tbuckley/cabot-search huggingface dataset:
(+)/(−)-Gerbeloid A, a pair of unprecedented coumarin-based polycyclic meroterpenoid enantiomers from Gerbera piloselloides: Structural elucidation, semi-synthesis, and lipid-lowering activity
Authors: Chenxu Zhao, Jingrong Li, Yue Hu, Lingyu Li, Meng Yu, Yunfeng Huang, Tao Zhang, Hai Shang, Zhongmei Zou
Journal: Acta Pharmaceutica Sinica B (2024)

A pair of coumarin-based polycyclic meroterpenoid enantiomers (+)/(−)-gerbeloid A [(+)-1a and (−)-1b] were isolated from the medicinal plant Gerbera piloselloides, which have a unique caged oxatricyclo [4.2.2.03,8] decene scaffold. Their planar and three-dimensional structures were exhaustively characterized by comprehensive spectroscopic data and X-ray diffraction analysis. Guided by the hypothetical biosynthetic pathway, the biomimetic synthesis of racemic 1 was achieved using 4-hydroxy-5-methylcoumarin and citral as the starting material via oxa-6π electrocyclization and intramolecular [2+2] photocycloaddition. Subsequently, the results of the biological activity assay demonstrated that both (+)-1a and (−)-1b exhibited potent lipid-lowering effects in 3T3-L1 adipocytes and the high-fat diet zebrafish model. Notably, the lipid-lowering activity of (+)-1a is better than that of (−)-1b at the same concentration, and molecular mechanism study has shown that (+)-1a and (−)-1b impairs adipocyte differentiation and stimulate lipolysis by regulating C/EBPα/PPARγ signaling and Perilipin signaling in vitro and in vivo. Our findings provide a promising drug model molecule for the treatment of obesity.
Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect
Authors: Ning Sheng, Rui Li, Yang Li, Zhe Wang, Lulu Wang, Yuhuan Li, Jinlan Zhang, Jiandong Jiang
Journal: Acta Pharmaceutica Sinica B (2024)

Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design.
The emerging role of tranexamic acid and its principal target, plasminogen, in skeletal health
Authors: Weixin Xie, Antonia Donat, Shan Jiang, Anke Baranowsky, Johannes Keller
Journal: Acta Pharmaceutica Sinica B (2024)

The worldwide burden of skeletal diseases such as osteoporosis, degenerative joint disease and impaired fracture healing is steadily increasing. Tranexamic acid (TXA), a plasminogen inhibitor and anti-fibrinolytic agent, is used to reduce bleeding with high effectiveness and safety in major surgical procedures. With its widespread clinical application, the effects of TXA beyond anti-fibrinolysis have been noticed and prompted renewed interest in its use. Some clinical trials have characterized the effects of TXA on reducing postoperative infection rates and regulating immune responses in patients undergoing surgery. Also, several animal studies suggest potential therapeutic effects of TXA on skeletal diseases such as osteoporosis and fracture healing. Although a direct effect of TXA on the differentiation and function of bone cells in vitro was shown, few mechanisms of action have been reported. Here, we summarize recent findings of the effects of TXA on skeletal diseases and discuss the underlying plasminogen-dependent and -independent mechanisms related to bone metabolism and the immune response. We furthermore discuss potential novel indications for TXA application as a treatment strategy for skeletal diseases.
Transplantation of dorsal root ganglia overexpressing the NaChBac sodium channel improves locomotion after complete SCI
Authors: Sonia Hingorani, Guillem Paniagua Soriano, Carlos Sánchez Huertas, Eva María Villalba Riquelme, Eric López Mocholi, Beatriz Martínez Rojas, Ana Alastrué Agudo, Sebastián Dupraz, Antonio Vicente Ferrer Montiel, Victoria Moreno Manzano
Journal: Molecular Therapy (2024)

Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRGs) genetically modified to express the NaChBac sodium channel could serve as a therapeutic option for functionally complete SCI. We found that NaChBac expression increased the intrinsic excitability of DRG neurons and promoted cell survival and neurotrophic factor secretion in vitro. Transplantation of NaChBac-expressing dissociated DRGs improved voluntary locomotion 7 weeks after injury compared to control groups. Animals transplanted with NaChBac-expressing DRGs also possessed higher tubulin-positive neuronal fiber and myelin preservation, although serotonergic descending fibers remained unaffected. We observed early preservation of the corticospinal tract 14 days after injury and transplantation, which was lost 7 weeks after injury. Nevertheless, transplantation of NaChBac-expressing DRGs increased the neuronal excitatory input by an increased number of VGLUT2 contacts immediately caudal to the injury. Our work suggests that the transplantation of NaChBac-expressing dissociated DRGs can rescue significant motor function, retaining an excitatory neuronal relay activity immediately caudal to injury.
Multiomics Analyses Provide New Insight into Genetic Variation of Reproductive Adaptability in Tibetan Sheep
Authors: Buying Han, Dehong Tian, Xue Li, Sijia Liu, Fei Tian, Dehui Liu, Song Wang, Kai Zhao
Journal: Molecular Biology and Evolution (2024)

Abstract Domestication and artificial selection during production-oriented breeding have greatly shaped the level of genomic variability in sheep. However, the genetic variation associated with increased reproduction remains elusive. Here, two groups of samples from consecutively monotocous and polytocous sheep were collected for genome-wide association, transcriptomic, proteomic, and metabolomic analyses to explore the genetic variation in fecundity in Tibetan sheep. Genome-wide association study revealed strong associations between BMPR1B (p.Q249R) and litter size, as well as between PAPPA and lambing interval; these findings were validated in 1,130 individuals. Furthermore, we constructed the first single-cell atlas of Tibetan sheep ovary tissues and identified a specific mural granulosa cell subtype with PAPPA-specific expression and differential expression of BMPR1B between the two groups. Bulk RNA-seq indicated that BMPR1B and PAPPA expressions were similar between the two groups of sheep. 3D protein structure prediction and coimmunoprecipitation analysis indicated that mutation and mutually exclusive exons of BMPR1B are the main mechanisms for prolific Tibetan sheep. We propose that PAPPA is a key gene for stimulating ovarian follicular growth and development, and steroidogenesis. Our work reveals the genetic variation in reproductive performance in Tibetan sheep, providing insights and valuable genetic resources for the discovery of genes and regulatory mechanisms that improve reproductive success.
One‐Pot Synthesis of Luminescent and Photothermal Carbon Boron‐Nitride Quantum Dots Exhibiting Cell Damage Protective Effects
Authors: Grazia M. L. Consoli, Ludovica Maugeri, Nicolò Musso, Antonino Gulino, Luisa D'Urso, Paolo Bonacci, Gianpiero Buscarino, Giuseppe Forte, Salvatore Petralia
Journal: Advanced Healthcare Materials (2024)

Abstract Zero‐dimensional boron nitride quantum dots (BNQDs) are arousing interest for their versatile optical, chemical, and biochemical properties. Introducing carbon contents in BNQDs nanostructures is a great challenge to modulate their physicochemical properties. Among the carbon moieties, phenolic groups have attracted attention for their biochemical properties and phenol‐containing nanomaterials are showing great promise for biomedical applications. Herein, the first example of direct synthesis of water dispersible BNQDs exposing phenolic and carboxylic groups is presented. The carbon‐BNQDs are prepared in a single‐step by solvent‐assisted reaction of urea with boronic reagents and are characterized by optical absorption, luminescence, Raman, Fourier transform infrared and NMR spectroscopy, X‐ray photoelectron spectroscopy, dynamic light scattering, and atomic force microscopy. The carbon‐BNQDs exhibit nanodimension, stability, high photothermal conversion efficiency, pH‐responsive luminescence and Z‐potential. The potential of the carbon‐BNQDs to provide photothermal materials in solid by embedding in agarose substrate is successfully investigated. The carbon‐BNQDs exhibit biocompatibility on colorectal adenocarcinoma cells (Caco‐2) and protective effects from chemical and oxidative stress on Caco‐2, osteosarcoma (MG‐63), and microglial (HMC‐3) cells. Amplicon mRNA‐seq analyses for the expression of 56 genes involve in oxidative‐stress and inflammation are performed to evaluate the molecular events responsible for the cell protective effects of the carbon‐BNQDs.
Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade
Authors: Hidetoshi Hayashi, Kenji Chamoto, Ryusuke Hatae, Takashi Kurosaki, Yosuke Togashi, Kazuya Fukuoka, Megumi Goto, Yasutaka Chiba, Shuta Tomida, Takayo Ota, Koji Haratani, Takayuki Takahama, Junko Tanizaki, Takeshi Yoshida, Tsutomu Iwasa, Kaoru Tanaka, Masayuki Takeda, Tomoko Hirano, Hironori Yoshida, Hiroaki Ozasa, Yuichi Sakamori, Kazuko Sakai, Keiko Higuchi, Hitoshi Uga, Chihiro Suminaka, Toyohiro Hirai, Kazuto Nishio, Kazuhiko Nakagawa, Tasuku Honjo
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.
The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia
Authors: Nicole Calakos, Zachary F Caffall
Journal: Journal of Clinical Investigation (2024)

The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health in the face of diverse stressors. In this Review, we discuss a relatively noncanonical role for the ISR in neuromodulatory neurons and its implications for synaptic plasticity, learning, and memory. Beyond its roles in stress response, the ISR has been extensively studied in the brain, where it potently influences learning and memory, and in the process of synaptic plasticity, which is a substrate for adaptive behavior. Recent findings demonstrate that some neuromodulatory neuron types engage the ISR in an "always-on" mode, rather than the more canonical "on-demand" response to transient perturbations. Atypical demand for the ISR in neuromodulatory neurons introduces an additional mechanism to consider when investigating ISR effects on synaptic plasticity, learning, and memory. This basic science discovery emerged from a consideration of how the ISR might be contributing to human disease. To highlight how, in scientific discovery, the route from starting point to outcomes can often be circuitous and full of surprise, we begin by describing our group's initial introduction to the ISR, which arose from a desire to understand causes for a rare movement disorder, dystonia. Ultimately, the unexpected connection led to a deeper understanding of its fundamental role in the biology of neuromodulatory neurons, learning, and memory.
The road to refractory graft-versus-host disease is paved with good intentions
Authors: Daniel North, Ronjon Chakraverty
Journal: Journal of Clinical Investigation (2024)

Refractory acute graft-versus-host disease (GVHD) occurs when the immune injury exceeds the capacity of injured tissues to regenerate and repair. While glucocorticoids have been used for decades to treat GVHD, Arnhold, Chang, and colleagues in this issue of the JCI question whether this approach can in fact be counterproductive. Using in vivo experimental models of GVHD and in vitro intestinal organoids, the study authors show that glucocorticoid exposure directly impeded small intestinal epithelial proliferation and survival, thus preventing the resolution of injury. These findings suggest that future treatment approaches for acute GVHD should include measures to reduce immune reactivity as well as interventions to actively promote tissue resilience.
Questioning risk compensation: pre-exposure prophylaxis (PrEP) and sexually transmitted infections among men who have sex with men, capital region of Denmark, 2019 to 2022
Authors: Sebastian von Schreeb, Susanne Kriegel Pedersen, Hanne Christensen, Kristina Melbardis Jørgsensen, Lene Holm Harritshøj, Frederik Boetius Hertz, Magnus Glindvad Ahlström, Anne-Mette Lebech, Suzanne Lunding, Lars Nørregaard Nielsen, Jan Gerstoft, Gitte Kronborg, Frederik N Engsig
Journal: Eurosurveillance (2024)

Background Pre-exposure prophylaxis (PrEP) effectively prevents HIV, but its association with sexually transmitted infections (STIs) has raised concerns about risk compensation, potentially impacting the expansion of PrEP programmes. Aim We examined the relationship between PrEP and the incidence of chlamydia, gonorrhoea and syphilis. Methods In this prospective cohort study, we compared STI rates before and after PrEP initiation among users in the capital region of Denmark (2019–2022), calculating incidence rate ratios adjusted for age and testing frequency (aIRR). To pinpoint when increases began, we plotted weekly STI rates, adjusting the timeline to correspond with PrEP initiation. Results The study included 1,326 PrEP users with a median age of 35 years. The STI incidence rate per 100,000 person-years rose from 35.3 before to 81.2 after PrEP start, with an aIRR of 1.35 (95% CI: 1.18–1.56). Notably, this increase preceded PrEP initiation by 10–20 weeks. Specific aIRR for chlamydia, gonorrhoea and syphilis were 1.23 (95% CI: 1.03–1.48), 1.24 (95% CI: 1.04–1.47) and 1.15 (95% CI: 0.76–1.72), respectively. In subanalyses for anatomical sites aIRR was 1.26 (95% CI: 1.01–1.56) for rectal chlamydia and 0.66 (95% CI: 0.45–0.96) for genital gonorrhoea. Conclusion We found a 35% increase in STI incidence associated with PrEP use. It started before PrEP initiation, challenging the assumption that PrEP leads to risk compensation. Instead, the data suggest that individuals seek PrEP during periods of heightened sexual risk-taking. Consequently, PrEP programmes should include sexual health consultations, STI testing, treatment and prevention strategies to prevent HIV and improve sexual health.
Molecular epidemiology identifies the expansion of the DENV2 epidemic lineage from the French Caribbean Islands to French Guiana and mainland France, 2023 to 2024
Authors: Raphaëlle Klitting, Géraldine Piorkowski, Dominique Rousset, André Cabié, Etienne Frumence, Alisé Lagrave, Anne Lavergne, Antoine Enfissi, George Dos Santos, Laurence Fagour, Raymond Césaire, Marie-Christine Jaffar-Bandjee, Nicolas Traversier, Patrick Gérardin, Rayane Amaral, Lucie Fournier, Lucie Leon, Frédérique Dorléans, Muriel Vincent, Albin Fontaine, Anna-Bella Failloux, Nazli Ayhan, Laura Pezzi, Gilda Grard, Guillaume André Durand, Xavier de Lamballerie
Journal: Eurosurveillance (2024)

In 2023, dengue virus serotype 2 (DENV2) affected most French overseas territories. In the French Caribbean Islands, viral circulation continues with &gt; 30,000 suspected infections by March 2024. Genome sequence analysis reveals that the epidemic lineage in the French Caribbean islands has also become established in French Guiana but not Réunion. It has moreover seeded autochthonous circulation events in mainland France. To guide prevention of further inter-territorial spread and DENV introduction in non-endemic settings, continued molecular surveillance and mosquito control are essential.
Atypical age distribution and high disease severity in children with RSV infections during two irregular epidemic seasons throughout the COVID-19 pandemic, Germany, 2021 to 2023
Authors: Wei Cai, Sophie Köndgen, Kristin Tolksdorf, Ralf Dürrwald, Ekkehard Schuler, Barbara Biere, Brunhilde Schweiger, Luise Goerlitz, Walter Haas, Thorsten Wolff, Silke Buda, Janine Reiche
Journal: Eurosurveillance (2024)

Background Non-pharmaceutical interventions (NPIs) during the COVID-19 pandemic affected respiratory syncytial virus (RSV) circulation worldwide. Aim To describe, for children aged &lt; 5 years, the 2021 and 2022/23 RSV seasons in Germany. Methods Through data and 16,754 specimens from outpatient sentinel surveillance, we investigated RSV seasonality, circulating lineages, and affected children’s age distributions in 2021 and 2022/23. Available information about disease severity from hospital surveillance was analysed for patients with RSV-specific diagnosis codes (n = 13,104). Differences between RSV seasons were assessed by chi-squared test and age distributions trends by Mann–Kendall test. Results RSV seasonality was irregular in 2021 (weeks 35–50) and 2022/23 (weeks 41–3) compared to pre-COVID-19 2011/12–2019/20 seasons (median weeks 51–12). RSV positivity rates (RSV-PR) were higher in 2021 (40% (522/1,291); p &lt; 0.001) and 2022/23 (30% (299/990); p = 0.005) than in prior seasons (26% (1,430/5,511)). Known globally circulating RSV-A (lineages GA2.3.5 and GA2.3.6b) and RSV-B (lineage GB5.0.5a) strains, respectively, dominated in 2021 and 2022/23. In 2021, RSV-PRs were similar in 1 – &lt; 2, 2 – &lt; 3, 3 – &lt; 4, and 4 – &lt; 5-year-olds. RSV hospitalisation incidence in 2021 (1,114/100,000, p &lt; 0.001) and in 2022/23 (1,034/100,000, p &lt; 0.001) was approximately double that of previous seasons’ average (2014/15–2019/20: 584/100,000). In 2022/23, proportions of RSV patients admitted to intensive care units rose (8.5% (206/2,413)) relative to pre-COVID-19 seasons (6.8% (551/8,114); p = 0.004), as did those needing ventilator support (6.1% (146/2,413) vs 3.8% (310/8,114); p &lt; 0.001). Conclusions High RSV-infection risk in 2–4-year-olds in 2021 and increased disease severity in 2022/23 possibly result from lower baseline population immunity, after NPIs diminished exposure to RSV.
The effects of antibiotic exposures on the gut resistome during hematopoietic cell transplantation in children
Authors: Sarah M. Heston, Rebecca R. Young, Kirsten Jenkins, Paul L. Martin, Andre Stokhuyzen, Doyle V. Ward, Shakti K. Bhattarai, Vanni Bucci, Mehreen Arshad, Nelson J. Chao, Patrick C. Seed, Matthew S. Kelly
Journal: Gut Microbes (2024)

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, β = 0.71, 95% CI: 0.64, 0.79; anaerobic, β = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, β = 0.81, 95% CI: 0.74, 0.90; anaerobic, β = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, β = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, β = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.