Identifying cell type-specific transcription factor-mediated activity immune modules reveal implications for immunotherapy and molecular classification of pan-cancer.

Systematic investigation of tumor-infiltrating immune (TII) cells is important to the development of immunotherapies, and the clinical response prediction in cancers. There exists complex transcriptional regulation within TII cells, and different immune cell types display specific regulation patterns. To dissect transcriptional regulation in TII cells, we first integrated the gene expression profiles from single-cell datasets, and proposed a computational pipeline to identify TII cell type-specific transcription factor (TF) mediated activity immune modules (TF-AIMs). Our analysis revealed key TFs, such as BACH2 and NFKB1 play important roles in B and NK cells, respectively. We also found some of these TF-AIMs may contribute to tumor pathogenesis. Based on TII cell type-specific TF-AIMs, we identified eight CD8+ T cell subtypes. In particular, we found the PD1 + CD8+ T cell subset and its specific TF-AIMs associated with immunotherapy response. Furthermore, the TII cell type-specific TF-AIMs displayed the potential to be used as predictive markers for immunotherapy response of cancer patients. At the pan-cancer level, we also identified and characterized six molecular subtypes across 9680 samples based on the activation status of TII cell type-specific TF-AIMs. Finally, we constructed a user-friendly web interface CellTF-AIMs (http://bio-bigdata.hrbmu.edu.cn/CellTF-AIMs/) for exploring transcriptional regulatory pattern in various TII cell types. Our study provides valuable implications and a rich resource for understanding the mechanisms involved in cancer microenvironment and immunotherapy.

The uS10c-BPG2 module mediates ribosomal RNA processing in chloroplast nucleoids.

In plant chloroplasts, certain ribosomal proteins (RPs) and ribosome biogenesis factors (RBFs) are present in nucleoids, implying an association between nucleoids and ribosome biogenesis. In Arabidopsis, the YqeH-type GTPase Brassinazole-Insensitive Pale Green2 (BPG2) is a chloroplast nucleoid-associated RBF. Here, we investigated the relationship between nucleoids and BPG2-involved ribosome biogenesis steps by exploring how BPG2 targets ribosomes. Our findings demonstrate that BPG2 interacts with an essential plastid RP, uS10c, in chloroplast nucleoids in a ribosomal RNA (rRNA)-independent manner. We also discovered that uS10c is a haploinsufficient gene, as the heterozygous deletion of this gene leads to variegated shoots and chlorophyll aggregation. uS10c is integrated into 30S ribosomal particles when rRNA is relatively exposed and also exists in polysome fractions. In contrast, BPG2 exclusively associates with 30S ribosomal particles. Notably, the interaction between BPG2 and 30S particles is influenced by the absence of uS10c, resulting in BPG2 diffusing in chloroplasts instead of targeting nucleoids. Further, our results reveal that the loss of BPG2 function and the heterozygous deletion of uS10c impair the processing of 16S and 23S-4.5S rRNAs, reduce plastid protein accumulation, and trigger the plastid signaling response. Together, these findings indicate that the uS10c-BPG2 module mediates ribosome biogenesis in chloroplast nucleoids.

ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Sugar status in preexisting leaves determines systemic stomatal development within newly developing leaves.

Stomata are pores found in the epidermis of stems or leaves that modulate both plant gas exchange and water/nutrient uptake. The development and function of plant stomata are regulated by a diverse range of environmental cues. However, how carbohydrate status in preexisting leaves might determine systemic stomatal formation within newly developing leaves has remained obscure. The glucose (Glc) sensor HEXOKINASE1 (HXK1) has been reported to decrease the stability of an ethylene/Glc signaling transcriptional regulator, EIN3 (ETHYLENE INSENSITIVE3). EIN3 in turn directly represses the expression of SUC2 (sucrose transporter 2), encoding a master transporter of sucrose (Suc). Further, KIN10, a nuclear regulator involved in energy homeostasis, has been reported to repress the transcription factor SPCH (SPEECHLESS), a master regulator of stomatal development. Here, we demonstrate that the Glc status of preexisting leaves determines systemic stomatal development within newly developing leaves by the HXK1-¦EIN3-¦SUC2 module. Further, increasing Glc levels in preexisting leaves results in a HXK1-dependent decrease of EIN3 and increase of SUC2, triggering the perception, amplification and relay of HXK1-dependent Glc signaling and thereby triggering Suc transport from mature to newly developing leaves. The HXK1-¦EIN3-¦SUC2 molecular module thereby drives systemic Suc transport from preexisting leaves to newly developing leaves. Subsequently, increasing Suc levels within newly developing leaves promotes stomatal formation through the established KIN10⟶ SPCH module. Our findings thus show how a carbohydrate signal in preexisting leaves is sensed, amplified and relayed to determine the extent of systemic stomatal development within newly developing leaves.

CRISPR/FnCas12a-mediated efficient multiplex and iterative genome editing in bacterial plant pathogens without donor DNA templates.

CRISPR-based genome editing technology is revolutionizing prokaryotic research, but it has been rarely studied in bacterial plant pathogens. Here, we have developed a targeted genome editing method with no requirement of donor templates for convenient and efficient gene knockout in Xanthomonas oryzae pv. oryzae (Xoo), one of the most important bacterial pathogens on rice, by employing the heterologous CRISPR/Cas12a from Francisella novicida and NHEJ proteins from Mycobacterium tuberculosis. FnCas12a nuclease generated both small and large DNA deletions at the target sites as well as it enabled multiplex genome editing, gene cluster deletion, and plasmid curing in the Xoo PXO99A strain. Accordingly, a non-TAL effector-free polymutant strain PXO99AD25E, which lacks all 25 xop genes involved in Xoo pathogenesis, has been engineered through iterative genome editing. Whole-genome sequencing analysis indicated that FnCas12a did not have a noticeable off-target effect. In addition, we revealed that these strategies are also suitable for targeted genome editing in another bacterial plant pathogen Pseudomonas syringae pv. tomato (Pst). We believe that our bacterial genome editing method will greatly expand the CRISPR study on microorganisms and advance our understanding of the physiology and pathogenesis of Xoo.

ABSCISIC ACID-INSENSITIVE 5-KIP-RELATED PROTEIN 1-SHOOT MERISTEMLESS modulates reproductive development of Arabidopsis.

Soil (or plant) water deficit accelerates plant reproduction. However, the underpinning molecular mechanisms remain unknown. By modulating cell division/number, ABSCISIC ACID-INSENSITIVE 5 (ABI5), a key bZIP (basic (region) leucine zippers) transcription factor, regulates both seed development and abiotic stress responses. The KIP-RELATED PROTEIN (KRP) cyclin-dependent kinases (CDKs) play an essential role in controlling cell division, and SHOOT MERISTEMLESS (STM) plays a key role in the specification of flower meristem identity. Here, our findings show that abscisic acid (ABA) signaling and/or metabolism in adjust reproductive outputs (such as rosette leaf number and open flower number) under water-deficient conditions in Arabidopsis (Arabidopsis thaliana) plants. Reproductive outputs increased under water-sufficient conditions but decreased under water-deficient conditions in the ABA signaling/metabolism mutants abscisic acid2-1 (aba2-1), aba2-11, abscisic acid insensitive3-1 (abi3-1), abi4-1, abi5-7, and abi5-8. Further, under water-deficient conditions, ABA induced-ABI5 directly bound to the promoter of KRP1, which encodes a CDK that plays an essential role in controlling cell division, and this binding subsequently activated KRP1 expression. In turn, KRP1 physically interacted with STM, which functions in the specification of flower meristem identity, promoting STM degradation. We further demonstrate that reproductive outputs are adjusted by the ABI5-KRP1-STM molecular module under water-deficient conditions. Together, our findings reveal the molecular mechanism by which ABA signaling and/or metabolism regulate reproductive development under water-deficient conditions. These findings provide insights that may help guide crop yield improvement under water deficiency.

ISL1-overexpressing BMSCs attenuate renal ischemia-reperfusion injury by suppressing apoptosis and oxidative stress through the paracrine action.

Ischemia-reperfusion injury (IRI) is a major event in renal transplantation, leading to adverse outcomes. Bone marrow mesenchymal stem cells (BMSCs) are novel promising therapeutics for repairing kidney injuries. The therapeutic efficacy of BMSCs with ISL1 overexpression in renal IRI and its underlying mechanism need to be investigated. The unilateral renal IRI rat model was established to mimic clinical acute kidney injury. Rats were injected with PBS, BMSCs-Scrambled or BMSCs-ISL1 via the tail vein at the timepoint of reperfusion, and then sacrificed after 24 h of reperfusion. The administration of BMSCs-ISL1 significantly improved renal function, inhibited tubular cells apoptosis, inflammation, oxidative stress in rats. In vitro, HKC cells subjected to H2O2 stimulation were pretreated with the conditioned medium (CM) of BMSCs-Scrambled or BMSCs-ISL1. The pretreatment of ISL1-CM attenuated apoptosis and oxidative stress induced by H2O2 in HKC cells. Our proteomic data suggested that haptoglobin (Hp) was one of the secretory proteins in ISL1-CM. Subsequent experiments confirmed that Hp was the important paracrine factor from BMSCs-ISL1 that exerted anti-apoptotic and antioxidant functions. Mechanistically, Hp played a cytoprotective role via the inhibition of ERK signaling pathway, which could be abrogated by Ro 67-7476, the ERK phosphorylation agonist. The results suggested that paracrine action may be the main mechanism for BMSCs-ISL1 to exert protective effects. As an important anti-apoptotic and antioxidant factor in ISL1-CM, Hp may serve as a new therapeutic agent for treating IRI, providing new insights for overcoming the long-term adverse effects of stem cell therapy.

Necroptosis-related genes allow novel insights into predicting graft loss and diagnosing delayed graft function in renal transplantation.

Ischemia-reperfusion injury (IRI) is an inevitable pathophysiological phenomenon in kidney transplantation. Necroptosis is an undoubtedly important contributing mechanism in renal IRI. We first screened differentially expressed necroptosis-related genes (DENRGs) from public databases. Eight DENRGs were validated by independent datasets and verified by qRT-PCR in a rat IRI model. We used univariate and multivariate Cox regression analyses to establish a prognostic signature, and graft survival analysis was performed. Immune infiltrating landscape analysis and gene set enrichment analysis (GSEA) were performed to understand the underlying mechanisms of graft loss, which suggested that necroptosis may aggravate the immune response, resulting in graft loss. Subsequently, a delayed graft function (DGF) diagnostic signature was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) and exhibited robust efficacy in validation datasets. After comprehensively analyzing DENRGs during IRI, we successfully constructed a prognostic signature and DGF predictive signature, which may provide clinical insights for kidney transplant.

Cost-Effective Cathode Interlayer Material for Scalable Organic Photovoltaic Cells.

Organic photovoltaic (OPV) cells have demonstrated remarkable success on the laboratory scale. However, the lack of cathode interlayer materials for large-scale production still limits their practical application. Here, we rationally designed and synthesized a cathode interlayer, named NDI-Ph. Benefiting from their well-modulated work function and self-doping effect, NDI-Ph-based binary OPV cells achieve an excellent power conversion efficiency (PCE) of 19.1%. NDI-Ph can be easily synthesized on a 100 g scale with a low cost of 1.96 $ g-1 using low-cost raw materials and a simple postprocessing method. In addition, the insensitivity to the film thickness of NDI-Ph enables it to maintain a high PCE at various coating speeds and solution concentrations, demonstrating excellent adaptability for high-throughput OPV cell manufacturing. As a result, a module with 21.9 cm2 active area achieves a remarkable PCEactive of 15.8%, underscoring the prospects of NDI-Ph in the large-scale production of OPV cells.

Fascin-1 limits myosin activity in microglia to control mechanical characterization of the injured spinal cord.

BACKGROUND: Mechanical softening of the glial scar region regulates axonal regeneration to impede neurological recovery in central nervous system (CNS) injury. Microglia, a crucial cellular component of the glial scar, facilitate neuronal survival and neurological recovery after spinal cord injury (SCI). However, the critical mechanical characterization of injured spinal cord that harmonizes neuroprotective function of microglia remains poorly understood. METHODS: Spinal cord tissue stiffness was assessed using atomic force microscopy (AFM) in a mouse model of crush injury. Pharmacological depletion of microglia using PLX5622 was used to explore the effect of microglia on mechanical characterization. Conditional knockout of Fascin-1 in microglia (Fascin-1 CKO) alone or in combination with inhibition of myosin activity was performed to delve into relevant mechanisms of microglia regulating mechanical signal. Immunofluorescence staining was performed to evaluate the related protein levels, inflammatory cells, and neuron survival after SCI. The Basso mouse scale score was calculated to assess functional recovery. RESULTS: Spinal cord tissue significantly softens after SCI. Microglia depletion or Fascin-1 knockout in microglia limits tissue softening and alters mechanical characterization, which leads to increased tissue pathology and impaired functional recovery. Mechanistically, Fascin-1 inhibits myosin activation to promote microglial migration and control mechanical characterization after SCI. CONCLUSIONS: We reveal that Fascin-1 limits myosin activity to regulate mechanical characterization after SCI, and this mechanical signal should be considered in future approaches for the treatment of CNS diseases.

Lactate promotes microglial scar formation and facilitates locomotor function recovery by enhancing histone H4 lysine 12 lactylation after spinal cord injury.

Lactate-derived histone lactylation is involved in multiple pathological processes through transcriptional regulation. The role of lactate-derived histone lactylation in the repair of spinal cord injury (SCI) remains unclear. Here we report that overall lactate levels and lactylation are upregulated in the spinal cord after SCI. Notably, H4K12la was significantly elevated in the microglia of the injured spinal cord, whereas exogenous lactate treatment further elevated H4K12la in microglia after SCI. Functionally, lactate treatment promoted microglial proliferation, scar formation, axon regeneration, and locomotor function recovery after SCI. Mechanically, lactate-mediated H4K12la elevation promoted PD-1 transcription in microglia, thereby facilitating SCI repair. Furthermore, a series of rescue experiments confirmed that a PD-1 inhibitor or microglia-specific AAV-sh-PD-1 significantly reversed the therapeutic effects of lactate following SCI. This study illustrates the function and mechanism of lactate/H4K12la/PD-1 signaling in microglia-mediated tissue repair and provides a novel target for SCI therapy.

Biomimetic Multifunctional Graphene-Based Coating for Thermal Management, Solar De-Icing, and Fire Safety: Inspired from the Antireflection Nanostructure of Compound Eyes.

Due to the ubiquitous and inexhaustible solar source, photothermal materials have gained considerable attention for their potential in heating and de-icing. Nevertheless, traditional photothermal materials, exemplified by graphene, frequently encounter challenges emanating from their elevated reflectance. Inspired by ocular structures, this study uses the Fresnel equation to enhance the photo-thermal conversion efficiency of graphene by introducing a polydimethylsiloxane (PDMS)/silicon dioxide (SiO2) coating, which reduces the light reflectance (≈20%) through destructive interference. The designed coating achieves an equilibrium temperature of ≈77 °C at one sun and a quick de-icing in ≈65 s, all with a thickness of 5 µm. Simulations demonstrate that applying this coating to high-rise buildings results in energy savings of ≈31% in winter heating. Furthermore, the combination of PDMS/SiO2 and graphene confers a notable enhancement in thermal stability through a synergistic flame-retardant mechanism, effectively safeguarding polyurethane against high temperatures and conflagrations, leading to marked reduction of 58% and 28% in heat release rate and total heat release. This innovative design enhances the photo-thermal conversion, de-icing function, and flame retardancy of graphene, thereby advancing its applications in outdoor equipment, high-rise buildings, and aerospace vessels.

Morphology Control for Efficient Nonfused Acceptor-Based Organic Photovoltaic Cells.

Non-fused electron acceptors have huge advantages in fabricating low-cost organic photovoltaic (OPV) cells. However, morphology control is a challenge as non-fused C─C single bonds bring more molecular conformations. Here, by selecting two typical polymer donors, PBDB-TF and PBQx-TF, the blend morphologies and its impacts on the power conversion efficiencies (PCEs) of non-fused acceptor-based OPV cells are studied. A selenium-containing non-fused acceptor named ASe-5 is designed. The results suggest that PBQx-TF has a lower miscibility with ASe-5 when compared with PBDB-TF. Additionally, the polymer networks may form earlier in the PBQx-TF:ASe-5 blend film due to stronger preaggregation performance, leading to a more obvious phase separation. The PBQx-TF:ASe-5 blend film shows faster charge transfer and suppressed charge recombination. As a result, the PBQx-TF:ASe-5-based device records a good PCE of 14.7% with a higher fill factor (FF) of 0.744, while the PBDB-TF:ASe-5-based device only obtains a moderate PCE of 12.3% with a relatively low FF of 0.662. The work demonstrates that the selection of donors plays a crucial role in controlling the blend morphology and thus improving the PCEs of non-fused acceptor-based OPV cells.

The bacterial patterns suggesting the dynamic features of tick-associated microorganisms in hard ticks.

BACKGROUND: Ticks are blood-feeding significant arthropods that can harbour various microorganisms, including pathogens that pose health risks to humans and animals. Tick-symbiont microorganisms are believed to influence tick development, but the intricate interactions between these microbes and the relationships between different tick-borne microorganisms remain largely unexplored. RESULTS: Based on 111 tick pool samples presenting questing and engorged statuses including 752 questing tick and 1083 engorged tick from cattle and goats, which were collected in two types of geographic landscape (semi-desert and alpine meadow). We observed significant variations in the composition of tick-borne microorganisms across different environments and blood-engorgement statuses, with a pronounced divergence in symbionts compared to environmental bacteria. Metabolic predictions revealed over 90 differential pathways for tick-borne microorganisms in distinct environments and more than 80 metabolic variations in response to varying blood engorgement statuses. Interestingly, nine pathways were identified, particularly related to chorismate synthesis and carbohydrate metabolism. Moreover, microbial network relationships within tick-borne microorganism groups were highly distinct across different environments and blood-engorgement statuses. The microbial network relationships of symbionts involve some pathogenic and environmental microorganisms. Regression modelling highlighted positive correlations between the Coxiella symbiont and related pathogens, while some environmental bacteria showed strong negative correlations with Coxiella abundance. We also identified commensal bacteria/pathogens in bacterial cooccurrence patterns. Furthermore, we tested pathogenic microorganisms of each tick sample analysis revealed that 86.36% (1601/1855) of the tick samples carried one or more pathogenic microorganisms, The total carrier rate of bacterial pathogens was 43.77% ((812/1855). Most blood samples carried at least one pathogenic microorganism. The pathogens carried by the ticks have both genus and species diversity, and Rickettsia species are the most abundant pathogens among all pathogens. CONCLUSION: Our findings underscore that the bacterial pattern of ticks is dynamic and unstable, which is influenced by the environment factors and tick developmental characteristics.

Glucose status within dark-grown etiolated cotyledons determines seedling de-etiolation upon light irradiation.

Exposure of dark-grown etiolated seedlings to light triggers the transition from skotomorphogenesis/etiolation to photomorphogenesis/de-etiolation. In the life cycle of plants, de-etiolation is essential for seedling development and plant survival. The mobilization of soluble sugars (glucose [Glc], sucrose, and fructose) derived from stored carbohydrates and lipids to target organs, including cotyledons, hypocotyls, and radicles, underpins de-etiolation. Therefore, dynamic carbohydrate biochemistry is a key feature of this phase transition. However, the molecular mechanisms coordinating carbohydrate status with the cellular machinery orchestrating de-etiolation remain largely opaque. Here, we show that the Glc sensor HEXOKINASE 1 (HXK1) interacts with GROWTH REGULATOR FACTOR5 (GRF5), a transcriptional activator and key plant growth regulator, in Arabidopsis (Arabidopsis thaliana). Subsequently, GRF5 directly binds to the promoter of phytochrome A (phyA), encoding a far-red light (FR) sensor/cotyledon greening inhibitor. We demonstrate that the status of Glc within dark-grown etiolated cotyledons determines the de-etiolation of seedlings when exposed to light irradiation by the HXK1-GRF5-phyA molecular module. Thus, following seed germination, accumulating Glc within dark-grown etiolated cotyledons stimulates a HXK1-dependent increase of GRF5 and an associated decrease of phyA, triggering the perception, amplification, and relay of HXK1-dependent Glc signaling, thereby facilitating the de-etiolation of seedlings following light irradiation. Our findings, therefore, establish how cotyledon carbohydrate signaling under subterranean darkness is sensed, amplified, and relayed, determining the phase transition from skotomorphogenesis to photomorphogenesis on exposure to light irradiation.

All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP.

The study aimed to compare the efficacy and safety of all-trans retinoic acid (ATRA) plus low-dose rituximab (LD-RTX) with LD-RTX monotherapy in corticosteroid-resistant or relapsed immune thrombocytopenia (ITP) patients. Recruited patients were randomized at a ratio of 2:1 into 2 groups: 112 patients received LD-RTX plus ATRA, and 56 patients received LD-RTX monotherapy. Overall response (OR), defined as achieving a platelet count of ≥30 × 109/L confirmed on ≥2 separate occasions (≥7 days apart), at least a doubling of the baseline platelet count without any other ITP-specific treatment, and the absence of bleeding within 1 year after enrollment, was observed in more patients in the LD-RTX plus ATRA group (80%) than in the LD-RTX monotherapy group (59%) (between-group difference, 0.22; 95% CI, 0.07-0.36). Sustained response (SR), defined as maintenance of a platelet count >30 × 109/L, an absence of bleeding, and no requirement for any other ITP-specific treatment for 6 consecutive months after achievement of OR during 1 year following enrollment, was achieved by 68 (61%) patients in the combination group and 23 (41%) patients in the monotherapy group (between-group difference, 0.20; 95% CI, 0.04-0.35). The 2 most common adverse events (AEs) for the combination group were dry skin and headache or dizziness. Our findings demonstrated that ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a promising treatment option for corticosteroid-resistant or relapsed adult ITP. This study is registered at www.clinicaltrials.gov as #NCT03304288.

Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4.

The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR­21­5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize ß-cell apoptosis at the early stage of islet transplantation.

Efficacy of chidamide maintenance therapy versus autologous stem cell transplantation versus observation as a post-remission choice in the survival of adult patients with peripheral T-cell lymphoma: Post hoc analysis of a prospective, multicenter, phase 2 study in China.

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .

Low concentrations of saracatinib promote definitive endoderm differentiation through inhibition of FAK-YAP signaling axis.

Optimizing the efficiency of definitive endoderm (DE) differentiation is necessary for the generation of diverse organ-like structures. In this study, we used the small molecule inhibitor saracatinib (SAR) to enhance DE differentiation of human embryonic stem cells and induced pluripotent stem cells. SAR significantly improved DE differentiation efficiency at low concentrations. The interaction between SAR and Focal Adhesion Kinase (FAK) was explored through RNA-seq and molecular docking simulations, which further supported the inhibition of DE differentiation by p-FAK overexpression in SAR-treated cells. In addition, we found that SAR inhibited the nuclear translocation of Yes-associated protein (YAP), a downstream effector of FAK, which promoted DE differentiation. Moreover, the addition of SAR enabled a significant reduction in activin A (AA) from 50 to 10 ng/mL without compromising DE differentiation efficiency. For induction of the pancreatic lineage, 10 ng/ml AA combined with SAR at the DE differentiation stage yielded a comparative number of PDX1+/NKX6.1+ pancreatic progenitor cells to those obtained by 50 ng/ml AA treatment. Our study highlights SAR as a potential modulator that facilitates the cost-effective generation of DE cells and provides insight into the orchestration of cell fate determination.

Identification of candidate SNPs and genes associated with resistance to nervous necrosis virus in leopard coral grouper (Plectropomus leopardus) using GWAS.

The leopard coral grouper (Plectropomus leopardus), which has become increasingly popular in consumption due to its bright body color and great nutritional, holds a high economic and breeding potential. However, in recent years, the P.leopardus aquaculture industry has been impeded by the nervous necrosis virus (NNV) outbreak, leading to widespread mortality among fry and juvenile grouper. However, the genetic basis of resistance to NNV in P. leopardus remains to be investigated. In the present study, we conducted a genome-wide association analysis (GWAS) on 100 resistant and 100 susceptible samples to discover variants and potential genes linked with NNV resistance. For this study, 157,926 high-quality single nucleotide polymorphisms (SNPs) based on whole genome resequencing were discovered, and eighteen SNPs loci linked to disease resistance were discovered. We annotated six relevant candidate genes, including sik2, herc2, pip5k1c, npr1, mybpc3, and arhgap9, which showed important roles in lipid metabolism, oxidative stress, and neuronal survival. In the brain tissues of resistant and susceptible groups, candidate genes against NNV infection showed significant differential expression. The results indicate that regulating neuronal survival or pathways involved in lipid metabolism may result in increased resistance to NNV. Understanding the molecular mechanisms that lead to NNV resistance will be beneficial for the growth of the P. leopardus breeding sector. Additionally, the identified SNPs could be employed as biomarkers of disease resistance in P. leopardus, which will facilitate the selective breeding of grouper.