bluuebunny/crossref_metadata_2025 huggingface dataset:
Induced Abortion and Out-of-State Travel Among Insured Women Before and After the Dobbs v. Jackson Women's Health Organization Decision
Authors: Odouard Ilina C. , Guadamuz Jenny S. , Chakraborty Apurba , Alexander G. Caleb , Qato Dima M.
Published: June 2024

OBJECTIVE:

To quantify changes in abortion rates and out-of-state travel for abortion among insured women before and after the Dobbs v. Jackson decision.

METHODS:

This was a cross-sectional analysis of IQVIA's anonymized, patient-level preadjudicated medical claims on induced medication or procedural abortions among 43.1 million insured women of reproductive age (15–49 years) in the United States. We used information from the Guttmacher Institute to stratify states based on post-Dobbs abortion access policy: 1) legal with protections, 2) legal with restrictions, 3) partial ban, and 4) full ban. The main outcomes were 1) total number and rate of abortions per 100,000 women of reproductive age and 2) proportion of women with out-of-state abortions before (July–December 2021) and after (July–December 2022) Dobbs.

RESULTS:

Between January 2021 and December 2022, a total of 212,875 women of reproductive age (mean±SD age 28.1±6.5 years) had at least one induced abortion. In a comparison of the pre-Dobbs period with the post-Dobbs periods, there were increases in both the total number of women with at least one abortion (from 54,634 to 57,017) and the rate of abortions (from 121.7 to 137.7/100,000). Increases in abortion rates were driven primarily by states where abortion is legal with protections (from 278.5 to 328.5/100,000), whereas abortion rates declined slightly in states with partial (from 16.1 to 15.0/100,000) and full (from 7.2 to 6.8/100,000) abortion bans. Increases in the percentage of women traveling out of state to obtain an abortion were observed only in restrictive states and were greatest in states with full abortion bans (27.4% before Dobbs to 53.4% after Dobbs) (P<.001).

CONCLUSION:

There was a modest increase in abortion rates among insured women nationally after Dobbs, with modest increases in abortions among residents of states with protective abortion policies and increases in out-of-state abortions among residents of full- and partial-ban states.
Characterization of Individuals With Hepatitis B Virus-Related Cirrhosis in a Large Integrated Health Care Organization, 2008-2019
Authors: Florea Ana , Pak Katherine J. , Gounder Prabhu , Malden Debbie E. , Im Theresa M. , Chitnis Amit S. , Wong Robert J. , Sahota Amandeep K. , Tartof Sara Y.
Published: June 2024

Context:

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a risk factor for cirrhosis. The management of HBV-related cirrhosis is challenging, with guidelines recommending treatment initiation and regular monitoring for those affected.

Objective:

Our study characterized Kaiser Permanente Southern California patients with HBV-related cirrhosis and assessed whether they received recommended laboratory testing and imaging monitoring.

Design:

Retrospective cohort study.

Setting and Participants:

We identified KPSC members aged ≥18 years with CHB (defined by 2, consecutive positive hepatitis B surface antigens ≥6 months apart) from 2008 to 2019. Of these patients, we further identified patients with potential HBV-related cirrhosis through ICD-10 code diagnosis, adjudicated via chart review.

Main Outcome Measures:

Age, race/ethnicity, laboratory tests (eg, alanine aminotransferase [ALT]), and hepatocellular carcinoma (HCC) screening (based on standard screening recommendations via imaging) were described in those with HBV-related cirrhosis versus those without.

Results:

Among patients with CHB, we identified 65 patients with HBV-related cirrhosis over ~8 years. Diabetes was the most common comorbidity and was approximately 3 times more prevalent among patients with cirrhosis compared to patients without cirrhosis (21.5% vs. 7.1%). Of the 65 patients with cirrhosis, 72.3% (N = 47) received treatment. Generally, we observed that liver function tests (eg, ALT) were completed frequently in this population, with patients completing a median of 10 (6, 16) tests/year. All patients with cirrhosis had ≥1 ALT completed over the study period, and almost all cirrhotic patients (N = 64; 98.5%) had ≥1 HBV DNA test. However, the proportion of yearly imaging visits completed varied across the study years, between 64.0% in 2012 and 87.5% in 2009; overall, 35% (N = 23) completed annual imaging.

Conclusions:

Our findings suggest that among patients with HBV-related cirrhosis, at the patient-level, completed imaging orders for HCC screening were sub-optimal. However, we observed adequate disease management practices through frequent liver function tests, linkage to specialty care, image ordering, and shared EHR between KPSC providers.
Injury to Anatomic Structures Due to Fixation Device in Management of Mandibular Fracture
Authors: Sahoo Nanda Kishore , Vaswani Himani
Published: June 2024

Introduction:

ORIF is the gold standard for the management of mandibular fractures. The chances of postoperative complications are due to infection, damage of the inferior alveolar nerve canal, or tooth root during the fixation of the fracture fragments. Fixation hardware placed in the vicinity of the vital structures may encroach on the anatomic structures, leading to postoperative complications.

Aim:

The aim of this study is to evaluate the injury to the anatomic structures in the proximity of the fracture line due to the fixation device.

Material and Methods:

This retrospective study was conducted in a tertiary care teaching hospital from July 2021 to June 2023. The cases of maxillofacial trauma reported and referred from peripheral centers were considered duly, applying the inclusion and exclusion criteria. Patients having mandibular fractures from one mandibular foramen to another with or without associated other facial fractures were treated by ORIF under general anesthesia. The patient was followed up at 1 week, 1 month, 3 months, and 6 months. The cases of postoperative complications were further investigated by CBCT.

Result:

There were 67 patients (56 males and 11 females) with 86 fracture lines in the age group of 18–55 years with an average age of 35.2 years. Postoperatively 7 patients presented with unilateral paresthesia of the lower lip and chin region. CBCT revealed that the mean distance of the screw from the inferior alveolar nerve canal was 3.02 mm. None of these cases had injury to the nerve canal or roots of teeth. All the patients recovered from paresthesia within 6 months.

Discussion:

Complications like injury to the inferior alveolar nerve (IAN) with sensory disturbances to the lower lip and chin, as well as tooth/tooth root fractures, may occur due to mandibular fracture, surgical manipulation, and fixation devices. The anatomic structures in the vicinity of the fracture line can be damaged during the fixation of the fracture fragments by the bone plates and screws. In the present study, it was found that 7 out of 67 patients presented with unilateral paresthesia of the lower lip and chin. CBCT analysis showed a considerable distance of 3.02 mm from the inferior alveolar nerve canal to the screws. There was no evidence of hardware encroachment on the IAN or tooth roots.

Conclusion:

Selection and placement of appropriate fixation devices, particularly the length of the bone screws, are crucial to avoid injury to the anatomic structures.
CHANGES OF HISTIDINE-RICH GLYCOPROTEIN LEVELS IN CRITICALLY ILL SEPTIC PATIENTS
Authors: Pradana Ayu Nabila Kusuma , Akahoshi Tomohiko , Guo Jie , Mizuta Yukie , Matsunaga Shuntaro , Narahara Sayoko , Murata Masaharu , Yamaura Ken
Published: June 2024

Background: Histidine-rich glycoprotein (HRG), a potential prognostic factor in sepsis, lacks clarity regarding its relevance in septic-induced shock, disseminated intravascular coagulation (DIC), and acute respiratory distress syndrome (ARDS) pathogenesis. This study investigated the association between HRG concentrations and these critical conditions. Methods: Blood samples were collected from 53 critically ill patients on days 1, 3, 5, and 7 after ICU admission at the Kyushu University Hospital. Daily clinical and laboratory data were recorded, and patient survival was assessed 28 days after ICU admission. Results: Serum HRG concentrations were significantly reduced on days 3, 5, and 7 in patients with septic shock and DIC but not in those with ARDS. While initial HRG levels on day one were not correlated with survival, nonsurvivors displayed decreased HRG levels, notably on days 3, 5, and 7 post-ICU admissions. The HRG levels remained stable in survivors. A progressive decrease was associated with higher mortality rates, particularly on days 5 and 7. On day 5, an HRG level with a cutoff of 25.5 μg/mL showed a sensitivity of 0.77 and a specificity of 0.75, indicating significantly lower survival rates (log-rank test, P < 0.05). Conclusion: HRG presents a potential intervention for critically ill sepsis patients, providing a novel strategy to enhance outcomes. Further research is needed to explore the therapeutic potential of HRG in sepsis management.
Staphylococcus aureus associated with surgical site infections in Western Kenya reveals genomic hotspots for pathogen evolution
Authors: Mogoi Nyabera Nicholas , Sifuna Anthony Wawire , Okoth Patrick Kirsteen , Reva Oleg , Malaba Rose , Negesa Ruth , Nyongesa Kuloba Peter , Osoro Kombo Ezra , Welch Martin
Published: June 2024

Objectives.
Staphylococcus aureus is one of the most common pathogens attributed to hospital infections. Although S. aureus infections have been well studied in developed countries, far less is known about the biology of the pathogen in sub-Saharan Africa.

Methods. Here, we report on the isolation, antibiotic resistance profiling, whole genome sequencing, and genome comparison of six multi-drug resistant isolates of S. aureus obtained from a referral hospital in Kakamega, Western Kenya.

Results. Five of the six isolates contained a 20.7 kb circular plasmid carrying blaZ (associated with resistance to β-lactam antibiotics). These five strains all belonged to the same sequence type, ST152. Despite the similarity of the plasmid in these isolates, whole genome sequencing revealed that the strains differed, depending on whether they were associated with hospital-acquired or community-acquired infections.

Conclusion. The intriguing finding is that the hospital-acquired and the community-acquired isolates of S. aureus belonging to the same genotype, ST152, formed two separate sub-clusters in the phylogenetic tree and differed by the repertoire of accessory virulence genes. These data suggest ongoing adaptive evolution and significant genomic plasticity.
Rising clindamycin resistance in group A Streptococcus in an Irish healthcare institution
Authors: Lapthorne Susan , McWade Robert , Scanlon Nuala , Ní Bhaoill Saoirse , Page Aoife , O'Donnell Clare , Dornikova Gabriela , Hannan Margaret , Lynch Breda , Lynch Maureen , Brady Deirdre
Published: June 2024

Group A streptococcus (GAS) can cause serious invasive disease in humans with a high mortality rate. An increase in GAS infections was reported in Ireland in 2022, and this increase has been sustained in 2023 and is paralleled by similar trends in Europe. Rising antimicrobial resistance is a global problem and presents significant challenges to clinicians treating GAS infection. There was a reported increase in clindamycin resistance in GAS isolates in Ireland in 2022. We examined antimicrobial susceptibility patterns of GAS isolates in our institution in 2022. Although all GAS isolates included in our study were susceptible to penicillin, we noted a high clindamycin resistance rate of 28 % in our invasive GAS isolates. We also noted high tetracycline and erythromycin resistance, 43 and 30 %, respectively. Our results could have implications for empiric antimicrobial prescribing guidelines for skin and soft tissue infections, which often include clindamycin as it inhibits the production of many virulence factors associated with GAS. In addition, macrolides are often the first line recommended antibiotic for patients with anaphylaxis to penicillin. This study emphasises the importance of continuous surveillance and antimicrobial susceptibility testing of invasive and non-invasive isolates in order to monitor trends in increasing antimicrobial resistance.
Detection of avian reovirus (ARV) by ELISA based on recombinant σB, σC and σNS full-length proteins and protein fragments
Authors: de Matos Tatiana Reichert Assunção , Palka Ana Paula Gori , de Souza Claudemir , Fragoso Stenio Perdigão , Pavoni Daniela Parada
Published: June 2024

Introduction. Avian reovirus (ARV) is associated with arthritis/tenosynovitis and malabsorption syndrome in chickens. The σC and σB proteins, both exposed to the virus capsid, are highly immunogenic and could form the basis for diagnostic devices designed to assess the immunological status of the flock.

Gap Statement. Commercial ARV ELISAs cannot distinguish between vaccinated and infected animals and might not detect circulating ARV strains.

Aim. We aimed to develop a customized test to detect the circulating field ARV strains as well as distinguish between vaccinated and unvaccinated animals.

Methodology. We developed ELISA assays based on recombinant (r) σB, σC and the nonstructural protein σNS and tested them using antisera of vaccinated and unvaccinated chickens as well as negative controls. Fragments of σB and σC proteins were also used to study regions that could be further exploited in diagnostic tests.

Results. Vaccinated and unvaccinated birds were positive by commercial ELISA, with no difference in optical density values. In contrast, samples of unvaccinated animals showed lower absorbance in the rσB and rσC ELISA tests and higher absorbance in the rσNS ELISA test than the vaccinated animals. Negative control samples were negative in all tests. Fragmentation of σB and σC proteins showed that some regions can differentiate between vaccinated and unvaccinated animals. For example, σB amino acids 128–179 (σB-F4) and σC amino acids 121–165 (σC-F4) exhibited 85 and 95% positivity among samples of vaccinated animals but only 5% and zero positivity among samples of unvaccinated animals, respectively.

Conclusion. These data suggest that unvaccinated birds might have been exposed to field strains of ARV. The reduction in absorbance in the recombinant tests possibly reflects an increased specificity of our test since unvaccinated samples showed less cross-reactivity with the vaccine proteins immobilized on ELISAs. The discrepant results obtained with the protein fragment tests between vaccinated and unvaccinated animals are discussed in light of the diversity between ARV strains.
Interplay of Long- and Short-term Synaptic Plasticity in a Spiking Network Model of Rat’s Episodic Memory
Authors: Chrysanthidis N. , Fiebig F. , Lansner A. , Herman P.
Published: June 2024

We investigated the interaction of long-term episodic processes with effects of short-term dynamics of recency. This work takes inspiration from a seminal experimental work involving an odor-in-context association task conducted on rats (Panoz-Brown et al., 2016). In the experimental task, rats were presented with odor pairs in two arenas serving as old or new contexts for specific odors-items. Rats were rewarded for selecting the odor that was new to the current context. New odor items were deliberately presented with higher recency relative to old items, so that episodic memory was put in conflict with non-episodic recency effects. To study our hypothesis about the major role of synaptic interplay of long- and short-term plasticity phenomena in explaining rats’ performance in such episodic memory tasks, we built a computational spiking model consisting of two reciprocally connected networks that stored contextual and odor information as consolidated and distributed memory patterns (cell assemblies). We induced context-item coupling between the two networks using Bayesian-Hebbian plasticity with eligibility traces to account for reward based learning. We first reproduced quantitatively and explained mechanistically the findings of the experimental study, and further simulated alternative tasks, e.g. where old odor items were instead encoded with higher recency, thus synergistically confounding episodic memory with effects of recency. Our model predicted that higher recency of old items enhances item-in-context memory by boosting the activations of old items resulting in further enhancement of memory performance. We argue that the model offers a computational framework for studying behavioral implications of the synaptic underpinning of different memory effects in experimental episodic memory paradigms.

Significance Statement

An important aspect of computational modeling is its ability to bridge spatial scales. Our cortical memory model represents a novel computational attempt to unravel neural and synaptic processes with mesoscopic manifestations underpinning the complex effects of short-term memory dynamics on episodic memory recall. We consider the quantitative match with Panoz-Brown et al.’s (2016) experimental findings, obtained in a detailed spiking network model constrained by available biological data, a significant step towards bridging the gap between behavioral correlates of episodic memory and synaptic mechanisms. Our findings and additional predictions on a suite of different episodic memory tasks invite further experimental examination.
Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner
Authors: Kane Alice E , Chellappa Karthikeyani , Schultz Michael B , Arnold Matthew , Li Jien , Amorim Joao , Diener Christian , Zhu Dantong , Mitchell Sarah J , Griffin Patrick , Tian Xiao , Petty Christopher , Conway Ryan , Walsh Katie , Shelerud Lukas , Duesing Charlotte , Mueller Amber , Li Karlin , McNamara Maeve , Shima Rafaella T. , Mitchell James , Bonkowski Michael S , de Cabo Rafael , Gibbons Sean M. , Wu Lindsay E , Ikeno Yuji , Baur Joseph A , Rajman Luis , Sinclair David A
Published: June 2024

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels ofAnerotruncus colihominis,a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.
Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s Disease
Authors: Rajani Rikesh M. , Ellingford Robert , Hellmuth Mariam , Harris Samuel S. , Taso Orjona S. , Graykowski David , Lam Francesca Kar Wey , Arber Charles , Fertan Emre , Danial John S. H. , Swire Matthew , Lloyd Marcus , Giovannucci Tatiana A. , Bourdenx Mathieu , Klenerman David , Vassar Robert , Wray Selina , Frigerio Carlo Sala , Busche Marc Aurel
Published: June 2024

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s Disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ, and play a key role in promoting abnormal neuronal hyperactivity in AD. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal functionin vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.
Quantification of transcript isoforms at the single-cell level using SCALPEL
Authors: Ake Franz , Fernández-Moya Sandra M. , Schilling Marcel , Ganesh Akshay Jaya , Gutiérrez-Franco Ana , Li Lei , Plass Mireya
Published: June 2024

Single-cell RNA sequencing (scRNA-seq) has facilitated the study of gene expression and the development of new tools to quantify transcript in individual cells. Yet, most of these methods have low sensitivity and accuracy. Here we present SCALPEL, a Nextflow-based tool to quantify and characterize transcript isoforms at the single-cell level using standard 3’ based scRNA-seq data. SCALPEL predictions have higher sensitivity than other tools and can be validated experimentally. We have used SCALPEL to study the changes in isoform usage during mouse spermatogenesis and in the differentiation of induced pluripotent stem cells (iPSCs) to neural progenitors. These analyses allow the identification of novel cell populations that cannot be defined using conventional gene expression profiles, confirm known changes in 3’ UTR length during cell differentiation, and identify cell-type specific miRNA signatures controlling isoform expression in individual cells. Together, our work highlights how SCALPEL expands the current scRNA-seq toolset to explore post-transcriptional gene regulation in individual cells from different species, tissues, and technologies to investigate the variability and the specificity of gene regulatory mechanisms at the single-cell level.
Dual DNA Replication Modes: Varying Fork Speeds and Initiation Rates within the spatial replication program inXenopus
Authors: Ciardo Diletta , Haccard Olivier , de Carli Francesco , Hyrien Olivier , Goldar Arach , Marheineke Kathrin
Published: June 2024

Large vertebrate genomes duplicate by activating tens of thousands of DNA replication origins, irregularly spaced along the genome. The spatial and temporal regulation of the replication process is not yet fully understood. To investigate the DNA replication dynamics, we developed a methodology called RepliCorr, which uses the spatial correlation between replication patterns observed on stretched single-molecule DNA obtained by either DNA combing or high-throughput optical mapping. The analysis revealed two independent spatiotemporal processes that regulate the replication dynamics in theXenopusmodel system. These mechanisms are referred to as a fast and a slow replication mode, differing by their opposite replication fork speed and rate of origin firing. We found that Polo-like kinase 1 (Plk1) depletion abolished the spatial separation of these two replication modes. In contrast, neither replication checkpoint inhibition nor Rif1 depletion affected the distribution of these replication patterns. These results suggest that Plk1 plays an essential role in the local coordination of the spatial replication program and the initiation-elongation coupling along the chromosomes inXenopus, ensuring the timely completion of the S phase.
Separating the genetic and environmental drivers of body temperature during the development of endothermy in an altricial bird
Authors: Winder Lucy A. , Hogger Gadsby Jacob , Wellman Eleanor , Pick Joel L. , Simons Mirre J.P. , Burke Terry
Published: June 2024

When altricial birds hatch, they are unable to regulate their own temperature, but by the time they fledge they are thermally independent. Early-life conditions have been shown to be an important factor contributing to an individuals’ performance in adult life. However, it is currently unknown to what extent body temperature during endothermy development is driven by genetic variation or by the early environment. We use thermal images of cross-fostered house sparrows (Passer domesticus) throughout the nestling period to separate genetic and environmental drivers of body temperature. Our results show small heritability of body temperature. We further found that there are effects from the natal environment which carry over into the late nestling stage. A correlation between early to the mid-nestling period was explained by the natal environment and during this period body temperature and growth follow independent developmental trajectories. Furthermore, higher body temperature is under viability selection independent of body mass. We, therefore, demonstrate the natal environment influences future offspring phenotype in a novel measure; body temperature. Our study provides the first study into the environmental and genetic drivers of body temperature variation in a wild bird, furthering our understanding of how an individuals’ traits evolve.
Analysis of coding gene expression from small RNA sequencing
Authors: Azadova Aygun , Ekperuoh Anthonia , Brooke Greg N. , Marco Antonio
Published: June 2024

The popularity of microRNA expression analyses is reflected by the existence of thousands of works in the literature in which sRNAseq has been performed in myriads of samples, but for which no matched total RNAseq exists. The lack of paired sequencing experiments severely restricts the analysis of microRNA-gene regulatory networks. We therefore explored whether protein-coding gene expression can be quantified from transcript fragments present in sRNAseq experiments. We first considered studies containing matched total RNA and small RNA from four human tissues and recovered transcript fragments from the small RNA experiments. We found that the expression levels of protein-coding gene transcripts from sRNAseq datasets was comparable to those from total RNAseq experiments (R2ranging 0.33-0.76). We then analysed the expression of both microRNAs and coding genes from the same sRNAseq experiments and demonstrated that known microRNA-target interactions are, as expected, inversely correlated with the expression profiles of these microRNA-mRNA pairs. To confirm the utility of this approach, we applied our method to investigate microRNAs and their targets in breast cancer patient samples for which only sRNAseq was performed and only microRNAs studied. We again identified a clear inverse correlation between the expression of microRNAs and mRNAs that they are predicted to regulate (i.e. presence of a target site). We also found that upregulation of mir-429 is associated with the downregulation of QKI, an RNA-binding protein, in breast cancer samples. In conclusion, although the analysis of mRNA fragments to study gene expression from sRNAseq experiments may have its limitations, it can be very informative in the study of microRNA-mRNA interactions.
TimiGP-Response: the pan-cancer immune landscape associated with response to immunotherapy
Authors: Li Chenyang , Hong Wei , Reuben Alexandre , Wang Linghua , Maitra Anirban , Zhang Jianjun , Cheng Chao
Published: June 2024

Accumulating evidence suggests that the tumor immune microenvironment (TIME) significantly influences the response to immunotherapy, yet this complex relationship remains elusive. To address this issue, we developed TimiGP-Response (TIME Illustration based on Gene Pairing designed for immunotherapy Response), a computational framework leveraging single-cell and bulk transcriptomic data, along with response information, to construct cell-cell interaction networks associated with responders and estimate the role of immune cells in treatment response. This framework was showcased in triple-negative breast cancer treated with immune checkpoint inhibitors targeting the PD-1:PD-L1 interaction, and orthogonally validated with imaging mass cytometry. As a result, we identified CD8+ GZMB+ T cells associated with responders and its interaction with regulatory T cells emerged as a potential feature for selecting patients who may benefit from these therapies. Subsequently, we analyzed 3,410 patients with seven cancer types (melanoma, non-small cell lung cancer, renal cell carcinoma, metastatic urothelial carcinoma, hepatocellular carcinoma, breast cancer, and esophageal cancer) treated with various immunotherapies and combination therapies, as well as several chemo- and targeted therapies as controls. Using TimiGP-Response, we depicted the pan-cancer immune landscape associated with immunotherapy response at different resolutions. At the TIME level, CD8 T cells and CD4 memory T cells were associated with responders, while anti-inflammatory (M2) macrophages and mast cells were linked to non-responders across most cancer types and datasets. Given that T cells are the primary targets of these immunotherapies and our TIME analysis highlights their importance in response to treatment, we portrayed the pan-caner landscape on 40 T cell subtypes. Notably, CD8+ and CD4+ GZMK+ effector memory T cells emerged as crucial across all cancer types and treatments, while IL-17-producing CD8+ T cells were top candidates associated with immunotherapy non-responders. In summary, this study provides a computational method to study the association between TIME and response across the pan-cancer immune landscape, offering resources and insights into immune cell interactions and their impact on treatment efficacy.
TissueViewer: A Web-Based Multiplexed Image Viewer
Authors: van IJzendoorn D.G.P. , Matusiak M. , West R.B. , van de Rijn M.
Published: June 2024

Datasets generated by spatial biology techniques such as multiplex immunofluorescence staining or spatial transcriptomics profiling of histologic sections carry a tremendous wealth of information. Several commercial platforms exist that can simultaneously acquire 1-1000 distinct marker signals (e.g., MIBI, CODEX, Orion, Nanostring CosMX SMI, Vizgen). However, due to the large size of these datasets, their viewing and sharing are slow, laborious, and require extensive computational resources. To overcome this, we developed TissueViewer, a web-based viewer designed to deliver high-resolution images over the internet with low bandwidth requirements and at high speed.
Weather and leaf age separately contribute to temporal shifts in phyllosphere community structure and composition
Authors: Heil Jacob A. , Simler-Williamson Allison , Striluk Miranda L. , Trawick Danielle , Capezza Rachel , DeFehr Chadwick , Osorio Aubrey , Finney Bruce , Turner Kathryn G. , Bittleston Leonora S.
Published: June 2024

Microbial communities living on plant leaves can positively or negatively influence plant health and, by extension, can impact whole ecosystems. Most research into the leaf microbiome consists of snapshots, and little is known about how microbial communities change over time. Weather and host physiological characteristics change over time and are often collinear with other time-varying factors, such as substrate availability, making it difficult to separate the factors driving microbial community change. We leveraged repeated measures over the course of an entire year to isolate the relative importance of environmental, host physiological, and substrate age-related factors on the assembly, structure, and composition of leaf-associated fungal communities. We applied both culturing and sequencing approaches to investigate these communities, focusing on a foundational, widely-distributed plant of conservation concern: basin big sagebrush (Artemisia tridentatasubsp.tridentata). We found that changes in alpha diversity were independently affected by the age of a community and the air temperature. Surprisingly, total fungal abundance and species richness were not positively correlated and responded differently, sometimes oppositely, to weather. With regard to beta diversity, communities were more similar to each other across similar leaf ages, air temperatures, leaf types, and δ13C stable isotope ratios. Nine different genera were differentially abundant with air temperature, δ13C, leaf type, and leaf age, and a set of 20 genera were continuously present across the year. Our findings highlight the necessity for longer-term, repeated sampling to parse drivers of temporal change in leaf microbial communities.

Open Research Statement

All ITS DNA amplicon sequence raw data are deposited in the NCBI Sequence Read Archive (SRA), BioProject number PRJNA1107252, data will be released upon publication. All community data, metadata, taxonomic data, and R code necessary to reproduce these results are deposited in the GitHub repository archived on Zenodo: 10.5281/zenodo.11106439.
Local adaptation, plasticity, and evolved resistance to hypoxic cold stress in high-altitude deer mice
Authors: Bautista Naim M. , Herrera Nathanael D. , Shadowitz Ellen , Wearing Oliver H. , Cheviron Zachary A. , Scott Graham R. , Storz Jay F.
Published: June 2024

A fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice (Peromyscus maniculatus) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6000 m. The final elevation of 6000 m far exceeds the highest attainable elevations within the species’ range, and therefore tests the animals’ ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species’ broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to a combination of genetically based local adaptation and plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives.

SIGNIFICANCE STATEMENT

In species that are distributed across steep environmental gradients, the ability to inhabit a broad range of conditions may be attributable to local adaptation and/or a generalized acclimatization capacity (phenotypic plasticity). By experimentally acclimating highland and lowland deer mice (Peromyscus maniculatus) to progressively increasing levels of hypoxia during a simulated ascent to 6000 m, we assessed the relative roles of evolved and plastic changes in thermogenic capacity. At especially severe levels of hypoxia, the superior thermogenic performance of highland natives relative to lowland conspecifics suggests that the broad fundamental niche of deer mice is largely attributable to local adaptation to different elevational zones, including evolved plasticity in gene expression and respiratory traits.
Highly effective verified lucid dream induction using combined cognitive-sensory training and wearable EEG: a multi-centre study
Authors: Jafarzadeh Esfahani Mahdad , Anna Christina Salvesen Leila , Picard-Deland Claudia , Matzek Tobi , Demsar Ema , van Buijtene Tinke , Libucha Victoria , Pedreschi Bianca , Bernardi Giulio , Zerr Paul , Adelhofer Nico , Schoch Sarah , Carr Michelle , Dresler Martin
Published: June 2024

The state of becoming aware that one is dreaming within an ongoing dream, referred to as lucid dreaming (LD), can occur spontaneously. Yet, since the occurrence of spontaneous LD is relatively rare, various methods have been proposed to induce LD. Existing scientific literature, however, has been constrained by either small sample sizes with limited generalizability, or by reliance on subjective measures without physiological signals. To address these limitations, we recorded verifiable LD using 2-channel EEG and an open-source dream engineering toolbox (Dreamento) in a large sample size of 60 participants collected across a multi-center study in the Netherlands (NL), Italy (IT), and Canada (CA). We employed a novel combination of the senses-initiated lucid dreaming (SSILD) method and a targeted lucidity reactivation (TLR) protocol. Our final sample consists of 60 participants who came twice to the lab for morning naps with a pre-sleep lucidity training paired with multimodal sensory cues (visual, auditory, tactile). Cues were presented again in REM sleep in one of the two naps (stimulation and sham conditions counterbalanced). This preprint reports results from NL and IT in 40 participants: we successfully induced signal-verified lucid dreams (SVLD) in 65% and 45% of NL and IT participants, respectively. Among these, 45% and 35% (NL and IT) of REM cueing and 35% and 15% (NL and IT) of REM sham sessions resulted in at least one SVLD. In NL, the REM cueing sessions yielded 37 predefined eye signals with an average continuously verified lucidity duration of 78.75 +- 54.85 s. The REM sham sessions resulted in 15 eye signals in the presence of LD report (i.e, SVLD) and had an average duration of 47.80 +- 22.49 s. In IT, 48 predefined eye signals were identified within REM cueing sessions, with an average overall duration (i.e., from the first to the last predefined eye signal) of 506.33 +- 643.73 s and an average continuously verified (consecutive eye signals) duration of 91.13 +- 70.87 s. In contrast, 10 predefined eye signals were identified during REM sham sessions, with an average overall duration of 546.5 +- 744.58 s and a single continuously verified episode that lasted 20 s. Preliminary findings suggest that REM cueing aids the initiation and maintenance of lucidity, facilitates objective estimation of LD duration, and increases dream control. Future research should focus on automating the tools we provided and conducting larger-scale fully automatised studies at home to further explore factors contributing to such high success rates.
Preliminary pharmacokinetics andin vivostudies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator
Authors: Costa Blaise M. , Hines De’Yana , Phillip Nakia , Boehringer Seth C. , Anandakrishnan Ramu , Council-Troche McAlister , Davis Jennifer L.
Published: June 2024

NMDAR channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated thein vivoeffects of CNS4, a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours post-intraperitoneal injection, with brain concentrations reach values up to 8.4% of those in plasma (64.9 vs. 5.47 µg/ml). Preliminary results showed that CNS4, a non-opioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared to saline. In a fear conditioning (FC) experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs. 1; females, 19 vs. 3). CNS4 also improved hyperarousal behavior (25 vs. 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after FC training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects like those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel non-opioid analgesic, warranting further investigation.

Significance

NMDA-subtype glutamate receptors are an attractive target for chronic pain and PTSD treatments as they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, CNS4.

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Evaluating approaches of training a generative large language model for multi-label classification of unstructured electronic health records
Authors: Vithanage Dinithi , Deng Chao , Wang Lei , Yin Mengyang , Alkhalaf Mohammad , Zhang Zhenyu , Zhu Yunshu , Soewargo Alan Christy , Yu Ping
Published: June 2024

Multi-label classification of unstructured electronic health records (EHR) is challenging due to the semantic complexity of textual data. Identifying the most effective machine learning method for EHR classification is useful in real-world clinical settings. Advances in natural language processing (NLP) using large language models (LLMs) offer promising solutions. Therefore, this experimental research aims to test the effects of zero-shot and few-shot learning prompting, with and without parameter-efficient fine-tuning (PEFT) and retrieval-augmented generation (RAG) of LLMs, on the multi-label classification of unstructured EHR data from residential aged care facilities (RACFs) in Australia. The four clinical tasks examined are agitation in dementia, depression in dementia, frailty index, and malnutrition risk factors, using the Llama 3.1-8B. Performance evaluation includes accuracy, macro-averaged precision, recall, and F1 score, supported by non-parametric statistical analyses. Results indicate that both zero-shot and few-shot learning, regardless of the use of PEFT and RAG, demonstrate equivalent performance across the clinical tasks when using the same prompting template. Few-shot learning consistently outperforms zero-shot learning when neither PEFT nor RAG is applied. Notably, PEFT significantly enhances model performance in both zero-shot and few-shot learning; however, RAG improves performance only in few-shot learning. After PEFT, the performance of zero-shot learning is equal to that of few-shot learning across clinical tasks. Additionally, few-shot learning with RAG surpasses zero-shot learning with RAG, while no significant difference exists between few-shot learning with RAG and zero-shot learning with PEFT. These findings offer crucial insights into LLMs for researchers, practitioners, and stakeholders utilizing LLMs in clinical document analysis.
A Multitrait Genome-Wide Association Study Reveals a Requirement for the Strigolactone Receptor MtDWARF14 in Optimal GOLVEN Signaling
Authors: Roy Sonali , Kang Yun , Zhang Shulan , Torres-Jerez Ivone , Jain Divya , Sanchez Bailey , Burghardt Liana , Cheng Xiaofei , Wen Jiangqi , Murray Jeremy D. , Scheible Wolf-Rüdiger , Udvardi Michael
Published: June 2024

GOLVEN/ROOT MERISTEM GROWTH FACTOR family of signaling peptides have been shown to control root lateral organ number, density and positioning in plants, although the signaling pathways involved remain obscure. A diverse set of 171Medicago truncatulaHapMap accessions with variation in responses to the GOLVEN 10 peptide, GLV10, were used to identify 74 significant loci controlling seven traits related to nodule formation and root architecture. Importantly, a single nucleotide polymorphism (SNP) in the upstream region of the MtGLV10 peptide-inducible strigolactone receptor gene,MtDWARF14was significantly associated with insensitivity of nodule density to GLV10, suggesting a link between strigolactone signaling and GLV10 responsiveness. Three independentd14mutants of the DWARF14gene were found to hypernodulate, while overexpression of the gene led to reduction in nodule number, phenocopying GLV10. A null mutant,mtd14-1, remained sensitive to GLV10’s effect on nodule density. However, at the transcriptional level, the mutant failed to effectively induce the expression of the GOLVEN marker genes,MtPLETHORA3andMtPINLIKES2. Our study uncovers a hitherto unknown link between the strigolactone and GLV peptide signaling pathways using genotype x environment analysis of Medicago HapMap lines and provides a putative molecular mechanism for recovery from frost damage to fine roots.
Glucose-regulated circular RNA Rabep1 regulates pancreatic beta-cell growth by modulating miR-335-3p/PTEN axis
Authors: Das Debojyoti , Shyamal Sharmishtha , Mishra Smruti Sambhav , Sadhukhan Susovan , Panda Amaresh Chandra
Published: June 2024

Circular RNAs (circRNAs) are a large family of closed-loop RNA molecules emerging as novel regulators of gene expression. Although several circRNAs are known to regulate various biological processes, the functions of most circRNAs expressed in pancreatic beta cells remain to be discovered. Since short-term glucose treatment induces pancreatic beta-cell growth and promotes insulin production, we wanted to explore the role of glucose-regulated circRNAs in pancreatic beta cell physiology. Our RNA-seq analysis identified more than 300 differentially expressed circRNAs in high-glucose compared to low-glucose treated beta TC6 cells. A subset of differentially expressed and abundant circRNAs was validated by various biochemical methods, including circular RNA Rabep1 (circRabep1). Moreover, the downregulation of circRabep1 in high glucose-treated beta TC6 cells suggested a possible function in beta-cell physiology. Furthermore, analysis of the circRabep1-miRNA-mRNA regulatory network discovered the association of circRabep1 with miR-335-3p, a suppressor of Pten expression. Importantly, inhibition of miRNA function by miR-335-3p inhibitor results in upregulation of PTEN levels, suppressing beta-cell growth and proliferation. Furthermore, silencing circRabep1 decreased PTEN expression by sponging miR-335-3p, promoting cell proliferation. We propose that the downregulation of circRabep1 in high-glucose treated beta-cell leads to an increase in beta-cell proliferation by suppressing PTEN expression through derepression of miR-335-3p.