Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.

Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.

Reward Contributions to Serotonergic Functions.

The brain serotonin systems participate in numerous aspects of reward processing, although it remains elusive how exactly serotonin signals regulate neural computation and reward-related behavior. The application of optogenetics and imaging techniques during the last decade has provided many insights. Here, we review recent progress on the organization and physiology of the dorsal raphe serotonin neurons and the relationships between their activity and behavioral functions in the context of reward processing. We also discuss several interesting theories on serotonin's function and how these theories may be reconciled by the possibility that serotonin, acting in synergy with coreleased glutamate, tracks and calculates the so-called beneficialness of the current state to guide an animal's behavior in dynamic environments.

D-LMBmap: a fully automated deep-learning pipeline for whole-brain profiling of neural circuitry.

Recent proliferation and integration of tissue-clearing methods and light-sheet fluorescence microscopy has created new opportunities to achieve mesoscale three-dimensional whole-brain connectivity mapping with exceptionally high throughput. With the rapid generation of large, high-quality imaging datasets, downstream analysis is becoming the major technical bottleneck for mesoscale connectomics. Current computational solutions are labor intensive with limited applications because of the exhaustive manual annotation and heavily customized training. Meanwhile, whole-brain data analysis always requires combining multiple packages and secondary development by users. To address these challenges, we developed D-LMBmap, an end-to-end package providing an integrated workflow containing three modules based on deep-learning algorithms for whole-brain connectivity mapping: axon segmentation, brain region segmentation and whole-brain registration. D-LMBmap does not require manual annotation for axon segmentation and achieves quantitative analysis of whole-brain projectome in a single workflow with superior accuracy for multiple cell types in all of the modalities tested.

Construction of a human cell landscape at single-cell level.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

SlBTB19 interacts with SlWRKY2 to suppress cold tolerance in tomato via the CBF pathway.

Cold stress restricts the metabolic and physiological activities of plants, thereby affecting their growth and development. Although broad-complex, tramtrack, and bric-à-brac (BTB) proteins are essential for diverse biological processes and stress responses, the mechanisms underlying BTB-mediated cold responses remain not fully understood. Here, we characterize the function of the cold-induced SlBTB19 protein in tomato (Solanum lycopersicum). Overexpression of SlBTB19 resulted in increased plant sensitivity to cold stress, whereas SlBTB19 knockout mutants exhibited a cold-tolerance phenotype. Further analyses, including protein-protein interaction studies and cell-free degradation assays, revealed that SlBTB19 interacts with and destabilizes the transcription factor SlWRKY2. Using virus-induced gene silencing (VIGS) to silence SlWRKY2 in both wild-type and slbtb19 mutants, we provided genetic evidence that SlWRKY2 acts downstream of SlBTB19 in regulating cold tolerance. Importantly, we demonstrated that SlWRKY2 positively regulates cold tolerance in a CRT/DRE binding factor (CBF)-dependent manner. Under cold stress, SlWRKY2 binds to the W-box in the CBF1 and CBF3 promoters, directly activating their expression. In summary, our findings identify a SlBTB19-SlWRKY2 module that negatively regulates the CBF-dependent cold tolerance pathway in tomato.

Directed evolution of adeno-associated virus for efficient gene delivery to microglia.

As the resident immune cells in the central nervous system (CNS), microglia orchestrate immune responses and dynamically sculpt neural circuits in the CNS. Microglial dysfunction and mutations of microglia-specific genes have been implicated in many diseases of the CNS. Developing effective and safe vehicles for transgene delivery into microglia will facilitate the studies of microglia biology and microglia-associated disease mechanisms. Here, we report the discovery of adeno-associated virus (AAV) variants that mediate efficient in vitro and in vivo microglial transduction via directed evolution of the AAV capsid protein. These AAV-cMG and AAV-MG variants are capable of delivering various genetic payloads into microglia with high efficiency, and enable sufficient transgene expression to support fluorescent labeling, Ca2+ and neurotransmitter imaging and genome editing in microglia in vivo. Furthermore, single-cell RNA sequencing shows that the AAV-MG variants mediate in vivo transgene delivery without inducing microglia immune activation. These AAV variants should facilitate the use of various genetically encoded sensors and effectors in the study of microglia-related biology.

Molecular-Sieving Separation of Methanol/Benzene Azeotrope by a Flexible Metal-Organic Framework.

Separation of methanol/benzene azeotrope mixtures is very challenging not only by the conventional distillation technique but also by adsorbents. In this work, we design and synthesize a flexible Ca-based metal-organic framework MAF-58 consisting of cheap raw materials. MAF-58 shows selective methanol-induced pore-opening flexibility. Although the opened pores are large enough to accommodate benzene molecules, MAF-58 shows methanol/benzene molecular sieving with ultrahigh experimental selectivity, giving 5.1 mmol g-1 high-purity (99.99%+) methanol and 2.0 mmol g-1 high-purity (99.97%+) benzene in a single adsorption/desorption cycle. Computational simulations reveal that the preferentially adsorbed, coordinated methanol molecules act as the gating component to selectively block the diffusion of benzene, offering a new gating adsorption mechanism.

Minimal residual disease profiling predicts pathological complete response in esophageal squamous cell carcinoma.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher's exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher's exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

In Situ Photogenerated Radicals of Hydroxyl Substituted Pyrene-Based Triphenylamines with Enhanced Transport and Free Doping/Post-Oxidation for Efficient Perovskite Solar Cells.

The high-performance hole transporting material (HTM) is one of the most important components for the perovskite solar cells (PSCs) in promoting power conversion efficiency (PCE). However, the low conductivity of HTMs and their additional requirements for doping and post-oxidation greatly limits the device performance. In this work, three novel pyrene-based derivatives containing methoxy-substituted triphenylamines units (PyTPA, PyTPA-OH and PyTPA-2OH) are designed and synthesized, where different numbers of hydroxyl groups are connected at the 2- or 2,7-positions of the pyrene core. These hydroxyl groups at the 2- or 2,7-positions of pyrene play a significantly role to enhance the intermolecular interactions that are able to generate in situ radicals with the assistance of visible light irradiation, resulting in enhanced hole transferring ability, as well as an enhanced conductivity and suppressed recombination. These pyrene-core based HTMs exhibit excellent performance in PSCs, which possess a higher PCE than those control devices using the traditional spiro-OMeTAD as the HTM. The best performance can be found in the devices with PyTPA-2OH. It has an average PCE of 23.44% (PCEmax = 23.50%), which is the highest PCE among the reported PSCs with the pyrene-core based HTMs up to date. This research offers a novel avenue to design a dopant-free HTM by the combination of the pyrene core, methoxy triphenylamines, and hydroxy groups.

The RALF2-FERONIA-MYB63 module orchestrates growth and defense in tomato roots.

Plant secreted peptides RAPID ALKALINISATION FACTORs (RALFs), which act through the receptor FERONIA (FER), play important roles in plant growth. However, it remains unclear whether and how RALF-FER contributes to the trade-off of plant growth-defense. Here, we used a variety of techniques such as CRISPR/Cas9, protein-protein interaction and transcriptional regulation methods to investigate the role of RALF2 and its receptor FER in regulating lignin deposition, root growth, and defense against Fusarium oxysporum f. sp. lycopersici (Fol) in tomato (Solanum lycopersicum). The ralf2 and fer mutants show reduced primary root length, elevated lignin accumulation, and enhanced resistance against Fol than the wild-type. FER interacts with and phosphorylates MYB63 to promote its degradation. MYB63 serves as an activator of lignin deposition by regulating the transcription of dirigent protein gene DIR19. Mutation of DIR19 suppresses lignin accumulation, and reverses the short root phenotype and Fol resistance in ralf2 or fer mutant. Collectively, our results demonstrate that the RALF2-FER-MYB63 module fine-tunes root growth and resistance against Fol through regulating the deposition of lignin in tomato roots. The study sheds new light on how plants maintain the growth-defense balance via RALF-FER.

CALMODULIN6 negatively regulates cold tolerance by attenuating ICE1-dependent stress responses in tomato.

Chilling temperatures induce an increase in cytoplasmic calcium (Ca2+) ions to transmit cold signals, but the precise role of Calmodulins (CaMs), a type of Ca2+ sensor, in plant tolerance to cold stress remains elusive. In this study, we characterized a tomato (Solanum lycopersicum) CaM gene, CALMODULIN6 (CaM6), which responds to cold stimulus. Overexpressing CaM6 increased tomato sensitivity to cold stress whereas silencing CaM6 resulted in a cold-insensitive phenotype. We showed that CaM6 interacts with Inducer of CBF expression 1 (ICE1) in a Ca2+-independent process and ICE1 contributes to cold tolerance in tomato plants. By integrating RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) assays, we revealed that ICE1 directly altered the expression of 76 downstream cold-responsive (COR) genes that potentially confer cold tolerance to tomato plants. Moreover, the physical interaction of CaM6 with ICE1 attenuated ICE1 transcriptional activity during cold stress. These findings reveal that CaM6 attenuates the cold tolerance of tomato plants by suppressing ICE1-dependent COR gene expression. We propose a CaM6/ICE1 module in which ICE1 is epistatic to CaM6 under cold stress. Our study sheds light on the mechanism of plant response to cold stress and reveals CaM6 is involved in the regulation of ICE1.

Decoding the Drive-Bath Interplay: A Guideline to Enhance Superconductivity.

Driven-dissipative physics lie at the core of quantum optics. However, the full interplay between a driven quantum many-body system and its environment remains relatively unexplored in the solid state realm. In this Letter, we inspect this interplay beyond the commonly employed stroboscopic Hamiltonian picture based on the specific example of a driven superconductor. Using the Shirley-Floquet and Keldysh formalisms as well as a generalization of the notion of superconducting fitness to the driven case, we show how a drive which anticommutes with the superconducting gap operator generically induces an unusual particle-hole structure in the spectral functions from the perspective of the thermal bath. Concomitant with a driving frequency which is near resonant with the intrinsic cutoff frequency of the underlying interaction, this spectral structure can be harnessed to enhance the superconducting transition temperature. Our work paves the way for further studies for driven-dissipative engineering of exotic phases of matter in solid-state systems.

New strategies to study in depth the metabolic mechanism of astaxanthin biosynthesis in Phaffia rhodozyma.

Astaxanthin, a ketone carotenoid known for its high antioxidant activity, holds significant potential for application in nutraceuticals, aquaculture, and cosmetics. The increasing market demand necessitates a higher production of astaxanthin using Phaffia rhodozyma. Despite extensive research efforts focused on optimizing fermentation conditions, employing mutagenesis treatments, and utilizing genetic engineering technologies to enhance astaxanthin yield in P. rhodozyma, progress in this area remains limited. This review provides a comprehensive summary of the current understanding of rough metabolic pathways, regulatory mechanisms, and preliminary strategies for enhancing astaxanthin yield. However, further investigation is required to fully comprehend the intricate and essential metabolic regulation mechanism underlying astaxanthin synthesis. Specifically, the specific functions of key genes, such as crtYB, crtS, and crtI, need to be explored in detail. Additionally, a thorough understanding of the action mechanism of bifunctional enzymes and alternative splicing products is imperative. Lastly, the regulation of metabolic flux must be thoroughly investigated to reveal the complete pathway of astaxanthin synthesis. To obtain an in-depth mechanism and improve the yield of astaxanthin, this review proposes some frontier methods, including: omics, genome editing, protein structure-activity analysis, and synthetic biology. Moreover, it further elucidates the feasibility of new strategies using these advanced methods in various effectively combined ways to resolve these problems mentioned above. This review provides theory and method for studying the metabolic pathway of astaxanthin in P. rhodozyma and the industrial improvement of astaxanthin, and provides new insights into the flexible combined use of multiple modern advanced biotechnologies.

Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases.

Ferroptosis is a newly discovered form of cell death that is featured in a wide range of diseases. Exosome therapy is a promising therapeutic option that has attracted much attention due to its low immunogenicity, low toxicity, and ability to penetrate biological barriers. In addition, emerging evidence indicates that exosomes possess the ability to modulate the progression of diverse diseases by regulating ferroptosis in damaged cells. Hence, the mechanism by which cell-derived and noncellular-derived exosomes target ferroptosis in different diseases through the system Xc-/GSH/GPX4 axis, NAD(P)H/FSP1/CoQ10 axis, iron metabolism pathway and lipid metabolism pathway associated with ferroptosis, as well as its applications in liver disease, neurological diseases, lung injury, heart injury, cancer and other diseases, are summarized here. Additionally, the role of exosome-regulated ferroptosis as an emerging repair mechanism for damaged tissues and cells is also discussed, and this is expected to be a promising treatment direction for various diseases in the future. Video Abstract.

Genome-wide characterization of cytochrome P450 genes reveals the potential roles in fruit ripening and response to cold stress in tomato.

Plant cytochrome P450 (CYP) superfamily, the largest enzyme metabolism family, has been identified in many species and plays a vital role in plant development and stress response via secondary metabolite biosynthesis. A comprehensive identification and functional investigation of CYPs in tomato plants would contribute to deeper understanding of their biological significance. In this study, 268 tomato CYP genes were identified and found to be unevenly located on 12 chromosomes. Based on the phylogenetic analysis, these 268 SlCYPs were classed into two distinct clades (A-type and non-A-type) and nine clans, including 48 families. Moreover, 67 tandem and 22 WGD (whole genome duplication)/segmental duplication events were detected, of which 12 SlCYP genes experienced both WGD/segmental and tandem duplication events, indicating that tandem duplication plays a major role in the expansion of the SlCYP family. Besides, 48 pairs containing 41 SlCYP and 44 AtCYP genes were orthologous, while 216 orthologous pairs were obtained between tomato and potato. The expression level of all SlCYP genes in tomato tissues at different development stages was analyzed, and most expressed SlCYPs showed a tissue-specific pattern. Meanwhile, 143 differentially expressed SlCYPs were identified under cold stress. Furthermore, the RT-qPCR results indicated that SlCYPs may be involved in fruit ripening and cold tolerance in tomato seedlings. These findings provide valuable insights into the evolutionary relationships and functional characteristics of SlCYPs, which can be utilized for further investigation of fruit metabolic pathways and cold tolerance in tomato.

Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity.

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.

Impact of pre-delivery medication treatment on delivery outcome in patients with primary immune thrombocytopenia: a cohort study.

BACKGROUND: Clinical research data showed a series of adverse events in the delivery period of primary immune thrombocytopenia (ITP) patients, including high cesarean section rate. Consensus report proposed that for patients with platelet count below 50 × 109/L, prednisone or intravenous immunoglobulins (IVIg) can be given to raise the platelet count in third trimester in preparation for labor. OBJECTIVES: To evaluate the effect of low-dose prednisone or IVIg therapy on delivery outcomes in patients with ITP. STUDY DESIGN: This was a cohort study that included pregnant women with ITP from January 2017 to December 2022. Patients with platelet counts of (20-50) ×109/L at the time of delivery (≥34 weeks) and who had not received any medication before were enrolled in the study. Patients were divided into the pre-delivery medication group (oral prednisone or IVIg) and untreated group according to their preferences. The differences in vaginal delivery rate, postpartum bleeding rate, and platelet transfusion volume between the two groups were compared using t-test, Wilcoxon rank-sum test, and χ2 test. Logistic regression analysis was used to identify the factors affecting vaginal delivery rate and postpartum bleeding rate, and multiple linear regression analysis was used to identify the factors affecting platelet transfusion volume. RESULTS: During the study period, a total of 96 patients with ITP were enrolled, including 70 in the pre-delivery medication group and 26 in the untreated group. The platelet count of pre-delivery medication group was 54.8 ± 34.5 × 109/L, which was significantly higher than that of untreated group 34.4 ± 9.0 × 109/L (p = .004). The vaginal delivery rate of the medication group was higher than the untreated group [60.0% (42/70) vs. 30.8% (8/26), χ2 = 6.49, p = .013]. After adjusting for the proportion of multiparous women and gestational weeks, the results showed that medication therapy during the peripartum period was associated with vaginal delivery (OR = 4.937, 95% CI: 1.511-16.136, p = .008). The postpartum bleeding rates were 22.9% (16/70) and 26.9% (7/26) in the medication group and untreated group, respectively, with no significant difference between the two groups (χ2 = 0.17, p = .789), while the platelet transfusion volume was lower in the medication group than untreated group [(1.1 ± 1.0) vs. (1.6 ± 0.8) U]. CONCLUSION: Pre-delivery medication therapy can increase vaginal delivery rate, reduce platelet transfusion volume, but does not decrease the incidence of postpartum hemorrhage.

What is the context?The high cesarean section rate has always been a prominent pregnancy issue in ITP patients. The data shows that the reason for cesarean section in most ITP patients may be related to early induced labor due to thrombocytopenia or patients' concerns of bleeding events during delivery. The study of treatment during the perinatal period is expected to further increase platelet count and prepare for safer delivery.What is new?To date, no study has focused on pre-delivery treatment for pregnant ITP patients. In this study, patients with a platelet count<50 × 109/L after 34 weeks can experience a significant increase in platelet count after receiving immunoglobulin or prednisone therapy. The results of this study preliminarily demonstrate IVIg or prednisone is a promising pre-delivery treatment for pregnant ITP patients in preparation for labor. The pre-delivery medication therapy can improve the rate of successful vaginal delivery and reduce the consumption of blood products.What is the impact?This study provides further evidence that the target threshold for platelets should be raised in late third trimester, with a platelet count above 50 × 109/L as the standard for delivery, in order to further reduce the cesarean section rate and blood product infusion in ITP patients.

Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs.

BACKGROUND: Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic cancer often accompany with dismal prognosis, highlighting the need to investigate mechanisms of drug resistance and develop therapies to overcome chemoresistance. METHODS: This research was filed with the Chinese Clinical Trial Registry (ChiCTR2200061320). In order to isolate primary normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) samples of pancreatic ductal adenocarcinoma (PDAC) and paracancerous pancreatic tissue from individuals diagnosed with PDAC were obtained. The exosomes were obtained using ultracentrifugation, and their characteristics were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. CAF-derived miRNAs were analyzed by RT-qPCR and high-throughput sequencing. Gemcitabine (GEM) was employed to promote ferroptosis, and ferroptosis levels were determined by monitoring lipid reactive oxygen species (ROS), cell survival, and intracellular Fe2+ concentrations. To assess in vivo tumor response to GEM therapy, a xenograft tumor mouse model was utilized. RESULTS: Exosomes derived from CAFs in PDAC did not exhibit innate GEM resistance. CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173-5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. CONCLUSION: This work demonstrates a novel mode of acquired chemoresistance in PDAC and identifies the miR-3173-5p/ACSL4 pathway as a promising treatment target for GEM-resistant pancreatic cancer.

Exploring the causal connection: insights into diabetic nephropathy and gut microbiota from whole-genome sequencing databases.

Over recent years, the prevalence of diabetes has been on the rise, paralleling improvements in living standards. Diabetic nephropathy (DN), a prevalent complication of diabetes, has also exhibited a growing incidence. While some clinical studies and reviews have hinted at a link between diabetic nephropathy and gut microbiota (GM), the nature of this connection, specifically its causative nature, remains uncertain. Investigating the causal relationship between diabetic nephropathy and gut microbiota holds the promise of aiding in disease screening and identifying novel biomarkers. In this study, we employed a two-sample Mendelian randomization analysis. Our dataset encompassed 4,111 DN patients from the GWAS database, juxtaposed with 308,539 members forming a control group. The aim was to pinpoint specific categories within the vast spectrum of the 211 known gut microbiota types that may have a direct causal relationship with diabetic nephropathy. Rigorous measures, including extensive heterogeneity and sensitivity analyses, were implemented to mitigate the influence of confounding variables on our experimental outcomes. Ultimately, our comprehensive analysis revealed 15 distinct categories of gut microbiota that exhibit a causal association with diabetic nephropathy. In summary, the phyla Bacteroidota and Verrucomicrobiae, the families Peptostreptococcaceae and Veillonellaceae, the genus Akkermansia, and the species Catenibacterium, Lachnoclostridium, Parasutterella, along with the orders Bacteroidales and Verrucomicrobiales, and the class Bacteroidetes were identified as correlates of increased risk for DN. Conversely, the family Victivallaceae, the species Eubacterium coprostanoligenes, and the Clostridium sensu stricto 1 group were found to be associated with a protective effect against the development of DN.These findings not only provide valuable insights but also open up novel avenues for clinical research, offering fresh directions for potential treatments.