bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness and safety of motion-style acupuncture treatment using traction for inpatients with acute low back pain caused by a traffic accident: A randomized controlled trial
Authors: Park Byung-Hak , Han Jeong-Hun , Park Jin-Hun , Min Tae-Woon , Lee Hyun-Jun , Lee Yoon Jae , Lee Sook-Hyun , Park Kyoung Sun , Ha In-Hyuk
Published: June 2024

Background:

Musculoskeletal symptoms, such as neck pain and low back pain (LBP) are common after a traffic accident (TA). While motion-style acupuncture treatment (MSAT) is effective in relieving pain, MSAT using traction (T-MSAT) has rarely been studied, and evidence for its efficacy and safety is lacking. To address this gap, this study aimed to assess the effectiveness and safety of T-MSAT for pain and functional disturbances in patients with acute LBP caused by a TA.

Methods:

This two-armed, parallel, assessor blinded randomized controlled trial, conducted at Jaseng Hospital of Korean Medicine, included 100 patients with acute LBP occurring within 1 week of a TA. The participants were randomly allocated (1:1 ratio) to receive either combined T-MSAT and integrative Korean medicine treatment (IKMT) or only conventional IKMT, applied for 3 consecutive days after admission. The primary outcome was the difference between numerical rating scale (NRS) scores for LBP at baseline and after treatment completion on day 4 after admission.

Results:

At the primary endpoint, the difference in NRS scores for LBP between the T-MSAT and control groups was 0.94 (95% confidence interval [CI] 0.40–1.48). The T-MSAT group showed a significantly lower NRS score for LBP than the control group. Differences in visual analogue scale (VAS) scores between the T-MSAT and control groups were significant at baseline and discharge. The area under the curve of the VAS score showed a significant difference (−46.86 [95% CI −85.13 to −8.59]), indicating faster pain reduction in the T-MSAT group than in the control group. Recovery (30% pain reduction) was achieved more rapidly in the T-MSAT group than in the control group (log-rank test P = .005). Meanwhile, the NRS, VAS, Oswestry disability index, and quality of life scores at discharge or at the 12-week follow-up showed no significant difference. The rates of mild adverse events (AEs) were comparable between the groups. No severe AEs were reported, and none of the AEs were associated with the clinical trial.

Conclusions:

T-MSAT combined with IKMT is a safe treatment that can effectively and quickly reduce initial pain in patients with LBP.
Relationship between salusin beta levels and the severity of acute pancreatitis in patients
Authors: Albayrak Bulent , Guneyin Emel Ayvaz , Celik Muhammet
Published: June 2024

Background:

This study aimed to evaluate the significance of serum salusin beta (SAL-β) levels in predicting the severity of acute pancreatitis (AP) in patients diagnosed with this condition and to assess its relationship with disease and prognosis.

Methods:

Sixty-four patients between 18 and 100 years of age diagnosed with AP, were included in the study. Patients were categorized into 3 groups based on the Revised Atlanta Classification: mild, moderate, and severe AP. Eighteen healthy adults were included as the control group. Sex, age, height, weight, presence of additional diseases, laboratory results, imaging findings, levels of white blood cells, neutrophil-lymphocyte ratio, mean platelet volume, amylase, lipase, sensitive C-reactive protein, sedimentation, and serum SAL-β were measured and recorded. SAL-β levels were reevaluated on the third day of hospitalization.

Results:

The average age of the patients included in the study was 62.66 ± 17.67. Gallstones were present in 64.1% of the patients. The difference in the SAL-β averages on the 1st and 3rd days was statistically significant (P < .05). On the first day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. Similarly, on the third day, the SAL-β averages of those with severe Atlanta scores were higher than those with mild and moderate Atlanta severity. According to receiver operating characteristic analysis using the Youden index, the cutoff value for SAL-β for severe pancreatitis was 178.8 pg/mL on the 1st day and 207.5 pg/mL on the 3rd day.

Conclusion:

SAL-β can be used to detect and monitor severe pancreatitis. Further extensive clinical studies with larger case series are needed.
Giant Cyst of Intrapancreatic Accessory Spleen Mimicking a Malignant Cystic Neoplasm of the Pancreas
Authors: Sun Yang , Luo Jieli , Huang Fengbo , Huang Pintong , Yu Risheng
Published: June 2024

Introduction

Epidermoid cyst in an intrapancreatic accessory spleen (ECIPAS) is an exceedingly rare pancreatic lesion that is always mistakenly suspected of malignancy preoperatively.

Case summary

A 25-year-old male patient incidentally found a giant mass in the left upper abdomen neighboring the hilum of the spleen. The patient denied any obvious discomfort. Except for a slightly elevated carbohydrate antigen 19-9 (CA-19-9, 43.5 U/mL), no abnormal laboratory test results were found. Contrast-enhanced computed tomography, conventional ultrasound, and magnetic resonance imaging were performed. The patient received a laparoscopic distal pancreatectomy. The final pathology showed ECIPAS. The postoperative course was uneventful and no signs of recurrence during 2 years of follow-up.

Discussion

For an incidental pancreatic cystic lesion, ECIPAS should be considered in the differential diagnosis. ECIPAS may mimic pancreatic cystadenoma. Imaging follow-up or surgical removal may be useful for the exclusion of malignant risks in ECIPAS.
Longitudinal controlled attenuation parameter and liver stiffness in children with and without perinatal HIV infection in South Africa
Authors: Rose Penelope C. , Davies Claire , Cotton Mark F. , Otwombe Kennedy , Browne Sara H. , Vaida Florin , Innes Steve , Nel Etienne De la Rey
Published: June 2024

Objectives:

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging cause of liver disease in HIV. Transient elastography (TE) with controlled attenuation parameter (CAP) measures liver stiffness as a marker of liver fibrosis and CAP as a measure of hepatic steatosis. Our aim was to evaluate longitudinal CAP and liver stiffness in children with perinatally acquired HIV (PHIV) on antiretroviral therapy (ART) from early life compared to children without HIV (HU).

Design:

Prospective cohort study.

Methods:

PHIV and HU were followed annually for two years. During the study, 60% of PHIV switched from older ART regimens to tenofovir disoproxil, lamivudine and dolutegravir (TLD). Longitudinal evolution of CAP and liver stiffness were investigated in two PHIV groups − on older ART and on TLD − compared to HU children using linear mixed effects models.

Results:

263 children and adolescents (112 PHIV, 151 HU) aged 7–20 years were followed. PHIV on older ART had CAP 8.61% (95% CI 4.42–12.97, P < 0.001) greater than HU and no significant difference in CAP between PHIV on TLD and HU. No significant difference in liver stiffness was found between PHIV on older ART regimens and PHIV on TLD compared to HU.

Conclusion:

PHIV on older ART had higher CAP than HU, whereas in PHIV switched to TLD there was no difference in CAP compared to HU. There was no difference in liver stiffness between either PHIV group and HU. This suggests starting ART early in life might protect PHIV from developing hepatic fibrosis.
Evaluating Islet Cell Isolation and Transplantation From Donors Following Medical Assistance in Dying
Authors: Parente Alessandro , Verhoeff Kevin , Kin Tatsuya , Hefler Joshua , Marfil-Garza Braulio A. , Sanchez-Fernandez Norberto , Lam Anna , Lyon James , O’Gorman Doug , Dajani Khaled Z. , Anderson Blaire L. , Bigam David L. , MacDonald Patrick E. , Shapiro A. M. James
Published: June 2024

Background.

Limited information is available regarding outcomes of islet cell isolation (ICI) and transplantation (ITx) using medical assistance in dying (MAiD) donors. We aimed to assess the feasibility and outcomes of ICI and ITx in MAiD donors.

Methods.

ICI and ITx from MAiD were compared with donation after circulatory death (DCD) type III between 2016 and 2023. Differences of isolated islet equivalents (IEQs), numeric viability and other quantitative in vitro metabolic measures were assessed.

Results.

Overall, 81 ICIs were available of whom 34 (42%) and 47 (58%) from MAiD and DCD-III, respectively. There were no differences of pancreas and digested tissue weight and islets viability among the 2 groups; however, cold ischemic time was longer in MAiD (11.5 versus 9.1 h; P = 0.021). The IEQ (P < 0.001) and percent trapped (P < 0.001) were higher in the DCD-III; however, MAiD islets demonstrated a higher purity (P = 0.020). Overall, 15 ITx were performed of whom 3 (8.8%) and 12 (25.5%) from MAiD and DCD-III, respectively (P = 0.056). Patients had a median fasting C-peptide of 0.51 ng/mL (interquartile range, 0.30–0.76 nmol/L), with no differences between groups (MAiD = 0.52 versus DCD-III = 0.51; P = 0.718). The median HbA1c was 6.2% (interquartile range, 5.7%–7%) (MAiD = 6.3% versus DCD-III = 6.1%; P = 0.815) and BETA2 scores (MAiD = 7.4 versus DCD-III = 12.8; P = 0.229) did not differ.

Conclusions.

ICI from MAiD donor pancreas may be successfully transplanted with comparable outcomes to DCD-III and may be used for research. These results justify additional efforts to consider MAiD as another valuable source of grafts for ITx. Further multicenter studies and larger clinical experience are needed to validate our findings.
Aequorivita sediminis sp. nov. and Aequorivita marina sp. nov., isolated from marine sediment
Authors: An Jing , Yu Qian , Xuan Xiao-Qi , Zhang Jing , Du Zong-Jun , Mu Da-Shuai
Published: June 2024

Two Gram-stain-negative, rod-shaped, non-motile, strictly aerobic strains, forming yellow colonies and designated F6058T and S2608T, were isolated from marine sediment collected in Weihai, PR China. Both strains grow at 4–40 °C (optimum, 30–33 °C), pH 6.0–7.5 (optimum, pH 6.5) and in the presence of 0–7.0 % (w/v) NaCl. The optimum NaCl concentrations for strains F6058T and S2608T were 2.0 % and 2.5 %, respectively. Phylogenetic analysis of the 16S rRNA gene sequences indicated that strains F6058T and S2608T share an evolutionary lineage with members of the genus Aequorivita. The isolates exhibited a 16S rRNA gene sequence similarity of 96.7 % to each other. Strains F6058T exhibited the highest 16S rRNA gene sequence similarity to Aequorivita xiaoshiensis F64183T (98.8 %), and S2608T was most similar to Aequorivita capsosiphonis A71T (96.9 %). Iso-C15:0, anteiso-C15:0 and iso-C17:0 3-OH were the major fatty acids of strains F6058T and S2608T. The sole respiratory quinone of both isolates was menaquinone 6 (MK-6). The polar lipid profiles of the isolates both consisted of phosphatidylethanolamine and phosphoglycolipids; however, strain F6058T exhibited one glycolipid, one aminolipid and two unidentified polar lipids, and strain S2608T also had two glycolipids and one unidentified polar lipid. The DNA G+C contents of strains F6058T and S2608T were 34.6 % and 37.7 mol%, respectively. Based on their phenotypic, chemotaxonomic and genomic characteristics, strains F6058T and S2608T were considered to represent novel species of the genus Aequorivita, for which the names Aequorivita sediminis sp. nov. and Aequorivita marina sp. nov. were proposed. The type strains are F6058T (=KCTC 92653T=MCCC 1H01358T) and S2608T (KCTC 92652T=MCCC 1H01361T).
Reverse engineering neuron type-specific and type-orthogonal splicing-regulatory networks using single-cell transcriptomes
Authors: Moakley Daniel F , Campbell Melissa , Anglada-Girotto Miquel , Feng Huijuan , Califano Andrea , Au Edmund , Zhang Chaolin
Published: June 2024

Cell type-specific alternative splicing (AS) enables differential gene isoform expression between diverse neuron types with distinct identities and functions. Current studies linking individual RNA-binding proteins (RBPs) to AS in a few neuron types underscore the need for holistic modeling. Here, we use network reverse engineering to derive a map of the neuron type-specific AS regulatory landscape from 133 mouse neocortical cell types defined by single-cell transcriptomes. This approach reliably inferred the regulons of 350 RBPs and their cell type-specific activities. Our analysis revealed driving factors delineating neuronal identities, among which we validated Elavl2 as a key RBP for MGE-specific splicing in GABAergic interneurons using an in vitro ESC differentiation system. We also identified a module of exons and candidate regulators specific for long- and short-projection neurons across multiple neuronal classes. This study provides a resource for elucidating splicing regulatory programs that drive neuronal molecular diversity, including those that do not align with gene expression-based classifications.
Keetia korupensis sp. nov. (Rubiaceae - Vanguerieae) a threatened lowland evergreen forest climber and the endemic plant species of Korup National Park, SW Region, Cameroon
Authors: Cheek Martin , Poundje Maguy , Pearce Laura
Published: June 2024

A review of the strictly endemic plant species of the Korup National Park, S.W. Region, Cameroon, is presented together with consideration of the importance of Korup for global plant conservation. Eighteen strict endemic species are known, 14 of which occur in lowland evergreen forest habitat (includingKeetia korupensis) and of which 3 are among the 29 grove-forming monodominant detarioid legume species for which Korup is world famous. Four of Korup’s endemic species are rheophytes restricted to the Mana (Ndian) River rapids and falls which is probably the most species diverse site for shrubby rheophytes on the African continent. No endemics are yet known from Korup’s submontane forest, possibly because this is comparatively small in extent.

Keetia korupensisCheek, a rainforest climber, is described and illustrated as strictly endemic, on current evidence, to the Korup National Park. The species differs from all other known species of the genus in its stipitate 2-seeded fruits which are twice as long as broad (vs non-stipitate and subisodiametric in most of the species) and for the 2 mm long stiff, skin-penetrating stem indumentum (vs non-injuring or soft in other long hairy species).Keetia korupensisis provisionally assessed using the IUCN standard as Vulnerable (VU D2).
Ecological and functional niches comparison reveals differentiated resource-use strategies and ecological thresholds in four key floating-leaved macrophytes
Authors: Dalla Vecchia Alice , Castellani Maria Beatrice , Azzella Mattia M. , Bolpagni Rossano
Published: June 2024

Niche theory has been widely used in ecology; however, few studies have attempted to combine information on functional and ecological niches (i.e. variation in traits and environmental requirements), especially for freshwater macrophytes.

In this study we aim to describe the functional and ecological niches of four key nymphaeid species (Nuphar lutea,Nymphaea alba,Nelumbo nuciferaandNymphoides peltata) to investigate their environmental tolerance and functional adaptability.

Twelve Italian populations per species were sampled. Functional and ecological niches were determined using hypervolumes based on eight functional traits and environmental variables, related to leaf structure and economics spectrum, and to water and sediment quality.

Among the three Italian native species,N. luteaandN. albashowed intermediate niche size and position in the functional and ecological space, althoughN. albaappears to be less competitive due to a small functional niche and lower trait performance, which could explain its general tendency to decline.N. peltataappeared more specialized in its environmental requirements and characterized by highly acquisitive leaves, while the invasive alienN. nuciferaexerted its competitive success by distinguishing its functional niche and expanding its ecological niche, through high investment of resources in leaves.

Overall, all four target species share similar ecological niches, colonizing eutrophic ecosystems typical of intensive agricultural landscapes, but show different patterns in their functional niche. We demonstrate the applicability of an approach based on both functional and ecological niches to unravel species’ adaptation and strategies.
On some alien species from Emilia-Romagna harbors (northern Adriatic Sea, Italy)
Authors: Lezzi M. , Mazziotti C.
Published: June 2024

Increased global trade has led to a surge in the introduction of non-indigenous species (NIS) worldwide. Ships, particularly merchant vessels and recreational yachts, act as vectors for these invasions by transporting NIS in ballast water or as hull fouling. This study investigates the introduction of new fouling NIS in the North Adriatic Sea. Our field research at the ports of Ravenna and Cesenatico identified several alien species, including new records for the North Adriatic Sea:Polyandrocarpa zorritensis, Aplidium accarenseandCelleporaria brunnea. Additionally, a significant presence of the cryptogenic speciesMolgula manhattensiswas observed in Cesenatico.
Embracing Uncertainty Reshapes the ETHYLENE INSENSITIVE2-Activated Ethylene Signaling Framework
Authors: Zhao Hangwei , Zhang Ying , Chen Yuying , Wang Chenrunshu , Liu Qian , Zhang Jingyi , Wen Chi-Kuang
Published: June 2024

Signal transduction of the gaseous plant hormone ethylene by ETHYLENE INSENSITIVE2 (EIN2) is proposed to be regulated at multiple levels. EIN2 is phosphorylated by CONSTITUTIVE TRIPLE-RESPONSE1 (CTR1), subject to the F-Box proteins [EIN2-TARGETING PROTEIN1 (ETP1) and ETP2]-mediated degradation, and cannot activate ethylene signaling. Ethylene prevents EIN2 phosphorylation and degradation, and EIN2 accumulates and activates the signaling. MAOHUZI3 LIKE1 (MHL1) and MHL2 stabilize EIN2, and themhl1 mhl2double mutation confers ethylene insensitivity. Here, we reported that the regulation of EIN2-activated ethylene signaling can be independent of CTR1-mediated phosphorylation, ETP1/ETP2-directed degradation, and MHL1/MHL2-dependent stabilization. Both theetp1 etp2double mutant and wild type showed identical ethylene dose-response curves, and the nontreatedmhl1 mhl2double mutant displayed substantial growth inhibition. The reported ethylene-insensitive root phenotype ofmhl1 mhl2seedlings requires sucrose and is associated with unknown loci. The ethylene receptor ETHYLENE RESPONSE1 (ETR1) and EIN2 interact at the rough endoplasmic reticulum. We propose that the docking of CTR1 to ETR1 promotes receptor signaling, which inhibits EIN2-activated ethylene signaling. The discrepancy between our findings and the current model is discussed. Our findings may disrupt the knowledge boundary of the present molecular model, developing a niche for findings outside the framework to advance our understanding of ethylene signaling.
Plant miRNAs Anti-Staphylococcus aureus:Therapeutic Perspective
Authors: Gharsallah Charfeddine
Published: June 2024

Staphylococcus aureusis a pathogen that has developed resistance to each new antibiotic introduced for half a century especially through the acquisition of themecAgene. This bacterial resistance to antibiotics represents a major public health problem. New revolutions are underway, in particular the design of drugs and vaccines targeting the system for detecting the regulatory quorum of the accessory gene (agr). It has been shown that the pathogenicity and resistance ofS. aureuscan be modulated through the intervention of this system. For this reason, we propose in this present work, a new therapeutic design based on anin silicostudy to identify plant miRNAs that could target this system as well as themecAgene based on recent studies showing the inter-realm regulation of human transcripts by plant miRNAs. Out of a total of 20643 miRNAs from mature plants, we identified 29 miRNAs, obtained by the selection criteria MFE ≥ -25 kcal / mol, which could potentially target selected genes ofS. aureus. Fifteen of them were selected on the basis of their thermodynamic stability. Interestingly, The seeds of ptc - miR171g and ptc - miR171h (Populus trichocarpa) both of which almost similar mature miRNA sequence was found to target UCCC region ofRNAIIIgene. miRNAs from plants targetingS. aureushave the potential to be developed as an alternative therapy of the future. To our knowledge, it is the first therapeutic alternative of the future via thein silicoidentification of plant miRNAs targeting pathogenic bacteria.

Graphical Abstract
Lipid vesicle formation by encapsulation of SMALPs in surfactant-stabilised droplets
Authors: Waeterschoot Jorik , Barniol-Xicota Marta , Verhelst Steven , Baatsen Pieter , Koos Erin , Lammertyn Jeroen , Casadevall i Solvas Xavier
Published: June 2024

Understanding the intricate functions of membrane proteins is pivotal in cell biology and drug discovery. The composition of the cell membrane is highly complex, with different types of membrane proteins and a huge variety of lipid species, Hence, studying cellular membranes in a complexity-reduced context is important to enhance our understanding of the roles of the different elements. However, reconstitution of membrane proteins in an environment that closely mimics the cell, like giant unilamellar vesicles (GUVs), remains challenging, often requiring detergents that compromise protein function. To address this challenge, we present a novel strategy to manufacture GUVs from styrene maleic acid lipid particles (SMALPs) that utilises surfactant-stabilised droplets as a template. Harnessing a new form of SMA linked to fluorescein, which we call FSMA, we demonstrate the assembly of SMALPs at the surfactant-stabilised droplet interface, resulting in the formation of GUVs when released upon addition of a demulsifying agent. The released vesicles appear similar to electroformed vesicles imaged with confocal light microscopy, but a fluorescein leakage assay and cryo-TEM imaging reveal their porous nature, potentially the result of residual interactions of SMA with the lipid bilayer. Our study represents a significant step towards opening new avenues for comprehensive protein research in a complexity-reduced, yet biologically relevant, setting.
Routine antimicrobial therapy for severe fever with thrombocytopenia syndrome does not improve prognosis: overlap weighting analysis using a nationwide inpatient database
Authors: Kutsuna Satoshi , Ohbe Hiroyuki , Matsui Hiroki , Yasunaga Hideo
Published: June 2024

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease that presents a formidable challenge due to the absence of established therapeutic strategies that are explicitly tailored to its management. This study aimed to assess the impact of routine antimicrobial therapy on patients diagnosed with SFTS in Japan. We conducted a comprehensive retrospective cohort analysis using extensive data from a national inpatient database.

Methodology/Principal Findings

This study scrutinized data from adult patients with SFTS and categorized them based on whether they received antimicrobial treatment within the initial 2 days of hospital admission. A meticulous evaluation was carried out on a range of outcomes, such as in-hospital mortality rates, overall costs associated with hospitalization, and length of hospital stay. Overlap weighting was applied along with multivariate regression models to enhance the reliability of the findings through confounder adjustment. The outcomes showed no significant improvement in the prognosis of patients with SFTS who received routine antimicrobial therapy. The use of antimicrobials did not yield statistically significant improvements in in-hospital mortality rates or other secondary outcomes, suggesting that such therapeutic interventions may not be necessary during the early stages of hospital admission.

Conclusion/Significance

This study underscores that the indiscriminate administration of antimicrobials does not substantively enhance the prognosis of patients with severe SFTS, hence dissuading the universal implementation of antimicrobials as a conventional component of therapeutic strategies in managing severe cases of SFTS.

Author summary

Severe fever with thrombocytopenia syndrome is a tick-borne infection that is endemic in East Asia, including Japan, China, and South Korea. At present, there are no effective antiviral drugs against SFTS. It has been reported that patients who received antimicrobial agents for SFTS early on had a better prognosis. To validate this study, we compared SFTS patients who received antimicrobials within 2 days of admission with those who did not, using Japanese DPC data. Overlap weighting was applied along with multivariate regression models to enhance the reliability of the findings through confounder adjustment. The results showed no difference in in-hospital mortality, hospitalization costs, or hospital days between the two groups. In conclusion, the analysis of patients with SFTS using a nationwide inpatient database revealed that routine antimicrobials did not improve patient prognosis. Further, our findings do not support the universal use of antimicrobials in patients with severe SFTS.
Spatially structured competition and cooperation alters algal carbon flow to bacteria
Authors: Kim Hyungseok , Brisson Vanessa L. , Casey John R. , Swink Courtney , Rolison Kristina A. , Golini Amber N. , Northen Trent R. , Weber Peter K. , Veličković Dušan , Buie Cullen R. , Mayali Xavier , Stuart Rhona K.
Published: June 2024

Microbial communities regulate the transformations of carbon in aquatic systems through metabolic interactions and food-web dynamics that can alter the balance of photosynthesis and respiration. Direct competition for resources is thought to drive microbial community assembly in algal systems, but other interaction modes that may shape communities are more challenging to isolate. Through untargeted metabolomics and metabolic modeling, we predicted the degree of resource competition between bacterial pairs when growing on model diatom
Phaeodactylum tricornutum-
derived substrates. In a subsequent sequential media experiment, we found that pairwise interactions were consistently more cooperative than predicted based on resource competition alone, indicating an unexpected role for cooperation in algal carbon processing. To link this directly to algal carbon fate, we chose a representative cooperative and competitive ‘influencer’ isolate and a model ‘recipient’ and applied single-cell isotope tracing in a custom porous microplate cultivation system. In the presence of live algae, the recipient drew down more algal carbon in the presence of the cooperative influencer compared to the competitive influencer, supporting the sequential experiment results. We also found that total carbon assimilation into bacterial biomass, integrated over influencer and recipient, was significantly higher for the cooperative interaction. Our findings support the notion that non-competitive interactions are critical for predicting algal carbon fate.

Significance Statement

Microbial interactions have widely been studied in the context of host resources but testing and measuring direct interactions in a lab has been particularly challenging. By combining untargeted metabolomics, sequential/(co-)culture, and metabolic modeling, we demonstrate that the presence of an unexpected interaction mode in a live system and show how it impacts the flow of host-derived resources. This top-down approach can help identify novel bacterial interactions that play a crucial role in microbial community-host ecosystems, which may have an impact in holobiont phenotypes including alga, fungal, or plant systems.
Transcriptomic comparison of in vitro models of the human placenta
Authors: Lapehn Samantha , Nair Sidharth , Firsick Evan J. , MacDonald James , Thoreson Ciara , Litch James A , Bush Nicole R. , Kadam Leena , Girard Sylvie , Myatt Leslie , Prasad Bhagwat , Sathyanarayana Sheela , Paquette Alison G.
Published: June 2024

Studying the human placenta through in vitro cell culture methods is necessary due to limited access and amenability of human placental tissue to certain experimental methods as well as distinct anatomical and physiological differences between animal and human placentas. Selecting an in vitro culture model of the human placenta is challenging due to representation of different trophoblast cell types with distinct biological roles and limited comparative studies that define key characteristics of these models. Therefore, the aim of this research was to create a comprehensive transcriptomic comparison of common in vitro models of the human placenta compared to bulk placental tissue from the CANDLE and GAPPS cohorts (N=1083). We performed differential gene expression analysis on publicly available RNA sequencing data from 6 common in vitro models of the human placenta (HTR-8/SVneo, BeWo, JEG-3, JAR, Primary Trophoblasts, and Villous Explants) and compared to CANDLE and GAPPS bulk placental tissue or cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast cell types derived from bulk placental tissue. All in vitro placental models had a substantial number of differentially expressed genes (DEGs, FDR<0.01) compared to the CANDLE and GAPPS placentas (Average DEGs=10,873), and the individual trophoblast cell types (Average DEGs=5,346), indicating that there are vast differences in gene expression compared to bulk and cell-type specific human placental tissue. Hierarchical clustering identified 53 gene clusters with distinct expression profiles across placental models, with 22 clusters enriched for specific KEGG pathways, 7 clusters enriched for high-expression placental genes, and 7 clusters enriched for absorption, distribution, metabolism, and excretion genes. In vitro placental models were classified by fetal sex based on expression of Y-chromosome genes that identified HTR-8/SVneo cells as being of female origin, while JEG-3, JAR, and BeWo cells are of male origin. Overall, none of the models were a close approximation of the transcriptome of bulk human placental tissue, highlighting the challenges with model selection. To enable researchers to select appropriate models, we have compiled data on differential gene expression, clustering, and fetal sex into an accessible web application:“Comparative Transcriptomic Placental Model Atlas (CTPMA)”which can be utilized by researchers to make informed decisions about their selection of in vitro placental models.
Coastal bacteria and protists assimilate viral carbon and nitrogen
Authors: Martínez Joaquín Martínez , Talmy David , Kimbrel Jeffrey A. , Weber Peter K. , Mayali Xavier
Published: June 2024

Free viruses are the most abundant type of biological particles in the biosphere, but the lack of quantitative knowledge about their consumption by heterotrophic protists and bacterial degradation has hindered the inclusion of virovory in biogeochemical models. Here, using isotope-labeled viruses added to three independent microcosm experiments with natural microbial communities followed by isotope measurements with single-cell resolution and flow cytometry, we quantified the flux of viral C and N into virovorous protists and bacteria and compared the loss of viruses due to abiotic vs biotic factors. We found that some protists can obtain most of their C and N requirements from viral particles and that viral C and N get incorporated into bacterial biomass. We found that bacteria and protists were responsible for increasing the daily removal rate of viruses by 33% to 85%, respectively, compared to abiotic processes alone. Our laboratory incubation experiments showed that abiotic processes removed roughly 50% of the viruses within a week, and adding biotic processes led to a removal of 83% to 91%. Our data provide direct evidence for the transfer of viral C and N back into the microbial loop through protist grazing and bacterial breakdown, representing a globally significant flux that needs to be investigated further to better understand and predictably model the C and N cycles of the hydrosphere.
Deciphering the RNA Modification Landscape in Arabidopsis Chloroplast tRNAs and rRNAs Reveals a Blend of Ancestral and Acquired Characteristics
Authors: Gołębiewska Kinga , Gregorová Pavlína , Sarin L. Peter , Gawroński Piotr
Published: June 2024

Chloroplasts in plant leaves are essential for protein synthesis, relying on transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) encoded by the chloroplast genome. Although post-transcriptional modifications of these non-coding RNAs are common in many systems, chloroplast tRNA and rRNA modifications are not well characterised.

In this study, we investigated the post-transcriptional modifications in chloroplast tRNAs and rRNAs ofArabidopsis thalianausing tRNA sequencing, liquid chromatography-mass spectrometry, targeted rRNA sequencing, and analysis of public data.

Our results revealed similarities between chloroplast non-coding RNAs and bacterial systems (e.g.,Escherichia coli), such as modification patterns at the anticodon-adjacent position and the variable loop of tRNAs, along with conserved modifications in the small subunit rRNA. Additionally, we identified features shared with eukaryotic systems that likely contribute to the correct three-dimensional structure of chloroplast tRNAs. Unique modifications were also discovered, including a potential novel modification at wobble position in tRNA-IleCAU, which may be crucial for distinguishing isoleucine codons from methionine codons, and chloroplast-specific rRNA modifications that likely compensate for altered ribosome structure.

These findings suggest that the chloroplast translation machinery, through co-evolution with its eukaryotic host, has adopted features beyond those typically found in bacteria, reflecting a blend of ancestral and acquired characteristics.
A new oculomotor model demystifies “Remarkable Saccades”
Authors: Heinen  , Chandna  , Singh  , Watamaniuk
Published: June 2024

Hering’s Law of binocular eye movement control guides most oculomotor research and supports diagnosis and treatment of clinical eye misalignment (strabismus). The law states that all eye movements are controlled by a unitary conjugate signal and a unitary vergence signal that sum. Recent evidence of temporally asynchronous inter-eye rotations during vergence (Chandna et al., 2021) challenges the viability of a unitary vergence signal. An alternative theory that might explain these anomalous results posits that the eyes are controlled independently. Yet independent control fails to explain a phenomenon known as “Remarkable Saccades” where an inappropriate saccade occurs from an eye aligned on a target during asymmetric vergence (Enright, 1992). We introduce a new model formulated to describe the Chandna et al. (2021) midline vergence result that generates remarkable saccades as an emergent property. The Hybrid Binocular Control model incorporates independent controllers for each eye with a cortical origin that interact with a unitary conjugate controller residing in brainstem. The model also accounts for behavioral variations in remarkable saccades when observers attend to an eye. Furthermore, it suggests more generally how the eyes are controlled during vergence and other voluntary eye movements, thus challenging documented oculomotor neural circuitry and suggesting that refinements are needed for clinical oculomotor interventions.
Oral vancomycin treatment alters levels of indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes during EAE
Authors: Bianchimano Paola , Leone Paola , Smith Emma M. , Gutierrez-Vazquez Cristina , Wind-andersen Erli , Bongers Gerold , Cristancho Sebastian , Weiner Howard L. , Clemente Jose C. , Tankou Stephanie K.
Published: June 2024

Astrocytes play important roles in the central nervous system (CNS) during health and disease. Prior studies have shown that gut commensals derived indole derivatives as well as secondary bile acids modulate astrocyte function during the late stage of EAE (recovery phase). Here we show that administering vancomycin to mice starting during the early stage of EAE improved disease recovery, an effect that is mediated by the gut microbiota. We observed that 6 taxa within theClostridia vadin BB60group were enriched in vancomycin treated mice compared to untreated EAE mice. Vancomycin-treated EAE mice also had elevated serum levels of the anti-inflammatory tryptophan derived metabolite, indole-3-lactic acid and decreased levels of deoxycholic acid, a pro-inflammatory secondary bile acid. RNA sequencing revealed altered expression of several genes belonging to the mammalian target of rapamycin (mTOR) pathway in astrocytes obtained during the late stage of EAE from vancomycin treated EAE mice. Furthermore, we observed a link between serum levels of indole derivatives and bile acids and expression of several genes belonging to the mTOR pathway. Interestingly, the mTOR signaling cascades have been implicated in several key biological processes including innate (e.g., astrocyte) immune responses as well as neuronal toxicity/degeneration. In addition, rapamycin, a specific inhibitor of mTOR, has been shown to inhibit the induction and progression of established EAE. Collectively, our findings suggest that the neuroprotective effect of vancomycin is at least partially mediated by indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes.

HIGHLIGHTS

Vancomycin attenuated established EAE through regulation of the microbiota

Vancomycin induced increased serum levels of indole-3-lactic acid, decreased serum levels of indoxyl-3-sulfate, p-cresol and decreased stool levels of deoxycholic acid

Vancomycin modulated the expression of mTOR pathway genes in astrocytes

Lactobacillus reuteriregulated the expression of mTOR pathway genes in astrocytes

Serum levels of indole-3-lactic acid, indoxyl-3-sulfate, p-cresol and deoxycholic acid correlated with expression of mTOR pathway genes in astrocytes
A haplotype-resolved view of human gene regulation
Authors: Vollger Mitchell R. , Swanson Elliott G. , Neph Shane J. , Ranchalis Jane , Munson Katherine M. , Ho Ching-Huang , Sedeño-Cortés Adriana E. , Fondrie William E. , Bohaczuk Stephanie C. , Mao Yizi , Parmalee Nancy L. , Mallory Benjamin J. , Harvey William T. , Kwon Younjun , Garcia Gage H. , Hoekzema Kendra , Meyer Jeffrey G. , Cicek Mine , Eichler Evan E. , Noble William S. , Witten Daniela M. , Bennett James T. , Ray John P. , Stergachis Andrew B.
Published: June 2024

Most human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We demonstrate that Fiber-seq Inferred Regulatory Elements (FIREs) enable the accurate quantification of chromatin accessibility across the 6 Gbp diploid human genome with single-molecule and single-nucleotide precision. We find that cells can harbor >1,000 regulatory elements with haplotype-selective chromatin accessibility (HSCA) and show that these elements preferentially localize to genomic loci containing the most human genetic diversity, with the human leukocyte antigen (HLA) locus showing the largest amount of HSCA genome-wide in immune cells. Furthermore, we uncover HSCA elements with sequence non-deterministic chromatin accessibility, representing likely somatic epimutations, and show that productive transcription from the inactive X chromosome is buttressed by clustered promoter-proximal elements that escape X chromosome inactivation.
Calorie Restriction Induces Degeneration of Neurons with Mitochondrial DNA Depletion by Altering ER-Mitochondria Calcium Transfer
Authors: Zhou Lingyan , Bao Feixiang , Zheng Jiajun , Ding Yingzhe , Xiao Jiahui , Zhang Jian , Qin Yongpeng , Yang Liang , Wu Yi , Meng Qi , Lu Manjiao , Long Qi , Hu Lingli , Wang Haitao , Huang shijuan , Chen Gong , Liu Xingguo
Published: June 2024

Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model where in mtDNA depletion induced by Herpes Simplex Virus Type 1 (HSV-1) protein-UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neuronsin vitro(rho-) causes epilepsy–like abnormal EEG. Caloric restriction (CR) is a strategy proven to reduce epileptic activity, however CR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating CR-induced mitochondrial calcium overload. Rho-neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho-neuron model. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that CR may not be a viable clinical intervention in patients with mtDNA depletion.
Cellular dsRNA interactome reveals the regulatory map of exogenous RNA sensing
Authors: Lim JinA , Lee Namseok , Ju Seonmin , Kim Jeesoo , Mun Subin , Jeon Moonhyeon , Lee Yong-ki , Lee Seok-Hoon , Ku Jayoung , Kim Sujin , Bae Sangsu , Kim Jong-Seo , Kim Yoosik
Published: June 2024

RNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the golden standard in identifying the RBP repertoire, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without any external stimulus. Notably, our dsRNA interactome contains proteins involved in sensing N6-methyladenosine RNAs and stress granule components. We further perform targeted CRISPR-Cas9 knockout functional screening and discover proteins that can regulate the interferon (IFN) response during exogenous RNA sensing. Interestingly, depleting dsRBPs mostly attenuate the IFN response, and they act as antiviral factors during human β-coronavirus HCoV-OC43 infection. Our dsRNA interactome capture provides an unbiased and comprehensive characterization of putative dsRBPs and will facilitate our understanding of dsRNA sensing in both physiological and pathological contexts.
NLRP3 inflammasome activation and altered mitophagy are key pathways in inclusion body myositis
Authors: Naddaf Elie , Nguyen Thi Kim Oanh , Watzlawik Jens O. , Gao Huanyao , Hou Xu , Fiesel Fabienne C. , Mandrekar Jay , Kokesh Eileen , Harmsen William S. , Lanza Ian R. , Springer Wolfdieter , Trushina Eugenia
Published: June 2024

Background

Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. Inflammation and mitochondrial dysfunction are the most common histopathological findings. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM patients, highlighting sex differences.

Methods

We included 38 IBM patients and 22 age- and sex-matched controls without myopathy. Bulk RNA sequencing, Meso Scale Discovery ELISA, western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants.

Results

We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome pathway being the most upregulated. On muscle histopathology, there is increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibers. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 activation. In the IBM muscle samples, we showed altered mitophagy, most significantly in males, with elevated levels of p-S65-Ubiquitin, a mitophagy marker. Furthermore, p-S65-Ubiquitin aggregates accumulated in muscle fibers that were mostly type 2 and devoid of cytochrome-c-oxidase reactivity. Type 2 muscle fibers are known to be more prone to mitochondrial dysfunction.NLRP3 RNAlevels correlated with p-S65-Ubiquitin levels in both sexes but with loss of in muscle strength only in males. Finally, we identified sex-specific molecular pathways in IBM, with females having activation of pathways that could offset some of the pathomechanisms of IBM.

Conclusions

NLRP3 inflammasome is activated in IBM, along with altered mitophagy particularly in males, which is of potential therapeutic significance. These findings suggest sex-specific mechanisms in IBM that warrant further investigation.
IP10 levels refine severity prognostication in COVID-19 and implicate causes of clinical deterioration: lessons for pandemic preparedness
Authors: Das Abhishek , Wei Jia , McKenzie Duncan , Snell Luke , Sasidharan Shruthi , Vantourout Pierre , Zlatareva Iva , Merrick Blair , Thomas Benjamin , Adiga Vasista , Hussain Khiyam , Batra Rahul , Davies Daniel , Su Jia , Bisnauthsing Karen , Martinez Lauren , Ahmed Asma , Bindhu Hima , Chetan Nirutha , Macrina Maria , Tripathi Himanshu , O’Hara Geraldine , Fairhead Cassandra , Drazdauskaite Gabija , Lock Helen , Dias Mary , Ibrahim Mohammad A. A. , Hayday Thomas , D’Souza George , Edgeworth Jonathan , Vyakarnam Annapurna , Pouwels Koen B , Hayday Adrian C.
Published: June 2024

Background

Emerging pandemics place immense strains on healthcare systems that may be ameliorated by rapid development of biomarkers whose measurements may predict disease severity and additionally inform about disease causation. Conspicuously, such routine measures rarely include immunological cytokines or chemokines, despite their contributions to host protection and immunopathology.

Methods

Multiplex bead-array and ELISA-based serum cytokine and chemokine measurements, routinely employed clinical laboratory measures, and clinical outcomes were collectively fed into predictive model development for prognostication of COVID-19 severity in an unvaccinated UK cohort (Discovery; early-to-mid 2020), with subsequent external validation among a pauci-vaccinated UK cohort (early 2021) and part-vaccinated India cohort (early 2022 to early 2023). Correlates of disease severity were assessed by high-content spectral flow cytometry.

Findings

Incorporating a practical test for the chemokine IP10 (a.k.a. CXCL10) alongside routine clinical laboratory assays increased at-admission test accuracy to prognosticate intensive care requirements or in-hospital mortality at 30 days in the Discovery and Validation cohorts. In the India cohort, high IP10 levels predicted terminal deterioration among unvaccinated persons. High-resolution immune-profiling within subsets of the Discovery and India cohorts associated a T cell-centric signature with disease severity and with high IP10 levels, thereby identifying candidate drivers of COVID-19 deterioration.

Conclusions

IP10 levels measured at or around hospital admission offer a practical biomarker enhancing COVID-19 patient outcome prognostication, particluarly in unvaccinated individuals, and offer mechanistic insights into pathogenesis. Thus, prompt application of systems immune-profiling in future pandemics might rapidly identify prognostic and mechanistic biomarkers of patient deterioration, aiding clinical decision-making at a time of severe healthcare strain.

Funding

Medical Research Council grant, CARDINNATE.