , Xu Min , Reyes Miguel
Published: September 2024

Dysregulated myeloid states are associated with disease severity in both sepsis and COVID-19. However, their relevance in non-COVID-19 viral infection, the factors driving their induction, and their role in tissue injury remain poorly understood. We performed a meta-analysis of 1,622,180 myeloid cells from 890 COVID-19 or sepsis patients and controls across 19 published blood scRNA-seq datasets, which revealed severity-associated gene programs in both neutrophils and monocytes pointing to emergency myelopoiesis (EM). Using published bulk transcriptional data from 562 individuals with non-COVID-19 viral disease, we show that these signatures are similarly upregulated during severe influenza and RSV infection. Analysis of transcriptional and proteomic responses in tocilizumab-treated COVID-19 patients show that IL-6 signaling blockade results in a partial reduction of EM signatures and a compensatory increase in the growth factor G-CSF. Using a cellular model of human myelopoiesis, we show that both IL-6 and G-CSF stimulate the production of myeloid cells that express EM signaturesin vitro. Using a mouse model of severe influenza infection, we demonstrate the effect of IL-6 and G-CSF signaling blockade on EM-associated myeloid cells, and highlight the opposing effects of EM-induced neutrophils and monocytes on tissue injury. Our study demonstrates the link between systemic cytokines and myeloid dysregulation during severe infection in humans, and highlights the cooperative role of IL-6 and G-CSF signaling in driving infection-induced myelopoiesis.
Bacterial genome encoded ParMs
Authors: Ali Samson , Koh Adrian , Popp David , Tanaka Kotaro , Kitaoku Yoshihito , Miyazaki Naoyuki , Iwasaki Kenji , Mitsuoka Kaoru , Robinson Robert C. , Narita Akihiro
Published: September 2024

ParMs generally exist on low copy number plasmids where they contribute to plasmid segregation and stable inheritance. We carried out bioinformatics analysis, which indicated that ParM genes are not only confined to plasmids but are also occasionally found on genomes. Here we report the discovery and characterization of two chromosome encoded ParMs (cParMs) from the genomes of Desulfitobacterium hafniense (Dh-cParM1) and Clostridium botulinum (Cb-cParM). Both cParMs form filaments, exhibit nucleotide hydrolysis, and possess characteristic ParM subunit structures. Dh-cParM1 forms single and tightly coupled double filaments and is highly conserved on the chromosomes of five of six Desulfitobacterium species. Interestingly, these bacteria have not been reported to harbour plasmids. Cb-cParM possesses unique properties. Its filaments were stable after nucleotide hydrolysis and Pi release, and its ParR, (Cb-cParR) did not affect the initial stage of Cb-cParM polymerization but displayed properties of a depolymerization factor for mature filaments. These results indicate functional, polymerizing ParMs can be encoded on genomes, suggesting that ParM roles may extend to other functions beyond plasmid segregation.
Wild type domestication: loss of intrinsic metabolic traits concealed by culture in rich media
Authors: Vezina Ben , Cooper Helena B. , Wisniewski Jessica A. , Parker Matthew H. , Jenney Adam W. J. , Holt Kathryn E. , Wyres Kelly L.
Published: September 2024

Background: Bacteria are typically isolated on rich media to maximise isolation success, removing them from their native evolutionary context. This eliminates selection pressures, enabling otherwise deleterious genomic events to accumulate. Here we present a cautionary tale of these 'quiet mutations' which can persist unnoticed in bacterial culture lines. Methods: We used a combination of microbiological culture (standard and minimal media conditions), whole genome sequencing and metabolic modelling to investigate putative Klebsiella pneumoniae L-histidine auxotrophs. Additionally, we used genome-scale metabolic modelling to predict auxotrophies among completed public genomes (n=2,637). Results: Two sub-populations were identified within a K. pneumoniae frozen stock, differing in their ability to grow in the absence of L-histidine. These sub-populations were the same 'strain', separated by eight single nucleotide variants and an insertion sequence-mediated deletion of the L-histidine biosynthetic operon. The His- sub-population remained undetected for >10 years despite its in inclusion in independent laboratory experiments. Genome-scale metabolic models predicted 0.8% public genomes contained greater than or equal to 1 auxotrophy, with purine/pyrimidine biosynthesis and amino acid metabolism most frequently implicated. Discussion: We provide a definitive example of the role of standard rich media culture conditions in obscuring biologically relevant mutations i.e. nutrient auxotrophies, and estimate the prevalence of such auxotrophies using public genome collections. While the prevalence is low, it is not insignificant given the thousands of K. pneumoniae that are isolated for global surveillance and research studies each year. Our data serve as a pertinent reminder that rich-media culturing can cause unnoticed wild type domestication.
The role of PilU in the surface behaviors of Pseudomonas aeruginosa
Authors: Zhang Jingchao , Luo Yan , Zong Yiwu , Lu Shangping , Shi Yi , Jin Fan , Zhao Kun
Published: September 2024

In Pseudomonas aeruginosa, the dynamic activity of type IV pilus (TFP) is essential for various bacterial behaviors. While PilU is considered a homolog of the TFP disassembling motor PilT, its specific roles remain unclear. Using pilus visualization and single-cell tracking techniques, we characterized TFP dynamics and surface behaviors in wild-type and DeltapilU mutants. We found that DeltapilU cells displayed increased TFP numbers but reduced cell movement and delayed microcolony formation. Interestingly, beyond affecting the twitching motility, DeltapilU cells formed a thick multilayered colony edge on semi-solid surfaces, slowing colony expansion. Cell-cell collision responses changed from touch-turn dominance in wild-type to touch-upright dominance in DeltapilU, affecting colony morphology and expansion. These findings expand our understanding of PilU's physiological roles and provide potential targets for developing strategies to control P. aeruginosa biofilm formation and virulence.
Effects of Health Technology Use and Digital Health Engagement on Clinical Trial Participation: Findings from the Health Information National Trends Survey
Authors: Peiper Nicholas C. , Furmanek Stephen , McCants Kelly , Brown Edward H.
Published: September 2024

Background

Clinical trials are critical to scientific advances and medical progress, although awareness and participation remain low in the general population. The existing literature indicates that clinical trial knowledge and participation is multifactorial. Yet, little is known about the association between clinical trial participation with health technology use and digital health engagement to search for health information, interact with medical providers, and seek health supports.

Objective

Examine the multivariate association between clinical trial knowledge and participation with past-year health technology use and digital health engagement with medical providers.

Design

Cross-sectional data from a federal surveillance system.

Participants

A total of 3,865 US adult respondents from the Health Information National Trends Survey 5, Cycle 4 conducted in 2020.

Main Measures

The two outcomes were clinical trial knowledge (no knowledge, a little knowledge, a lot of knowledge) and participation (never invited, invited did not participate, invited and participated). There were four binary indicators of health technology use for the following purposes in the past year: searching for health or medical information, communicating with a doctor’s office, looking up medical test results, and making medical appointments. There were four binary indicators of digital health engagement in the past year: sharing health information on social media, participating in a health forum or support group, watching health-related videos on YouTube, and awareness of ClinicalTrials.gov.

Key Results

Survey-weighted multivariate regression models demonstrated that awareness of ClinicalTrials.gov had the largest associations with clinical trial knowledge and participation. Digital technology use to engage with medical providers and electronic health records was associated with clinical participation, although the vast majority of respondents had never been invited.

Conclusions

Findings from this study can inform the design of large-scale digital health campaigns and quality improvement programs focused on increasing clinical trial participation.
Neural emotion regulation during pregnancy – a fMRI study investigating a transdiagnostic mental health factor in healthy first-time pregnant women
Authors: Weinmar Franziska , Kogler Lydia , Rehbein Elisa , Morawetz Carmen , Sundström-Poromaa Inger , Skalkidou Alkistis , Derntl Birgit
Published: September 2024

Pregnancy is a psycho-neuro-endocrinological transition phase in which a plethora of hormone levels rise substantially, modulating socioemotional functions, brain structures, and networks and thus presenting a window of vulnerability for mental health. A transdiagnostic factor for psychopathology is emotion regulation, which is influenced by sex hormones, such as estradiol (E2), across the menstrual cycle on the behavioral and neural level. Whether this is also the case in the antepartum period remains unknown. For the first time, behavioral and neural emotion regulation were investigated in healthy primiparous pregnant females with extremely high E2 levels during the second trimester (N = 15) using a functional magnetic resonance imaging (fMRI) paradigm. Results were compared with naturally-cycling females with high E2 levels (after E2-administration, N = 16) and low E2 levels (early follicular phase, N = 16). Although pregnant females reported the lowest trait use of cognitive reappraisal, all females successfully regulated their emotions by applying cognitive reappraisal in the scanner. On the neural level, all females had increased activity in the left middle frontal gyrus during downregulation of negative emotions. Pregnant females showed no significant differences in functional connectivity (psychophysiological interaction, resting-state) related to emotion regulation compared to the nonpregnant group. However, group differences emerged for amygdala activation. In pregnant females, increased amygdala activity predicted reduced regulation success and was positively associated with depression scores. This first fMRI study during pregnancy indicates that depression scores are reflected in heightened amygdala activity already observable in the antepartum period. Thus, through its association with reduced regulation success, increased amygdala activity suggests a neural risk marker for peripartum mental health. Future research needs to investigate emotion regulation in pregnant and postpartum women to further understand pregnancy-related changes and associations of mood, emotional and neural functions. Eventually, this will allow enhanced identification, prevention, and treatment of peri- and postpartum mental ill-health.
Improved resolution of influenza vaccination responses with high-throughput live virus microneutralisation
Authors: Adams Lorin , Stevenson-Leggett Phoebe , Le Lee Jia , Bazire James , Dowgier Giulia , Hobbs Agnieszka , Roustan Chloë , Borg Annabel , Carr Christine , Innocentin Silvia , Webb Louise MC , Smith Callie , Bawumia Philip , Lewis Nicola , O’Reilly Nicola , Kjaer Svend , Linterman Michelle A , Harvey Ruth , Wu Mary Y , Carr Edward J
Published: September 2024

Influenza remains a significant threat to human and animal health. Assessing serological protection against influenza has relied upon haemagglutinin inhibition assays, which are used to gauge existing immune landscapes, seasonal vaccine decisions and in systems vaccinology studies. Here, we adapt our high-throughput live virus microneutralisation assay for SARS-CoV-2, benchmark against haemagglutinin inhibition assays, and report serological vaccine responsiveness in a cohort of older (>65yo) community dwelling adults (n=73), after the adjuvanted 2021-22 Northern Hemisphere quadrivalent vaccine. We performed both assays against all four viruses represented in the vaccine (A/Cambodia/H3N2/2020, A/H1pdm/Victoria/2570/2019, B/Yamagata/Phuket/2013, BVIC/Washington/02/201), using sera drawn on days 0 [range: d-28 to d0], 7 [d6-10] and 182 [d161-196] with respect to vaccination. We found population-level concordance between the two assays (Spearman’s correlation coefficient range 0.48-0.88; all P≤1.4 × 10−5). The improved granularity of microneutralisation was better able to estimate fold-changes of responses, and quantify the inhibitory effect of pre-existing antibody. Our high-throughput method offers an alternative approach to assess influenza-specific serological responses with improved resolution.
Machine Learning Insights into HLA Noncoding Sequence Mismatches and Their Impact on DPB1 Matching in Hematopoietic Cell Transplantation
Authors: Askar Medhat , Mosbruger Timothy L. , Shaw Grace Tzun-Wen , Kim Haedong , Duan Yuncheng , Allen Andrew S. , Duke Jamie L. , Olson Timothy S. , Monos Dimitri S. , Hayeck Tristan J.
Published: September 2024

Purpose

HCT is vital for treating hematological malignancies, relying on HLA matching between unrelated patient-donor pairs to significantly reduce adverse outcomes. Recent studies recognize the potential impact of HLA-DPB1 mismatches on HCT outcomes. Multiple approaches focus on finding better-tolerated HLA-DPB1 mismatches. Additionally, recent studies suggest matching at noncoding HLA sequence may improve HCT outcomes. This study aims to evaluate different approaches for categorizing DPB1 mismatches in patient-donor pairs and explore the potential impact of noncoding mismatches (available in class I HLA genes) on clinical outcomes.

Methods

A retrospective study of 5,106 HCT pairs using Cox proportional hazards models, weighted by a machine learning algorithm, evaluates the impact of particular combinations of HLA-DPB1 mismatches in the context of noncoding HLA class I mismatches on outcomes of HCT. HLA-DPB1 mismatch criteria included T-cell epitope permissive/non-permissive mismatches, expression markers, and evolutionary clade mismatches.

Results

Two HLA-DPB1 mismatches, using multiple criteria, lead to significant hazards of acute graft versus host disease grades 2-4, in the T cell replete group. When HLA-DPB1 mismatches occurred across evolutionary clades (DP2 allele/low-expression patient vs DP5 allele/high-expression in the donor), the deplete group showed significant hazards for treatment-related mortality (TRM) (HR=1.94, p-value=8.9×10-7) and overall survival (OS) (HR=1.67, p-value=1.3×10-5) for additive effects of noncoding mismatches with two HLA-DPB1 mismatches.

Conclusion

Two HLA-DPB1 mismatches remain to predict worse outcomes. However, noncoding mismatches in HLA class I genes confer elevated hazards of TRM and OS in conjunction with mismatches across evolutionary branches of HLA-DPB1. Therefore, noncoding mismatches may inform donor selection in the presence of HLA-DPB1 mismatches and improve HCT outcomes, emphasizing the utility of comprehensive sequencing of HLA alleles in HCT settings.
High power transient 12-29Hz beta event features as early biomarkers of Alzheimer's Disease conversion: a MEG study
Authors: Shpakivska-Bilan Danylyna , Susi Gianluca , Zhou David , Alvarez Jesus Cabrera , Carvajal Blanca P , Pereda Ernesto , Lopez Maria Eugenia , Bruna Ricardo , Maestu Fernando , Jones Stephanie R
Published: September 2024

A typical pattern observed in M/EEG recordings of Mild Cognitive Impairment (MCI) patients progressing to Alzheimer's disease is a continuous slowing of brain oscillatory activity. Definitions of oscillatory slowing are imprecise, as they average across time and frequency bands, masking the finer structure in the signal and potential reliable biomarkers of the disease. Recent studies show that high averaged band power can result from transient increases in power, termed 'events' or 'bursts'. To better understand MEG oscillatory slowing in AD progression, we analyzed features of high-power oscillatory events and their relationship to cognitive decline. MEG resting-state oscillations were registered in age-matched patients with MCI who later convert (CONV, N=41) or do not convert (NOCONV, N=44) to AD, in a period of 2.5 years. To distinguish future CONV from NOCONV, we characterised the rate, duration, frequency span and power of transient high-power events in the alpha and beta band in anterior cingulate (ACC) and precuneus (PC). Results revealed event-like patterns in resting-state power in both the alpha and beta-bands, however only beta-band features were predictive of conversion to AD, particularly in PC. Specifically, compared to NOCONV, CONV had a lower number of beta events, along with lower power events and a trend toward shorter duration events in PC (p < 0.05). Beta event durations were also significantly shorter in ACC (p < 0.01). Further, this reduced expression of beta events in CONV predicted lower values of mean relative beta power, increased probability of AD conversion, and poorer cognitive performance. Our work paves the way for reinterpreting M/EEG slowing and examining beta event features as a new biomarker along the AD continuum, and a potential link to theories of inhibitory cognitive control in neurodegeneration. These results may bring us closer to understanding the neural mechanisms of the disease that help guide new therapies.
Comparing the test performance of dried-blood-spot and plasma HIV recent infection testing samples in a nationally scaled sex worker programme in Zimbabwe
Authors: Rice Brian D , Jones Harriet S , Machingura Fortunate , Gaihai Leah , Makamba Memory , Chanyowedza Thomas , Masvikeni Panganai , Matsikire Edward , Matambanadzo Primrose , Musemburi Sithembile , Chida Phillip N , Dirawo Jeffery , Mugurungi Owen , Bourdin Sarah , Hargreaves James R , Murphy Gary , Cowan Frances M
Published: September 2024

Recency testing can provide strategic insights as to whether a person newly diagnosed with HIV recently acquired their infection or not. To understand potential biases associated with HIV recency testing, we explored the extent sample type influences whether a person is assigned as being recent. Implementing a laboratory-based Recent Infection Testing Algorithm (RITA) across the Centre for Sexual Health and HIV/AIDS Research (CeSHHAR) key populations programme in Zimbabwe between October 2021 and January 2023, we compared plasma-based and dried-bloodspot (DBS) HIV recency samples. Over the study period, 24,976 individual female sex workers HIV tested, of whom 9.5% (2,363/24,979) newly tested HIV positive. Of these 2,363 women, 55.5% (1311/2,363) were offered and gave consent for a sample to be taken for DBS recency and viral load testing, among whom 11.7% (153/1,311) were classified as having a recent infection. A subset of 464 women were offered and consented to paired sample collection, among whom 10.1% (47) and 12.3% (57) of plasma and DBS samples, respectively, were classified as recent. Overall, categorical determination was good, with 97% of results concordant. Of 58 women with paired sample collection who had a test result classified as recent, 46 (79.3%) were concordant recent on both DBS and plasma, with 12 (20.7%) being dis-concordant. Of these 12 women’s samples, 11 were deemed long-standing by the plasma assay but recent by the paired DBS, and one deemed long-standing by DBS but recent by the paired plasma sample. Depending on use-case and setting, there are trade-offs when considering DBS or plasma-based samples between test performance and ease of implementation. Our data can help inform statistical adjustments to harmonise cut-offs on DBS and plasma assays, thereby improving the use and interpretation of recency assays in population-level HIV surveillance activities.
Lipoprotein (a) is associated with increased risk of Abdominal Aortic Aneurysm
Authors: Sharma Pranav , Judy Renae , Yuan Shuai , Gellatly Corry , Saxby Katie L. , Bown Matthew J. , Levin Michael G. , Damrauer Scott M.
Published: September 2024

Introduction

Lipoprotein(a) (Lp(a)) is a circulating apolipoprotein B (ApoB) containing particle that has been observationally linked to atherosclerotic cardiovascular disease and is the target of emerging therapeutics. Recent work has highlighted the role of circulating lipoproteins in abdominal aortic aneurysm (AAA). We sought to triangulate human observational and genetic evidence to evaluate the role of Lp(a) in AAA.

Methods

We tested the association between circulating levels of Lp(a) and clinically diagnosed abdominal aortic aneurysms while controlling for traditional AAA risk factors and levels of ApoB using logistic regression among 795 individuals with and 374,772 individuals without AAA in the UK Biobank (UKB). Multivariable Mendelian randomization (MVMR) was used to test for putatively causal associations between Lp(a) and AAA controlling for ApoB. Genetic instruments for Lp(a) and ApoB were created from genome-wide association studies (GWAS) of Lp(a) and ApoB comprising 335,796 and 418,505 UKB participants, respectively. The instruments were tested for association with AAA using data from a GWAS of 39,221 individuals with and 1,086,107 without AAA.

Results

Elevated Lp(a) levels were observationally associated with an increased risk of AAA (OR 1.04 per 10 nmol/L Lp(a); 95%CI 1.02-1.05; P<0.01). Clinically elevated Lp(a) levels (>150nmol/L) were likewise associated with an increased risk of AAA (OR 1.47; 95% CI 1.15-1.88; P < 0.01) when compared to individuals with Lp(a) levels <150nmol/L. MVMR confirmed a significant, ApoB-independent association between increased Lp(a) and increased risk of AAA (OR 1.13 per SD increase in Lp(a); 95%CI 1.02-1.24; P<0.02).

Conclusion

Both observational and genetic analyses support an association between increased Lp(a) and AAA risk that is independent of ApoB. These findings suggest that Lp(a) may be a therapeutic target for AAA and drive the inclusion of AAA as an outcome in clinical trials of Lp(a) antagonists.
Cohort profile: The Camden Study – a pregnancy cohort study of pregnancy complications and birth outcomes in Camden, New Jersey, USA
Authors: Shiau Stephanie , Chen Xinhua , April-Sanders Ayana , Francis Ellen C. , Rawal Shristi , Hansel Megan , Adeyemi Kehinde , Rivera-Núñez Zorimar , Barrett Emily S.
Published: September 2024

Background

Pregnancy is a unique stage of the life course characterized by trade-offs between the nutritional, immune, and metabolic needs of the mother and fetus. The Camden Study was originally initiated to examine nutritional status, growth, and birth outcomes in adolescent pregnancies and expanded to study dietary and molecular predictors of pregnancy complications and birth outcomes in young women.

Methods

From 1985-2006, 4765 pregnant participants aged 12 years and older were recruited from Camden, NJ, one of the poorest cities in the U.S. The cohort reflects a population under-represented in perinatal cohort studies (45% Hispanic, 38% non-Hispanic Black, 17% White participants; 98% using Medicaid in pregnancy). Study visits, including questionnaires, dietary assessments, and biospecimen collection, occurred in early and late pregnancy as well as at delivery. Medical records were abstracted, and a subset of mothers and infants participated in a six-week postpartum visit.

Results

Over the last five decades, the Camden Study has provided data toward the publication of numerous peer-reviewed papers. Results show that adolescent linear growth in pregnancy is associated with smaller birth size, possibly due to impaired hemodynamics. In the context of preterm birth and other perinatal outcomes, analyses of nutritional data have demonstrated the importance of micronutrients (e.g., folate, iron, zinc), as well as glucose/insulin dynamics and prenatal supplement use. More recent analyses have begun to unpack the biochemical pathways in pregnancy that may be shaped by race as an indicator for systemic racism.

Conclusions

The Camden Study data and biorepositories are well-positioned to support future research aimed at better understanding perinatal health in under-represented women and infants. Linkages to subsequent health and administrative records and the potential for recontacting participants over 18-39 years after initial participation may provide key insights into the trajectories of maternal and child health across the life course.
Comparative transcriptome and variant analyses of the pancreatic islets of a rat model of obese type 2 diabetes identifies a frequently distributed nonsense mutation in the lipocalin 2 gene
Authors: Yokoi Norihide , Adachi Naoki , Hirokoji Tomoki , Nakano Kenta , Yoshihara Minako , Shigenaka Saki , Urakawa Ryuya , Taniguchi Yukio , Yoshida Yusaku , Yokose Shigeo , Suyama Mikita , Okamura Tadashi
Published: September 2024

We have recently established the Zucker fatty diabetes mellitus (ZFDM) rat as a novel model of obese type 2 diabetes (T2D), originating from the obese Zucker fatty (ZF) rat harboring a missense mutation in the leptin receptor gene. Pathogenesis of dysfunction of the pancreatic islets and genetic factors of T2D in ZFDM rats remain unknown. Here, we perform comparative transcriptome and variant analyses of the pancreatic islets between the two strains. Among differentially expressed genes irrespective of obesity and glucose intolerance states, we identify a nonsense mutation, c.409C>T (p.Gln137X), in the lipocalin 2 (Lcn2) gene which encodes a secreted protein called neutrophil gelatinase-associated lipocalin, a well-known biomarker for inflammation. Interestingly, we find that theLcn2mutation is distributed widely in rat species, such as commonly used DA and F344 strains. We examine theLcn2mutation as a strong candidate gene for T2D in ZFDM rats by using genome editing of ZFDM rats in which the nonsense mutation is replaced with a wild-type nucleotide. We find that the genome editing well works but also observe that there is no significant difference in the development of T2D between genome-edited and original ZFDM rats. Finally, we perform a genetic linkage analysis by using backcross progeny between ZF and ZFDM rats and confirm that theLcn2mutation exhibits no significant association with the onset of T2D. Our data indicate that several rat strains would serve asLcn2deficient models, contributing to elucidate pathophysiological roles of Lcn2 in a wide variety of phenotypes.
Savings in visuomotor learning is associated with connectivity changes within a cerebello-thalamo-cortical network encoding movement errors
Authors: Struber Lucas , Lamalle Laurent , Barraud Pierre-Alain , Courvoisier Aurelien , Rafael Laboissiere , Ito Takayuki , Nougier Vincent , Ostry David J , Cignetti Fabien
Published: September 2024

Savings refers to faster relearning upon re-exposure to a previously experienced movement perturbation. One theory suggests that the brain recognizes past errors and is therefore more able to learn from them. If true, there should be a modification of the neural response to errors during re-exposure to a perturbation. To test this idea, we imaged the brains of participants who underwent two sessions (1 day apart) of adaptation to a visuomotor perturbation and investigated brain responses to movement errors. The magnitude of movement error was entered into different types of GLMs to study error-related activation and co-activation (or functional connectivity). We identified a cerebello-thalamo-cortical network involved in the processing of movement errors during adaptation. We found that connectivity between regions of this network (i.e., between the cerebellum and the thalamus, and between the primary somatosensory cortex and the anterior cingulate cortex) became stronger during re-adaptation. Importantly, participants with the largest increases in connectivity strength were those who demonstrated the largest amounts of savings. These results establish a relationship between the ability of the brain to represent errors and the phenomenon of savings.
Metastatic tumor cells in bone marrow differ from paired neuroblastoma tumor and contain subsets with therapy-resistant characteristics
Authors: Hochheuser Caroline , Boltjes Arjan , Keller Kaylee M. , Tol Simon , van de Mheen Marieke , Pita Barros Carolina , van Gestel-Fadaie Zeinab , van Kuilenburg André B. P. , van Hooff Sander , Voermans Carlijn , Molenaar Jan J. , Tytgat Godelieve A. M. , Timmerman Ilse
Published: September 2024

Bone marrow (BM) is a common site for solid tumor metastasis, often causing poor outcome. Here, we define the characteristics of BM-disseminated tumor cells (DTCs) using neuroblastoma as a model. We combined single-cell RNA-sequencing (scRNA-seq) and cell-surface protein analysis using 7 paired BM and primary tumor (PT) samples and found that DTCs contain a higher percentage of cycling cells and higher expression of neurodevelopmental genes compared to corresponding PT cells. In 6 patients, the copy number variation profile differed between PT cells and DTCs, indicating spatial heterogeneity. Within the BM, we detected dormant DTCs with potentially reduced chemosensitivity; this population contained cells expressing low levels of the immunotherapeutic antigen GD2 and increased NGFR expression. In conclusion, we characterized DTCs that are particularly challenging to target, offering new avenues for developing therapeutic strategies designed to target all subpopulations within the highly complex metastatic site, thereby preventing the development of drug-resistant clones.
LncRNATAALis a Modulator ofTie1-Mediated Vascular Function in Diabetic Retinopathy
Authors: Ranjan Gyan , Arora Samriddhi , Sharma Sarmeela , Sharma Lakshita , Bhoyar Rahul C , Senthivel Vigneshwar , Scaria Vinod , Chakrabarti Subhabrata , Kaur Inderjeet , Sivasubbu Sridhar , Motiani Rajender K
Published: September 2024

Diabetic retinopathy (DR), a leading cause of vision impairment and blindness, is characterized by abnormal retinal vascular changes due to chronic hyperglycemia. TheTie-1signaling pathway, essential for vascular growth and remodeling, has emerged as a key therapeutic target, though its molecular mechanisms and interactome remain largely unclear. Through a protein-centric approach, we identified a novel lncRNA and named itTie1-associated angiogenic lncRNA (TAAL).TAALlncRNA regulates endothelial cell migration, proliferation, tube formation, and permeability by modulating ER-calcium homeostasis and cytoskeleton dynamics. In zebrafish,taalmodulation led to angiogenic defects, which were rescued by humanTAALorthologue. Our molecular studies further revealed thatTAALnegatively regulatesTie1protein via ubiquitin-mediated degradation. Notably,TAALexpression is upregulated in the blood of DR patients and downregulated in endothelial DR cell models. Overexpression ofTAALrestored endothelial permeability and VE-cadherin surface expression. These findings establishTAALas a novel regulator ofTie1protein turnover, with potential therapeutic implications for diabetic retinopathy.
Intracortical injection of immune checkpoint inhibitor promotes monocyte/macrophage infiltration and restores microglial function and neuronal activity in an AD mouse model
Authors: Park Taeyoung , Chang Leechung , Chung Seung Won , Lee Seowoo , Bae Sungjun , Condello Carlo , Kim Yong Ho , Lee Jaecheol , Kim Han-Joo , Kwon Ho-Keun , Suh Minah
Published: September 2024

Understanding the intricate interplay among immune responses and homeostatic cell function in Alzheimer's disease (AD) remains challenging. Here, we present a novel strategy to mitigate AD pathology by directly modulating the immune checkpoint PD-1/PD-L1 signaling pathway in the brain, where elevated levels of microglial PD-1 and astrocytic PD-L1 have been observed. We found that a single intracortical injection of anti-PD-L1 antibody facilitates the infiltration of peripheral immune cells into the brain, including IL-10-secreting Ly6C+ monocytes. Subsequently, this leads to the restoration of microglial homeostatic functions including an increase in P2RY12 expression, which enhances microglial process extension. This cascade of events following anti-PD-L1 injection is crucial for regulating abnormally hyperactive neurons and reducing amyloid-beta plaques. These findings suggest that the direct application of immune checkpoint blockade in the brain could offer a new approach to managing the delicate cell-cell interactions among neurons, glial cells, and peripheral immune cells in the AD brain.
Molecular rotors provide insight into the mechanism of formation and conversion ofα-synuclein aggregates
Authors: Allerton Siân C. , Kuimova Marina K. , Aprile Francesco A.
Published: September 2024

α-Synuclein is an intrinsically disordered protein that forms amyloids in Parkinson’s disease. Currently, detection methods predominantly report on the formation of mature amyloids but have poor sensitivity to the early-stage, toxic oligomers. Molecular rotors are fluorophores that sense changes in the viscosity of their local environment. Here, we monitorα-synuclein oligomer formation using the fluorescence lifetime of molecular rotors. We detect oligomer formation and conversion into amyloids forwild typeand twoα-synuclein variants; the pathological mutant A30P and ΔPα-synuclein, which lacks a master regulator region of aggregation (residues 36-42). We report that A30Pα-synuclein shows a similar rate of oligomer formation compared towild type α-synuclein, whereas ΔPα-synuclein shows delayed oligomer formation. Additionally, both variants demonstrate a slower conversion of oligomers to amyloids. Our method provides a quantitative approach to unveiling the complex mechanism ofα-synuclein aggregation which is key to understanding the pathology of Parkinson’s disease.
Loss of Neurofibromin Induces Inflammatory Macrophage Phenotypic Switch and Retinal Neovascularization via GLUT1 Activation
Authors: Zaidi Yusra , Tritz Rebekah , Zaidi Nida , Nabi Faisal , Zaidi Syed Adeel H. , Morsy Abdelhakim , Harris Valerie , Racine Rilee , Hudson Farlyn Z. , Bordan Zsuzsanna , Kennard Simone , Batori Robert , Huo Yuqing , Csanyi Gabor , Belin de Chantemèle Eric J. , Lei Kecheng , Boulis Nicholas M. , Fulton David J. , Khan Rizwan Hasan , Caldwell Ruth B. , Stansfield Brian K.
Published: September 2024

Persons with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome, are largely protected from diabetes and exhibit evidence of enhanced glucose metabolism, which is replicated in mice harboringNf1mutations. A hallmark of NF1-associated neurofibromas and sarcomas is the high density of inflammatory macrophages and targeting macrophages appears efficacious in models of NF1. Inflammatory macrophages rely on glycolysis to rapidly generate ATP; thus, identifying whether neurofibromin, the protein encoded by theNF1gene, controls glucose uptake and/or glycolysis in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specificNf1knockout mice, we demonstrate that neurofibromin complexes with glucose transporter 1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane in macrophages. In turn, glucose internalization and glycolysis are highly up regulated and provoke putative reparative (M2) macrophages to undergo inflammatory phenotypic switch. Inflammatory M1 macrophages and inflammatory-like M2 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in mice harboring macrophage-specificNf1deletion. These studies identify a clear mechanism for the enhanced glycolysis and low risk for diabetes observed in persons with NF1 and provide a novel therapeutic target for manifestations of NF1.
Isotonic and minimally invasive optical clearing media for live cell imagingex vivoandin vivo
Authors: Inagaki Shigenori , Nakagawa-Tamagawa Nao , Huynh Nathan , Kambe Yuki , Yagasaki Rei , Manita Satoshi , Fujimoto Satoshi , Noda Takahiro , Mori Misato , Teranishi Aki , Takeshima Hikari , Naitou Yuki , Yokoyama Tatsushi , Sakamoto Masayuki , Hayashi Katsuhiko , Kitamura Kazuo , Tagawa Yoshiaki , Okuda Satoru , Sato Tatsuo K. , Imai Takeshi
Published: September 2024

Tissue clearing has been widely used for fluorescence imaging of fixed tissues, but not for live tissues due to its toxicity. Here we develop minimally invasive optical clearing media for fluorescence imaging of live mammalian tissues. Light scattering is minimized by adding spherical polymers with low osmolarity to the extracellular medium. A clearing medium containing bovine serum albumin (SeeDB-Live) is minimally invasive to live cells, allowing for structural and functional imaging of live tissues, such as spheroids, organoids, acute brain slices, and the mouse brainin vivo. SeeDB-Live minimally affects the electrophysiological properties and sensory responses of neurons. We demonstrate its utility for widefield imaging of subcellular voltage dynamics, such as backpropagating action potentials, in acute brain slices. We also utilize SeeDB-Live for widefield voltage imaging of dozens of dendritesin vivo, demonstrating population dynamics. Thus, SeeDB-Live expands the scale and modalities of fluorescence imaging of live mammalian tissues.