bluuebunny/crossref_metadata_2025 huggingface dataset:
Factor XI/XIa Inhibitors: A New Approach to Anticoagulation
Authors: Whiteson Harris Z. , Frishman William H.
Published: December 2023

For more than 60 years, anticoagulation drugs have served as a mainstay in preserving and improving the cardiovascular health of patients across the globe. Functioning to reduce a patient’s ability to produce blood clots, prescription rates for anticoagulants have been steadily rising year-over-year both in the United States and abroad. Despite decades of clinical usage, modern-day anticoagulants have been shown to predispose an individual to pathological bleeding. Even in seemingly benign instances of bleeding, patients on anticoagulation therapy might require intensive and expensive medical procedures or monitoring. Understanding the clinical implications of pathological bleeding, research and development of future anticoagulants seeking to minimize these effects. One emerging category of anticoagulant drugs are Factor XI/XIa (FXI) inhibitors. Targeting the coagulation cascade, clinical trials of Factor XIa inhibitors have shown promising results in preventing blood clot formation without increasing the instances of spontaneous and/or pathological bleeding events. While still in phase II and III clinical trials, and potentially years away from being implemented as standard of care, these novel drugs might have the potential to improve the safety and quality of life of patients taking anticoagulants. In this review, we discuss a brief history of anticoagulation therapy, followed by an analysis of the potential risks, benefits, and implications of Factor XI/XIa inhibitors across elements of patient care.
Endohepatology in clinical practice: EUS-guided portal pressure measurement combined with EUS-guided liver biopsy and variceal screening and treatment in outpatients
Authors: Kim Sung , Lewey Scot , Meuller Laura , Adler Douglas G.
Published: December 2023

Background and Objectives

EUS-guided portal pressure gradient (PPG) is a novel technique that permits a true, direct measure of portal vein pressure and hepatic vein pressure. This article details our experience and lessons learned from 20 consecutive outpatient EUS-PPG procedures performed at a single center, along with simultaneous EUS-guided liver biopsy, variceal screening, and variceal banding.

Methods

Data on the first 20 patients who underwent EUS-PPG at a single center were retrospectively viewed and analyzed. The effects of various liver diseases or other patient-related factors on the clinical and technical success of EUS-PPG measurements, as well as EUS-guided liver biopsy (EUS-LB), were evaluated. During the procedure, if esophageal varices were encountered, they were assessed, and if felt to be clinically indicated, endoscopic variceal ligation was performed.

Results

The 20 patients included 10 male and 10 female patients. All procedures were technically successful. In all patients, the portal vein and hepatic veins could be easily identified. One adverse event of bleeding occurred during the EUS-PPG measuring procedure. All 20 EUS-LBs were technically successful and yielded adequate samples for histological evaluations, with an average of 25 complete portal tracts per sample. Among patients with esophageal varices, 40% of patients underwent banding. The mean EUS-PPG among 5 patients with esophageal varices was 11.6 mm Hg, compared with 3.2 mm Hg among 15 patients without esophageal varices.

Conclusion

This study demonstrates that EUS-PPG is a novel, safe, reproducible, and effective technique. Also, the fact that EUS-PPG, EUS-LB, variceal screening, and variceal banding could be performed in 1 session and on an outpatient basis speaks to the growing relevance and impact of the nascent field of endohepatology.
Dose–response association between physical activity and blood pressure among Chinese adults: a nationwide cross-sectional study
Authors: Guan Tianjia , Cao Man , Zheng Congyi , Zhou Haoqi , Wang Xin , Chen Zuo , Zhang Linfeng , Cao Xue , Tian Yixin , Guo Jian , Han Xueyan , Wang Zengwu
Published: December 2023

Objectives:

The aim of this study was to examine the dose–response associations of physical activity with blood pressure (BP) and hypertension risk among Chinese adults.

Methods:

Derived from the national community-based China Hypertension Survey database during 2012--2015, a total of 203 108 residents aged at least 18 years were included. Individual-level physical activity was evaluated using a standardized questionnaire, and minutes of metabolic equivalent tasks per week (MET-min/week) were calculated, integrating domain, intensity, frequency, and duration. Multivariable linear and logistic regressions were used to estimate associations of physical activity with BP and hypertension risk, and restricted cubic spline regressions were performed for their nonlinear dose–response relationships.

Results:

Overall, the median total physical activity (TPA) was 3213.0 MET-min/week and the prevalence of physical inactivity was 14.8%. TPA was negatively associated with BP. Increasing TPA levels was related to a steep decrease in systolic BP, up to approximately 2500 MET-min/week, with more modest benefits above that level of TPA. Higher levels of domain-specific and intensity-specific physical activity were found to be associated with lower BP levels and hypertension risk, except for the association between vigorous-intensity physical activity and systolic BP. We found that TPA within the range of 2000--4000 MET-min/week, a higher frequency and shorter duration were inversely associated with diastolic BP levels.

Conclusion:

Total, domain-specific, and intensity-specific physical activity were inversely related to BP levels, respectively, in a dose–response fashion. Of a given amount, higher-frequency, shorter-duration, and lower-intensity physical activity produced more beneficial effects.
ADAR1 gene mutations in two Chinese pedigrees with dyschromatosis symmetrica hereditaria
Authors: Cao Ya-Qi , Han Chun-Yu , Han Jian-Wen
Published: December 2023

Introduction:

Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominantly inherited disease with high penetrance. Patients with DSH display a mixture of hyperpigmented and hypopigmented macules on the dorsal aspects of the extremities and freckle-like macules on the face.

Case presentation:

We identified mutations in two Chinese pedigrees with DSH using whole-exome sequencing (WES) and verified these mutations with PCR-Sanger sequencing. We found a previously reported mutation, c.2433_2434del (p.A813Qfs*29), in exon 7 of ADAR1 in the patient of pedigree one and a novel mutation, c.3301G>T(p.V1101F), in exon 13 of ADAR1 in the patients of pedigree two.

Discussion:

We have identified two gene mutations, one of which may be a novel mutation. At present, the main focus is to improve the color of skin lesions. Laser therapy and sun protection can to some extent alleviate skin lesions.

Conclusion:

The findings of the current case have expanded the range of ADAR1 mutations associated with DSH and may be of great help for future clinical genetic counseling.
Telemental Health Use Is Associated With Lower Health Care Spending Among Medicare Beneficiaries With Major Depression
Authors: Peña Maria T. , Lindsay Jan A. , Li Ruosha , Deshmukh Ashish A. , Swint John M. , Morgan Robert O.
Published: December 2023

Background:

Some policymakers are concerned that expanding telehealth coverage may increase Medicare expenditures. However, there is limited evidence on the association of telehealth use with utilization and spending among Medicare beneficiaries with major depression.

Objective:

To examine the differences in spending and utilization among telemental health users and non-telemental health users with major depression.

Methods:

We examined 2014–2019 traditional Medicare claims data for beneficiaries aged ≥50 years with major depression in Texas. Multivariable generalized linear models were used to assess the relationships between telemental health use and Medicare spending and utilization while adjusting for patient demographics and programmatic and clinical factors.

Results:

In each of the years between 2014 and 2019, an average of 4.6% Medicare beneficiaries with major depression had at least 1 telemental health visit. Compared with beneficiaries without a telemental health visit, those who had a telemental health visit were significantly more likely to be enrolled in Medicaid, be Medicare eligible due to a disability, live in a lower income area or in a rural area, and have a higher comorbidity index. Beneficiaries utilizing telemental health services incurred higher unadjusted Medicare spending than those not receiving telemental health services. However, this difference appeared due to beneficiary and programmatic characteristics rather than telemental health use. Adjusting for model covariates, the telemental health group had lower overall per member per year predicted spending, inpatient admissions, and emergency department visits than non-telemental health users.

Conclusion:

Our findings suggest that telemental health care use may improve access to mental health care without increasing Medicare spending among telemental health users in Texas.
Real-World Patient Experience With Pancreatic Enzyme Replacement Therapy in the Treatment of Exocrine Pancreatic Insufficiency
Authors: Barkin Jodie A. , Harb Diala , Kort Jens , Barkin Jamie S.
Published: December 2023

Objectives

This study aimed to provide patients insights on the management of exocrine pancreatic insufficiency (EPI) with pancreatic enzyme replacement therapy (PERT).

Materials and Methods

A survey of 75 members of Inspire's Pancreatitis or Pancreatic Cancer Support communities was conducted. Eligibility included having EPI secondary to chronic pancreatitis, pancreatic cancer, pancreatic surgery, or acute pancreatitis, and current/past PERT experience.

Results

Patients were 73% female, 57% aged 50 to 69 years, and 85% White, with PERT prescribed by a gastroenterologist/pancreatologist for 64%. Only approximately half of respondents agreed that their healthcare provider provided detailed information about EPI (54%) or how PERT works to treat EPI (56%). Most respondents (83%) reported searching for information about EPI, 56% were taking PERT solely before or after eating, 36% reported taking suboptimal PERT doses, and 39% reported no follow-up. In addition, 24% decreased their PERT dosage without consulting their physician, and 21% reported purposely skipping PERT.

Conclusions

This study reveals potential barriers to effective treatment of EPI with PERT, including lack of patient education, mainly how and when to take PERT, gaps in appropriate dosing, and lack of patient follow-up. Continued focus on patient and provider education is essential to address these gaps and optimize the treatment of EPI.
Online discussions of sexually transmitted infections (STIs) during COVID-19: Insights from the social media platform Reddit
Authors: Renfro Kaytlin J. , Haderxhanaj Laura T. , Loosier Penny S. , Hogben Matthew , Aral Sevgi O.
Published: December 2023

Background

With the onset of the COVID-19 pandemic, reported rates of chlamydia and gonorrhea dropped and remained low for several months of 2020 as compared to 2019. Additional data are needed to reveal causes of reported rate changes. Here, we analyze STI-related conversations from the online-discussion platform Reddit to gain insight into the role of the pandemic on public experience of STIs in 2020.

Method

We collected data from Pushshift’s and Reddit’s application programming interfaces via programs coded in Python. We focused data collection on the ‘r/STD’ subreddit. Collected submissions contained the term(s) “covid” and/or “coronavirus” and were submitted between 01/01/2020 and 12/31/2020. We collected the title and text of each submission. We used a Latent Dirichlet Allocation (LDA) algorithm to create a topic model of post content and complemented this approach with key term analysis and qualitative hand-coding.

Results

Of the 288 posts collected, 148 were complete and included in analyses. LDA revealed four main topics in the collected posts: narration of sexual experiences, STI testing, crowdsourcing of visual STI diagnoses, and descriptions of STI-related pains and treatments. Hand-coding of COVID-19 mentions revealed pandemic-related anxieties about STI care seeking and experienced delays in and changes to quality of STI care received.

Conclusions

References to COVID-19 and associated mitigation efforts were woven into Reddit posts pertaining to several domains of STI care. These data support the notion that Reddit discussions may represent a valuable source of STI information, standing to corroborate and further contextualize STI survey and surveillance work.
Antenatal and intrapartum care for women with gestational diabetes: a best practice implementation project
Authors: Stan Daniela , Mazilu Doina C. , Zazu Mariana , Nedelcu Viorica , Teodor Monica , Brătilă Elvira , Vrbová Tereza , Klugar Miloslav , Klugarová Jitka
Published: December 2023

Objectives:

This project aimed to improve the quality of antenatal and intrapartum care for women with gestational diabetes (GD) by increasing nursing and midwifery care compliance with best practice recommendations.

Introduction:

GD is one of the most common diseases that can lead to several important maternal and fetal complications.

Methods:

This project was based on JBI's evidence implementation approach and included a baseline audit, the implementation of strategies, and a follow-up audit. The project was conducted in an obstetrics-gynecology department of a hospital in Bucharest, and the sample included 30 pregnant women with GD from that ward.

Results:

Regarding antenatal care, the baseline audit revealed low compliance (63%–87%) for criterion 2 (specific education), criterion 3 (multidisciplinary team), criterion 4 (individualized care plan), criterion 5 (training on self-monitoring), criterion 8 (dietician consultation), and criterion 10 (physical exercise program). Compliance with criterion 9 (physiotherapist consultation) was nil. Higher compliance (90%–100%) was reported for criterion 1 (screening for GD), criterion 6 (self-monitoring), and criterion 7 (maintenance of glycemic values). The intrapartum care audit criteria regarding maintaining blood glucose levels had compliance rates of 97% (criteria 13 and 14), 73% (criterion 11), and 67% (criterion 12). As a result of implementing the most appropriate strategies, maximum improvement was observed for all 12 audit criteria found to be deficient in the baseline audit.

Conclusions:

Strategies were identified and applied to successfully implement the best practices (educational programs and improved procedures). However, specific actions, such as regular targeted audits and continuous monitoring, are needed to maintain long-term results.
Thermococcus thermotolerans sp. nov., a hyperthermophilic archaeon isolated from a chimney in the Southwest Indian Ocean
Authors: Yang Yi , Leng Hao , Fan Qilian , Xiao Xiang , Zhao Weishu
Published: December 2023

An anaerobic hyperthermophilic archaeon was isolated from a black smoker chimney with a snail attachment at a water depth of 2 739 m in the Southwest Indian Ocean. The sample was taken from the chimney exterior wall. The enrichment was conducted under a continuous culture with temperature fluctuation of 80–130 °C over 24 h for 42 days at 28 MPa. The isolation was performed at 90 °C at 0.1 MPa. Cells of the isolated strain 813A4T were irregular cocci. Strain 813A4T grew at 60–94 °C (optimal growth at 85 °C) at 0.1 MPa, and growth was detected at up to 99 °C at 28 MPa. At 85 °C, the strain was able to grow at pressures ranging from 0.1 to 110 MPa (optimal pressure, 0.1–40 MPa). At 85 °C, the cells of 813A4T grew at pH 5.5–9 (optimal, pH 7.0) and a NaCl concentration of 1.0–4.0 % (w/v; optimum concentration, 2.5 % NaCl). Strain 813A4T utilized yeast extract, tryptone and peptone as single carbon sources for growth. Elemental sulphur stimulated its growth. The G+C content of the complete genome was 53.48 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 813A4T belonged to the genus

Thermococcus

, with the highest sequence similarity to

Thermococcus barossii

SHCK-94T (99.73 %). The average nucleotide identity between strains 813A4T and SHCK-94T was 82.56 %. All these data indicated that strain 813A4T should be classified as representing a novel species of the genus

Thermococcus

, for which Thermococcus thermotolerans sp. nov. is proposed. The type strain is 813A4T (=JCM 39367T=MCCC M28628T).
Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease
Authors: Levites Yona , Dammer Eric B. , Ran Yong , Tsering Wangchen , Duong Duc , Abreha Measho , Gadhavi Joshna , Lolo Kiara , Trejo-Lopez Jorge , Phillips Jennifer , Iturbe Andrea , Erquizi Aya , Moore Brenda D. , Ryu Danny , Natu Aditya , Dillon Kristy , Torrellas Jose , Moran Corey , Ladd Thomas , Afroz Farhana , Islam Tariful , Jagirdar Jaishree , Funk Cory C. , Robinson Max , Borchelt David R. , Ertekin-Taner Nilüfer , Kelly Jeffrey W. , Heppner Frank L. , Johnson Erik C. B. , McFarland Karen , Levey Allan I. , Prokop Stefan , Seyfried Nicholas T. , Golde Todd E.
Published: December 2023

We report a highly significant correlation between human Alzheimer’s disease (AD) brain proteome changes and those in CRND8 APP695NL/F transgenic mice. Comparing protein changes observed in the CRND8 mice with co-expression networks derived from human Alzheimer’s disease (AD), reveals both conserved and divergent module changes. Many proteins in the most highly conserved module (M42, matrisome) accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic neuronal processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of Aβ in plaques and in blood vessels; further, recombinant MDK and PTN enhance Aβ aggregation into amyloid structures. Multiple M42 proteins bind to fibrillar Aβ42 and a non-human amyloid fibrilin vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart. Notably, our findings establish that proteomic changes in modules observed in human AD brains define an Aβ amyloid “responsome” that is well conserved from mouse models to humans. Further, distinct amyloid structures appear to serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions, and this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.
Marine heatwaves favour resistant Mediterranean octocoral populations at the expense of their speed of recovery
Authors: Capdevila Pol , Zentner Yanis , Rovira Graciel·la , Garrabou Joaquim , Medrano Alba , Linares Cristina
Published: December 2023

1. The effects of climate change are now more pervasive than ever. Marine ecosystems have been particularly impacted by climate change, with Marine Heat Waves (MHWs) being a strong driver of mass mortality events. Even in the most optimistic greenhouse gas emission scenarios, MHWs will continue to increase in frequency, intensity, and duration. For this reason, understanding the resilience of marine species to the increase of MHWs is crucial to predicting their viability under future climatic conditions.

2. In this study, we explored the consequences of Marine Heatwaves (MHWs) on the resilience of a Mediterranean key octocoral species,Paramuricea clavata, to further disturbances to their population structure. To quantifyP. clavata’s capacity to resist and recover from future disturbances, we used demographic information collected from 1999 to 2022, from two different sites in the NW Mediterranean Sea.

3. Our results showed that the differences in the dynamics of populations exposed and those not exposed to MHWs were driven mostly by differences in mean survivorship and growth. We also showed that after MHWsP. clavatapopulations had slower rates of recovery but did not experience changes in resistance. Populations exposed to MHWs had lower resistance elasticity to progression but higher stasis compared to unexposed populations. In contrast, the only demographic process showing some differences when comparing the speed of recovery elasticity values between populations exposed and unexposed to MHWs was stasis. Finally, under scenarios of increasing frequency of MHWs, the extinction ofP. clavatapopulations will accelerate and their capacity to recover after further disturbances will be hampered.

4. Overall, these findings confirm that future climatic conditions will make octocoral populations even more vulnerable to further disturbances. These results highlight the importance of limiting local impacts on marine ecosystems to dampen the consequences of climate change.
Ridge regression baseline model outperforms deep learning method for cancer genetic dependency prediction
Authors: Chang Daniel , Zhang Xiang
Published: December 2023

Accurately predicting genetic or other cellular vulnerabilities of unscreened, or difficult to screen, cancer samples will allow vast advancements in precision oncology. We re-analyzed a recently published deep learning method for predicting cancer genetic dependencies from their omics profiles. After implementing a ridge regression baseline model with an alternative, simplified problem setup, we achieved a model that outperforms the original deep learning method. Our study demonstrates the importance of problem formulation in machine learning applications and underscores the need for rigorous comparisons with baseline approaches.
Vaxign-DL: A Deep Learning-based Method for Vaccine Design and its Evaluation
Authors: Zhang Yuhan , Huffman Anthony , Johnson Justin , He Yongqun
Published: December 2023

Reverse vaccinology (RV) provides a systematic approach to identifying potential vaccine candidates based on protein sequences. The integration of machine learning (ML) into this process has greatly enhanced our ability to predict viable vaccine candidates from these sequences. We have previously developed a Vaxign-ML program based on the eXtreme Gradient Boosting (XGBoost). In this study, we further extend our work to develop a Vaxign-DL program based on deep learning techniques. Deep neural networks assemble non-linear models and learn multilevel abstraction of data using hierarchically structured layers, offering a data-driven approach in computational design models. Vaxign-DL uses a three-layer fully connected neural network model. Using the same bacterial vaccine candidate training data as used in Vaxign-ML development, Vaxign-DL was able to achieve an Area Under the Receiver Operating Characteristic of 0.94, specificity of 0.99, sensitivity of 0.74, and accuracy of 0.96. Using the Leave-One-Pathogen-Out Validation (LOPOV) method, Vaxign-DL was able to predict vaccine candidates for 10 pathogens. Our benchmark study shows that Vaxign-DL achieved comparable results with Vaxign-ML in most cases, and our method outperforms Vaxi-DL in the accurate prediction of bacterial protective antigens.
Aurora Kinase A Inhibition plus Tumor Treating Fields Suppress Glioma Cell Proliferation in a Cilium-Independent Manner
Authors: Tian Jia , Mallinger Julianne C. , Shi Ping , Ling Dahao , Deleyrolle Loic P. , Lin Min , Khoshbouei Habibeh , Sarkisian Matthew R.
Published: December 2023

Tumor Treating Fields (TTFields) have been shown to extend the survival of glioblastoma (GBM) patients. TTFields interfere with a broad range of cellular processes which may contribute to their efficacy. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis can further suppress GBM cell proliferation in vitro. Aurora Kinase A (AURKA) promotes both cilia disassembly and GBM growth in vitro and in xenograft models. Inhibitors of AURKA such as Alisertib have been previously demonstrated to inhibit cilia disassembly and increase the frequency of cilia in various cell types. However, here we show that physiological concentrations of Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo with Alisertib. This activity of Alisertib seems to be glioma cell specific as it did not reduce neuronal or glial cilia frequencies in mixed primary cell cultures from mouse forebrain. Furthermore, Alisertib depletion of glioma cilia appears specific to AURKA inhibition, as a potent AURKB inhibitor, AZD1152, had no effect on GBM ciliary frequency. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking,ARL13b, or U87MG cells which are naturally devoid of ARL13B+cilia. This result is not surprising given the wide range of pathways regulated by AURKA in addition to cilia. Nonetheless, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib has been shown to cross the blood brain barrier and inhibit intracranial growth of xenografted tumor models, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.
Hot spots drive uptake and short-term processing of organic and inorganic carbon and nitrogen in intertidal sediments
Authors: Riekenberg Philip M. , Eyre Bradley D. , van der Meer Marcel T.J. , Oakes Joanne M.
Published: December 2023

This study uses dual-labelled (13C and15N) stable isotope applications to examine uptake and short-term processing of carbon (C) and nitrogen (N) by microbial communities in intertidal sediment from three subtropical estuarine sites. We examine differences in microbial uptake and retention that arise due to domination of microbial processing by either microphytobenthos or heterotrophic bacteria. We compare amino acids and algal dissolved organic matter (Algal DOM) and glucose and NH4+versus newly fixed microphytobenthos C (MPB-C) and NH4+usingin situapplications across 24 h to identify uptake into the microbial community and sediment OM. Algal DOM had preferential C uptake and more retention across 24 h indicating precursors incorporated into biosynthetic pathways for biomass. Conversely, amino acid C was not incorporated or rapidly respired to DIC but displayed clear preferential uptake and retention of15N. Short-term (24 h) retention of glucose was higher than MPB-C, while uptake of15N from NH4+was similar between treatments, potentially indicating glucose-stimulated export of15N via coupled nitrification-dentrification. Despite careful selection of similar sites and sediment types, we found substantial variability between replicates and sites in the uptake and processing of labeled substrate that challenged traditional statistical analysis due to non-homogenous variance. Uptake variability across orders of magnitude is likely due to disproportionate processing of substrates occurring in hotspots of microbial processing within sediment. Development of analytical techniques to provide robust strategies to handle variability caused by abiotic and biotic factors will allow greater clarity surroundingin situbiogeochemical processing in intertidal environments.
Development of a Nanoparticle-Based Tendon-Targeting Drug Delivery System to Pharmacologically Modulate Tendon Healing
Authors: Adjei-Sowah Emmanuela , Chandrasiri Indika , Xiao Baixue , Liu Yuxuan , Ackerman Jessica E. , Soto Celia , Nichols Anne E. C. , Nolan Katherine , Benoit Danielle S.W. , Loiselle Alayna E.
Published: December 2023

Tendon regeneration following acute injury is marred by a fibrotic healing response that prevents complete functional recovery. Despite the high frequency of tendon injuries and the poor outcomes, including functional deficits and elevated risk of re-injury, there are currently no pharmacological therapies in clinical use to enhance the healing process. Several promising pharmacotherapies have been identified; however, systemic treatments lack tendon specificity, resulting in poor tendon biodistribution and perhaps explaining the largely limited beneficial effects of these treatments on the tendon healing process. To address this major unmet need, we leveraged our existing spatial transcriptomics dataset of the tendon healing process to identify an area of the healing tendon that is enriched for expression ofAcp5. Acp5encodes tartrate-resistant acid phosphatase (TRAP), and we demonstrate robust TRAP activity in the healing tendon. This unexpected finding allowed us to refine and apply our existing TRAP binding peptide (TBP) functionalized nanoparticle (NP) drug delivery system (DDS) to facilitate improved delivery of systemic treatments to the healing tendon. To demonstrate the translational potential of this drug delivery system, we delivered the S100a4 inhibitor, Niclosamide to the healing tendon. We have previously shown that genetic knockdown of S100a4 enhances tendon healing. While systemic delivery of Niclosamide did not affect the healing process, relative to controls, TBP-NP delivery of Niclosamide enhanced both functional and mechanical outcome measures. Collectively, these data identify a novel tendon-targeting drug delivery system and demonstrate the translational potential of this approach to enhance the tendon healing process.
Expanded Expression of Pro-Neurogenic Factor SoxB1 during Larval Development of GastropodLymnaea stagnalisSuggests Preadaptation to Prolonged Neurogenesis in Mollusca
Authors: Kurtova Anastasia I. , Finoshin Alexander D. , Aparina Margarita S. , Gazizova Guzel R. , Kozlova Olga S. , Voronova Svetlana N. , Shagimardanova Elena I. , Ivashkin Evgeny G. , Voronezhskaya Elena E.
Published: December 2023

The diversity in the organization of the nervous system in mollusks raises intriguing questions about its development and evolution. Our study aims to gain a deeper understanding of how the nervous system forms in Mollusca by examining the involvement of SoxB-family transcription factors in the early development of neurogenic zones. Specifically, we explore the expression patterns of two SoxB genes in the gastropodLymnaea stagnalis, namely Ls-SoxB1 and Ls-SoxB2, across various developmental stages. Through a combination of in situ hybridization chain reaction, immunohistochemistry, and proliferation assays, we examine the dynamic spatial distribution of Ls- SoxB1 and Ls-SoxB2, with a particular emphasis on the formation of central ring ganglia and the identification of active proliferative zones. Our findings reveal that Ls-SoxB1 exhibits expanded ectodermal expression from the gastrula to the postmetamorphic stage, evident at both transcriptional and translational levels. Throughout larval development, Ls-SoxB1 is expressed in the ectoderm of the head, foot, and visceral complex, as well as in ganglia anlagen and sensory cells. In contrast, the expression of Ls-SoxB2 in the ectoderm is observed until the veliger stage, after which it persists in subepithelial layer cells and ganglia rudiments. Proliferation assay reveals a uniform distribution of dividing cells in the ectoderm at all developmental stages, indicating the absence of distinct neurogenic zones with increased proliferation in gastropods. Our findings highlight that Ls-SoxB1 exhibit widespread expression patterns in both location and time compared to other Lophotrochozoa species. This prolonged expression of SoxB genes in gastropods can be interpreted as a form of transcriptional neoteny, playing a crucial role in the diversification of nervous systems. Thus, it serves as a preadaptation to prolonged neurogenesis and an increase in the central nervous system complexity in Mollusca.
Familiarity training enhance straightening of neural trajectory for video prediction
Authors: Qiu Wentao , Huang Ge , Mukundan Mirudhula , Lee Tai Sing
Published: December 2023

Predictive processing in the visual system is pivotal for efficient sensory-driven behaviors. Previous research has shown that the visual system transforms sequential inputs into straighter temporal trajectories. However, the specific role of ‘neural straightening’ in predictive processing, especially in how learning reshapes this phenomenon for enhanced prediction, remains unclear. To address this, we analyzed V2 population activity in macaques during familiarity training with video stimuli. Our findings reveal that repeated exposure to the same movies significantly enhances neural straightening, indicating a critical role of learning in refining neural trajectories for prediction. In parallel, our studies with the deep predictive network model, Pred-Net, demonstrated similar enhancements in neural straightening in response to familiar movies. This underscores a strong association between neural straightening and predictive coding. Together, our results provide novel insights into the adaptive mechanisms of the visual cortex, enriching our understanding of how learning shapes neural path-ways for efficient prediction.
An automated and fast sample preparation workflow for laser microdissection guided ultrasensitive proteomics
Authors: Makhmut Anuar , Qin Di , Hartlmayr David , Seth Anjali , Coscia Fabian
Published: December 2023

Spatial tissue proteomics integrating whole-slide imaging, laser microdissection and ultrasensitive mass spectrometry is a powerful approach to link cellular phenotypes to functional proteome states in (patho)physiology. To be applicable to large patient cohorts and low sample input amounts, including single-cell applications, loss-minimized and streamlined end-to-end workflows are key. We here introduce an automated sample preparation protocol for laser microdissected samples utilizing the cellenONE® robotic system, which has the capacity to process 192 samples in three hours. Following laser microdissection collection directly into the proteoCHIP LF 48 or EVO 96 chip, our optimized protocol facilitates lysis, formalin de-crosslinking and tryptic digest of low-input archival tissue samples. The seamless integration with the Evosep ONE LC system by centrifugation allows ‘on-the-fly’ sample clean-up, particularly pertinent for laser microdissection workflows. We validate our method in human tonsil archival tissue, where we profile proteomes of spatially-defined B-cell, T-cell and epithelial microregions of 4,000 µm2to a depth of ∼2,000 proteins and with high cell type specificity. We finally provide detailed equipment templates and experimental guidelines for broad accessibility.
Metabolic abnormalities in the bone marrow cells of young offspring born to obese mothers
Authors: Phillips Elysse , Alharithi Yem , Kadam Leena , Coussens Lisa M. , Kumar Sushil , Maloyan Alina
Published: December 2023

Intrauterine metabolic reprogramming occurs in obese mothers during gestation, putting the offspring at high risk of developing obesity and associated metabolic disorders even before birth. We have generated a mouse model of maternal high-fat diet-induced obesity that recapitulates the metabolic changes seen in humans. Here, we profiled and compared the metabolic characteristics of bone marrow cells of newly weaned 3-week-old offspring of dams fed either a high-fat (Off-HFD) or a regular diet (Off-RD). We utilized a state-of-the-art targeted metabolomics approach coupled with a Seahorse metabolic analyzer. We revealed significant metabolic perturbation in the offspring of HFD-fed vs. RD-fed dams, including utilization of glucose primarily via oxidative phosphorylation, and reduction in levels of amino acids, a phenomenon previously linked to aging. Furthermore, in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, we identified a unique B cell population expressing CD19 and CD11b, and found increased expression of Cyclooxygenase-2 (COX-2) on myeloid CD11b, and on CD11bhiB cells, with all the populations being significantly more abundant in offspring of dams fed HFD but not a regular diet. Altogether, we demonstrate that the offspring of obese mothers show metabolic and immune changes in the bone marrow at a very young age and prior to any symptomatic metabolic disease.
Altered Glia-Neuron Communication in Alzheimer’s Disease Affects WNT, p53, and NFkB Signaling Determined by snRNA-seq
Authors: Soelter Tabea M. , Howton Timothy C. , Clark Amanda D. , Oza Vishal H. , Lasseigne Brittany N.
Published: December 2023

Background

Alzheimer’s disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer’s disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer’s disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.

Methods

Using public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in a second and third independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.

Results

Cell-cell communication between glia and neurons is altered in Alzheimer’s disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We identified ligand-receptor pairs in three independent datasets and found involvement of the Alzheimer’s disease risk genesAPPandAPOEacross datasets. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely,MYCandTP53, which are associated with WNT and p53 signaling, respectively, had decreased TF activity in Alzheimer’s disease, along with decreased WNT and p53 pathway activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and increased TF activity ofNFIL3, an NFkB signaling-associated transcription factor.

Conclusions

Cell-cell communication between glia and neurons in Alzheimer’s disease is altered in a cell-type-specific manner involving Alzheimer’s disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.
FAIR Header Reference genome: A TRUSTworthy standard
Authors: Wright Adam , Wilkinson Mark D , Mungall Chris , Cain Scott , Richards Stephen , Sternberg Paul , Provin Ellen , Jacobs Jonathan L , Geib Scott , Raciti Daniela , Yook Karen , Stein Lincoln , Molik David C
Published: December 2023

The lack of interoperable data standards among reference genome data-sharing platforms inhibits cross-platform analysis while increasing the risk of data provenance loss. Here, we describe the FAIR-bioHeaders Reference genome (FHR), a metadata standard guided by the principles of Findability, Accessibility, Interoperability, and Reuse (FAIR) in addition to the principles of Transparency, Responsibility, User focus, Sustainability, and Technology (TRUST). The objective of FHR is to provide an extensive set of data serialisation methods and minimum data field requirements while still maintaining extensibility, flexibility, and expressivity in an increasingly decentralised genomic data ecosystem. The effort needed to implement FHR is low; FHR's design philosophy ensures easy implementation while retaining the benefits gained from recording both machine and human-readable provenance.
Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis
Authors: Ehinger Yann , Laguesse Sophie , Phamluong Khanhky , Salvi Alexandra , Sei Yoshitaka J. , Hoisington Zachary W. , Soneja Drishti , Gunasekaran Sowmya , Nakamura Ken , Ron Dorit
Published: December 2023

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR-34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR-34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.
MolPad: An R-Shiny Package for Cluster Co-Expression Analysis in Longitudinal Microbiomics
Authors: Ma Kaiyan , Thairu Margaret W. , Sankaran Kris
Published: December 2023

The R-Shiny package MolPad provides an interactive dashboard for understanding the dynamics of longitudinal molecular co-expression in microbiomics. The main idea for addressing the issue is first to use a network to overview major patterns among their predictive relationships and then zoom into specific clusters of interest. It is designed with a focus-plus-context analysis strategy and automatically generates links to online curated annotations. The dashboard consists of a cluster-level network, a bar plot of taxonomic composition, a line plot of data modalities, and a table for each pathway. Further, the package includes functions that handle the data processing for creating the dashboard. This makes it beginner-friendly for users with less R programming experience. We illustrate these methods with a case study on a longitudinal metagenomics analysis of the cheese microbiome.
Metabolic imprints in the hydrogen isotopes ofArchaeoglobus fulgidustetraether lipids
Authors: Rhim Jeemin H. , Kopf Sebastian , McFarlin Jamie , Maloney Ashley E. , Batther Harpreet , Harris Carolynn M. , Zhou Alice , Feng Xiahong , Weber Yuki , Hoeft-McCann Shelley , Pearson Ann , Leavitt William D.
Published: December 2023

The stable hydrogen isotope composition of archaeal lipids is emerging as a potential paleoenvironmental proxy, adding to the well-established application of plant leaf wax-derivedn-alkanes in paleohydrological reconstruction. A handful of studies reported relatively invariant and depleted hydrogen isotope compositions for archaeal lipids despite the range of different organisms and growth conditions explored. However, how modes of metabolism and physiological state (growth phase) affect the hydrogen isotope signatures of archaeal lipids remains poorly understood, limiting our ability to interpret archaeal lipid biomarker records from the environment. Here we conducted water isotope label experiments with a metabolically flexible and well-studied model archaeonArchaeoglobus fulgidusand quantified the hydrogen isotope fractionation between lipids and water in response to different carbon substrates and electron donor-acceptor pairs. The2H/1H fractionation between lipids and water (εL/W) was overall negative, ranging from –280 to –226 ‰, and overlapped with the ranges observed for other archaea in previous studies. Isotope flux-balance model results suggest that ≥80 % and ≥50 % of lipid-bound H inA. fulgiduscultures directly reflect water isotope compositions (i.e., not via organic substrate or H2) during autotrophy and heterotrophy, respectively. The model results also suggest the final saturation during isoprenoid lipid biosynthesis catalyzed by a flavoenzyme geranylgeranyl reductase likely contributes to the large2H/1H fractionation observed in this study, consistent with previous isotope flux-balance model results for a different archaeon. Finally, we synthesized available data to compare εL/Wpatterns across all three domains of life: Bacteria, Archaea and Eukarya. Emerging patterns between archaeal and eukaryotic lipids are consistent with the notion of highly fractionating geranylgeranyl reductase, and the patterns between archaeal and bacterial lipids suggest that the general state of energy limitation may also contribute to large, negative values of εL/Wobserved in prokaryotic lipids. Altogether, these findings lend further support for the potential of archaeal lipid εL/Was a paleohydrological proxy and provide a broader insight into the2H/1H fractionation mechanisms potentially shared among prokaryotic and eukaryotic lipid biomarkers.
Dynamics of drug delivery determines course of evolution of antibiotic responses in bacteria
Authors: Crow John C. , Geng Hao , Sullivan Timothy J. , Soucy Shannon M. , Schultz Daniel
Published: December 2023

To adjust to sudden shifts in conditions, microbes possess regulated genetic mechanisms that sense environmental challenges and induce the appropriate responses. The initial evolution of microbes in new environments is thought to be driven by regulatory mutations, but it is not clear how this evolution is affected by how quickly conditions change (i.e. dynamics). Here, we perform experimental evolution on continuous cultures of tetracycline resistantE. coliin different dynamical regimens of drug administration. We find that cultures evolved under gradually increasing drug concentrations acquire fine-tuning mutations adapting an alternative efflux pump to tetracycline. However, cultures that are instead periodically exposed to large drug doses evolve transposon insertions resulting in loss of regulation of the main mechanism of tetracycline resistance. A mathematical model shows that sudden drug exposures overwhelm regulated responses, which cannot induce resistance fast enough. These results help explain the frequent loss of regulation of resistance in clinical pathogens.
Antiviral humoral immunity against SARS-CoV-2 Omicron subvariants induced by XBB.1.5 monovalent vaccine in infection-naïve and XBB-infected individuals
Authors: Kosugi Yusuke , Kaku Yu , Hinay Alfredo A , Guo Ziyi , Uriu Keiya , Kihara Minoru , Saito Fumitake , Uwamino Yoshifumi , Kuramochi Jin , Shirakawa Kotaro , Takaori-Kondo Akifumi ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Sato Kei
Published: December 2023

To control infection with SARS-CoV-2 Omicron XBB subvariants, the XBB.1.5 monovalent mRNA vaccine has been available since September 2023. However, we have found that natural infection with XBB subvariants, including XBB.1.5, does not efficiently induce humoral immunity against the infecting XBB subvariants. These observations raise the possibility that the XBB.1.5 monovalent vaccine may not be able to efficiently induce humoral immunity against emerging SARS-CoV-2 variants, including a variety of XBB subvariants (XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and HK.3) as well as BA.2.86. To address this possibility, we collected two types of sera from individuals vaccinated with the XBB.1.5 vaccine; those who had not been previously infected with SARS-CoV-2 and those who had been infected with XBB subvariants prior to XBB.1.5 vaccination. We collected sera before and 3-4 weeks after vaccination, and then performed a neutralization assay using these sera and pseudoviruses.