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To enhance the design and research work on dynamic characteristics of high-rise laminated timber buildings, this paper carried out a modal analysis study on one of the largest laminated timber buildings in China. The finite element calculating modal analysis was carried out using SAP2000 software, and the experimental modal analysis of the building was carried out via environmental excitation. The calculating modal results and the experimental modal results showed good agreement. The calculating modal frequency values were generally lower than the experimental modal frequency values. The natural frequencies obtained by the two methods appeared in the Y-direction first-order bending mode and had values of 2.03 and 2.5 Hz, respectively. The corresponding frequencies of the first-order torsional mode were 2.82 and 3.25 Hz, respectively. The distribution of the CLT core tube along the length direction of the building has an impact on the vibration mode. The six-story part shows the second-order bending form, while the four-story section only shows the first-order bending form. The above work provides a case study and reference for the simulation and modal analysis of high-rise laminated timber buildings, demonstrating the critical role of the core tube structure in such wooden buildings. This insight contributes to a better understanding of structural performance and design considerations in similar projects.

Abstract Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas.

ABSTRACTDouble minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

BackgroundMetagenomic next-generation sequencing (mNGS) technology has been widely used to diagnose various infections. Based on the most common pathogen profiles, targeted mNGS (tNGS) using multiplex PCR has been developed to detect pathogens with predesigned primers in the panel, significantly improving sensitivity and reducing economic burden on patients. However, there are few studies on summarizing pathogen profiles of pulmonary infections in immunocompetent and immunocompromised patients in Jilin Province of China on large scale.MethodsFrom January 2021 to December 2023, bronchoalveolar lavage fluid (BALF) or sputum samples from 546 immunocompetent and immunocompromised patients with suspected community-acquired pneumonia were collected. Pathogen profiles in those patients on whom mNGS was performed were summarized. Additionally, we also evaluated the performance of tNGS in diagnosing pulmonary infections.ResultsCombined with results of mNGS and culture, we found that the most common bacterial pathogens were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii in both immunocompromised and immunocompetent patients with high detection rates of Staphylococcus aureus and Enterococcus faecium, respectively. For fungal pathogens, Pneumocystis jirovecii was commonly detected in patients, while fungal infections in immunocompetent patients were mainly caused by Candida albicans. Most of viral infections in patients were caused by Human betaherpesvirus 5 and Human gammaherpesvirus 4. It is worth noting that, compared with immunocompetent patients (34.9%, 76/218), more mixed infections were found in immunocompromised patients (37.8%, 14/37). Additionally, taking final comprehensive clinical diagnoses as reference standard, total coincidence rate of BALF tNGS (81.4%, 48/59) was much higher than that of BALF mNGS (40.0%, 112/280).ConclusionsOur findings supplemented and classified the pathogen profiles of pulmonary infections in immunocompetent and immunocompromised patients in Jilin Province of China. Most importantly, our findings can accelerate the development and design of tNGS specifically used for regional pulmonary infections.

Bacillus anthracis is a Gram-positive bacterium that can cause acute infection and anthracnose, which is a serious concern for human health. Determining Bacillus anthracis through its spore biomarker dipicolinic acid (DPA) is crucial, and there is a strong need for a method that is rapid, sensitive, and selective. Here, we created Eu(III)-coordination polymers (Eu-CPs) with surfaces that have abundant carboxyl and hydroxyl groups. This was achieved by using citric acid and europium nitrate hexahydrate as precursors in a straightforward one-pot hydrothermal process. These Eu-CPs were then successfully utilized for highly sensitive DPA determination. The fluorescence (FL) emission of Eu-CPs, which is typically weak due to the coordination of Eu(III) with water molecules, was significantly enhanced in the presence of DPA. This enhancement is attributed to the competitive binding between DPA’s carboxyl or hydroxyl groups and water molecules. As a result, the absorbed energy of DPA, when excited by 280 nm ultraviolet light, is transferred to Eu-CPs through an antenna effect. This leads to the emission of the characteristic red fluorescence of Eu3+ at 618 nm. A strong linear relationship was observed between the enhanced FL intensity and DPA concentration in the range of 0.5–80 μM. This relationship allowed for a limit of detection (LOD) of 15.23 nM. Furthermore, the Eu-CPs we constructed can effectively monitor the release of DPA from Bacillus subtilis spores, thereby further demonstrating the potential significance of this strategy in the monitoring and management of anthrax risk. This highlights the novelty of this approach in practical applications, provides a valuable determination technique for Bacillus anthracis, and offers insights into the development cycle of microorganisms.

BackgroundInfection is the main cause of death for patients after allogeneic hematopoietic stem cell transplantation (HSCT). However, pathogen profiles still have not been reported in detail due to their heterogeneity caused by geographic region.ObjectiveTo evaluate the performance of metagenomic next-generation sequencing (mNGS) and summarize regional pathogen profiles of infected patients after HSCT.MethodsFrom February 2021 to August 2022, 64 patients, admitted to the Department of Hematology of The First Hospital of Jilin University for HSCT and diagnosed as suspected infections, were retrospectively enrolled.ResultsA total of 38 patients were diagnosed as having infections, including bloodstream (n =17), pulmonary (n =16), central nervous system (CNS) (n =4), and chest (n =1) infections. Human betaherpesvirus 5 (CMV) was the most common pathogen in both bloodstream (n =10) and pulmonary (n =8) infections, while CNS (n =2) and chest (n =1) infections were mainly caused by Human gammaherpesvirus 4 (EBV). For bloodstream infection, Mycobacterium tuberculosis complex (n =3), Staphylococcus epidermidis (n =1), and Candida tropicalis (n =1) were also diagnosed as causative pathogens. Furthermore, mNGS combined with conventional tests can identify more causative pathogens with high sensitivity of 82.9% (95% CI 70.4-95.3%), and the total coincidence rate can reach up to 76.7% (95% CI 64.1-89.4%).ConclusionsOur findings emphasized the importance of mNGS in diagnosing, managing, and ruling out infections, and an era of more rapid, independent, and impartial diagnosis of infections after HSCT can be expected.

Abstract Axon regeneration of dorsal root ganglia (DRG) neurons after peripheral axotomy involves reconfiguration of gene regulatory circuits to establish regenerative gene programs. However, the underlying mechanisms remain unclear. Here, through an unbiased survey, we show that the binding motif of Bmal1, a central transcription factor of the circadian clock, is enriched in differentially hydroxymethylated regions (DhMRs) of mouse DRG after peripheral lesion. By applying conditional deletion of Bmal1 in neurons, in vitro and in vivo neurite outgrowth assays, as well as transcriptomic profiling, we demonstrate that Bmal1 inhibits axon regeneration, in part through a functional link with the epigenetic factor Tet3. Mechanistically, we reveal that Bmal1 acts as a gatekeeper of neuroepigenetic responses to axonal injury by limiting Tet3 expression and restricting 5hmC modifications. Bmal1-regulated genes not only concern axon growth, but also stress responses and energy homeostasis. Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.

Multispectral remote sensing data with abundant spectral information can be used to compute vegetation indices to improve the accuracy of Ginkgo biloba yield prediction. The limited spatial resolution of multispectral cameras restricts the detail capture over wide farmland, but super-resolution (SR) reconstruction methods can enhance image quality. However, most existing SR models have been trained on images processed from downsampled high-resolution (HR) images, making them less effective in reconstructing real low-resolution (LR) images. This study proposes a GAN-based super-resolution reconstruction method (RMSRGAN) for multispectral remote sensing images of Ginkgo biloba trees in real scenes. A U-Net-based network is employed instead of the traditional discriminator. Convolutional block attention modules (CBAMs) are incorporated into the Residual-in-Residual Dense Blocks (RRDBs) of the generator and the U-Net of the discriminator to preserve image details and texture features. An unmanned aerial vehicle (UAV) equipped with a multispectral camera was employed to capture field multispectral remote sensing images of Ginkgo biloba trees at different spatial resolutions. Four matching HR and LR datasets were created from these images to train RMSRGAN. The proposed model outperforms the traditional models by achieving superior results in both quantitative evaluation metrics (peak signal-to-noise ratio (PSNR) is 32.490, 31.085, 27.084, 26.819, and structural similarity index (SSIM) is 0.894, 0.881, 0.832, 0.818, respectively) and qualitative evaluation visualization. Furthermore, the efficiency of our proposed method was tested by generating individual vegetation indices (VIs) from images taken before and after reconstruction to predict the yield of Ginkgo biloba. The results show that the SR images exhibit better R2 and RMSE values than LR images. These findings show that RMSRGAN can improve the spatial resolution of real multispectral images, increasing the accuracy of Ginkgo biloba yield prediction and providing more effective and accurate data support for crop management.

Biomechanical mechanisms orchestrating stem cell dynamics in development remain unclear. Here the authors show that guidance receptor Plexin-B2 organizes actomyosin contractility, cytoskeletal tension and adhesion during multicellular development of human embryonic stem cells and neuroprogenitor cells.

Plasmonic nanomaterials have attracted great attention in the field of catalysis and sensing for their outstanding electrical and optical properties. Here, a representative type of nonstoichiometric Cu2−xSe nanoparticles with typical near-infrared (NIR) localized surface plasma resonance (LSPR) properties originating from their copper deficiency was applied to catalyze the oxidation of colorless TMB into their blue product in the presence of H2O2, indicating they had good peroxidase-like activity. However, glutathione (GSH) inhibited the catalytic oxidation of TMB, as it can consume the reactive oxygen species. Meanwhile, it can induce the reduction of Cu(II) in Cu2−xSe, resulting in a decrease in the degree of copper deficiency, which can lead to a reduction in the LSPR. Therefore, the catalytic ability and photothermal responses of Cu2−xSe were decreased. Thus, in our work, a colorimetric/photothermal dual-readout array was developed for the detection of GSH. The linear calibration for GSH concentration was in the range of 1–50 μM with the LOD as 0.13 μM and 50–800 μM with the LOD as 39.27 μM. To evaluate the practicability of the assay, tomatoes and cucumbers were selected as real samples, and good recoveries indicated that the developed assay had great potential in real applications.

Herein, the preparation of AuAgPt alloy yolk‐shell nanostructures with tunable elemental compositions and morphologies by conducting the mild, successive galvanic replacement reaction (GRR) between Au@Ag core‐shell nanocubes and H2PtCl6 is reported. In particular, the resulting products can be featured with well‐defined cubic frames and the distribution of all the three metals over the whole particle, which is enabled by the unique “etching and regrowth” mechanism. Due to the strong absorbance in visible region, the current products exhibit superb performances in two localized surface plasmon resonance (LSPR)‐based applications, photothermal heat conversion, and plasmon‐enhanced catalytic reduction of 4‐nitrophenol (4‐NP). In particular, the optimized photothermal heat conversion efficiency and the apparent rate constant of photocatalytic 4‐NP reduction reach 12.9% and 0.155 min−1, respectively, for the sample AuAgPt‐6 and AuAgPt‐12, respectively. Herein the present study, a feasible strategy for fabrication of plasmonic‐active multimetallic alloy nanocrystals with yolk‐shell structure and cubic frame‐like edges is offered and their promising use in photothermal heat conversion and photocatalysis is validated, which could be extended to other alloys or material combinations for rational design of nanoscale materials with plasmon‐enhanced properties.

Huang et al demonstrate that glioblastoma cells upregulate axon guidance molecule Plexin-B2 to gain invasiveness and that Plexin-B2 promotes glioblastoma cell infiltration along axon fiber tracts in intracranial transplant models by modulating cellular biomechanics.

Effective identification of apple leaf diseases can reduce pesticide spraying and improve apple fruit yield, which is significant to agriculture. However, the existing apple leaf disease detection models lack consideration of disease diversity and accuracy, which hinders the application of intelligent agriculture in the apple industry. In this paper, we explore an accurate and robust detection model for apple leaf disease called Apple-Net, improving the conventional YOLOv5 network by adding the Feature Enhancement Module (FEM) and Coordinate Attention (CA) methods. The combination of the feature pyramid and pan in YOLOv5 can obtain richer semantic information and enhance the semantic information of low-level feature maps but lacks the output of multi-scale information. Thus, the FEM was adopted to improve the output of multi-scale information, and the CA was used to improve the detection efficiency. The experimental results show that Apple-Net achieves a higher mAP@0.5 (95.9%) and precision (93.1%) than four classic target detection models, thus proving that Apple-Net achieves more competitive results on apple leaf disease identification.

Background: Glioblastoma (GBM), a highly malignant brain tumor, invariably recurs after therapy. Quiescent GBM cells represent a potential source of tumor recurrence, but little is known about their molecular underpinnings. Methods: Patient-derived GBM cells were engineered by CRISPR/Cas9-assisted knock-in of an inducible histone2B-GFP (iH2B-GFP) reporter to track cell division history. We utilized an in vitro 3D GBM organoid approach to isolate live quiescent GBM (qGBM) cells and their proliferative counterparts (pGBM) to compare stem cell properties and therapy resistance. Gene expression programs of qGBM and pGBM cells were analyzed by RNA-Seq and NanoString platforms. Findings: H2B-GFP-retaining qGBM cells exhibited comparable self-renewal capacity but higher therapy resistance relative to pGBM. Quiescent GBM cells expressed distinct gene programs that affect cell cycle control, metabolic adaptation, and extracellular matrix (ECM) interactions. Transcriptome analysis also revealed a mesenchymal shift in qGBM cells of both proneural and mesenchymal GBM subtypes. Bioinformatic analyses and functional assays in GBM organoids established hypoxia and TGFβ signaling as potential niche factors that promote quiescence in GBM. Finally, network co-expression analysis of TCGA glioma patient data identified gene modules that are enriched for qGBM signatures and also associated with survival rate. Interpretation: Our in vitro study in 3D GBM organoids supports the presence of a quiescent cell population that displays self-renewal capacity, high therapy resistance, and mesenchymal gene signatures. It also sheds light on how GBM cells may acquire and maintain quiescence through ECM organization and interaction with niche factors such as TGFβ and hypoxia. Our findings provide a starting point for developing strategies to tackle the quiescent population of GBM. Fund: National Institutes of Health (NIH) and Deutsche Forschungsgemeinschaft (DFG). Keywords: Glioblastoma, Tumor quiescence, H2B-GFP, GBM organoid, Proneural-mesenchymal transition, Stem cell niche

The smart meta-superconductor MgB2 and Bi(Pb)SrCaCuO increase the superconducting transition temperature (TC), but the changes in the transport critical current density (JC) and Meissner effect are still unknown. Here, we investigated the JC and Meissner effect of smart meta-superconductor MgB2 and Bi(Pb)SrCaCuO. The use of the standard four-probe method shows that Y2O3:Eu3+ and Y2O3:Eu3++Ag inhomogeneous phase significantly increase the JC, and JC decreases to a minimum value at a higher temperature. The Meissner effect was measured by direct current magnetization. The doping of Y2O3:Eu3+ and Y2O3:Eu3++Ag luminescent inhomogeneous phase causes a Meissner effect of MgB2 and Bi(Pb)SrCaCuO at a higher temperature, while the non-luminescent dopant reduces the temperature at which samples have Meissner effect. The introduction of luminescent inhomogeneous phase in conventional MgB2 and copper oxide high-temperature Bi(Pb)SrCaCuO superconductor increases the TC and JC, and Meissner effect is exerted at higher temperature. Therefore, smart meta-superconductivity is suitable for conventional and copper oxide high-temperature superconductors.

Incorporating with inhomogeneous phases with high electroluminescence (EL) intensity to prepare smart meta-superconductors (SMSCs) is an effective method for increasing the superconducting transition temperature (Tc) and has been confirmed in both MgB2 and Bi(Pb)SrCaCuO systems. However, the increase of ΔTc (ΔTc = Tc ‒ Tcpure) has been quite small because of the low optimal concentrations of inhomogeneous phases. In this work, three kinds of MgB2 raw materials, namely, aMgB2, bMgB2, and cMgB2, were prepared with particle sizes decreasing in order. Inhomogeneous phases, Y2O3:Eu3+ and Y2O3:Eu3+/Ag, were also prepared and doped into MgB2 to study the influence of doping concentration on the ΔTc of MgB2 with different particle sizes. Results show that reducing the MgB2 particle size increases the optimal doping concentration of inhomogeneous phases, thereby increasing ΔTc. The optimal doping concentrations for aMgB2, bMgB2, and cMgB2 are 0.5%, 0.8%, and 1.2%, respectively. The corresponding ΔTc values are 0.4, 0.9, and 1.2 K, respectively. This work open a new approach to reinforcing increase of ΔTc in MgB2 SMSCs.

Abstract Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.

In contrast to central nervous system neurons, dorsal root ganglia (DRG) neurons can switch to a regenerative state after peripheral axotomy. In a screen for chromatin regulators of the regenerative responses in this conditioning lesion paradigm, we identified Tet methylcytosine dioxygenase 3 (Tet3) as upregulated in DRG neurons, along with increased 5-hydroxymethylcytosine (5hmC). We generated genome-wide 5hmC maps in adult DRG, which revealed that peripheral and central axotomy (leading to no regenerative effect) triggered differential 5hmC changes that are associated with distinct signaling pathways. 5hmC was altered in a large set of regeneration-associated genes (RAGs), including well-known RAGs, such as Atf3, Bdnf, and Smad1, that regulate axon growth potential of DRG neurons, thus supporting its role for RAG regulation. Our analyses also predicted HIF-1, STAT, and IRF as potential transcription factors that may collaborate with Tet3 for 5hmC modifications. Intriguingly, central axotomy resulted in widespread 5hmC modifications that had little overlap with those of peripheral axotomy, thus potentially constituting a roadblock for regeneration. Our study revealed 5hmC dynamics as a previously unrecognized epigenetic mechanism underlying the divergent responses after axonal injury.

Prenatal hypoxic injury (HI) is a leading cause of neurological disability. The immediate and long-term effects of hypoxia on progenitor homeostasis and developmental progression during early human brain development remain unclear. This gap is due to difficulty to access human fetal brain tissues and inadequate animal models to study human corticogenesis. Recent optimizations of cerebral organoid models derived from human embryonic stem (ES) cells present new opportunities to investigate pathophysiology of prenatal HI. Here, we implemented a transient HI model using human cerebral organoids with dorsal forebrain specification. We demonstrated that transient hypoxia resulted in immediate and prolonged apoptosis in cerebral organoids, with outer radial glia (oRG), a progenitor population more prominent in primates, and differentiating neuroblasts/immature neurons suffering larger losses. In contrast, neural stem cells in ventricular zone displayed relative resilience to HI and exhibited a shift of cleavage plane angle favoring symmetric division, thereby providing a mechanism to replenish the stem cell pool. Furthermore, we defined the vulnerable window and neurodifferentiation stages that are particularly sensitive to HI. Understanding cell type-specific and stage-dependent effects of prenatal HI on survival and mitotic behavior of human neuroprogenitor subtypes during early human corticogenesis helps elucidate the etiology of neurodevelopmental disorders, and provides a therapeutic starting point to protect the vulnerable populations at critical timeframes.

Injury to the nervous system triggers a multicellular response in which epigenetic mechanisms play an important role in regulating cell type-specific transcriptional changes. Here, we summarize recent progress in characterizing neuronal intrinsic and extrinsic chromatin reconfigurations and epigenetic changes triggered by axonal injury that shape neuroplasticity and glial functions. We specifically discuss regeneration-associated transcriptional modules comprised of transcription factors and epigenetic regulators that control axon growth competence. We also review epigenetic regulation of neuroinflammation and astroglial responses that impact neural repair. These advances provide a framework for developing epigenetic strategies to maximize adaptive alterations while minimizing maladaptive stress responses in order to enhance axon regeneration and achieve functional recovery after injury.

Interactions of human natural killer (NK) cell inhibitory receptors with polymorphic HLA-A, -B and -C molecules educate NK cells for immune surveillance against tumor cells. The KIR A haplotype encodes a distinctive set of HLA-specific NK cell inhibiting receptors having strong influence on immunity. We observed higher frequency of KIR A homozygosity among 745 healthy Chinese Southern Han than 836 adult patients representing three types of leukemia: ALL (OR = 0.68, 95% CI = 0.52–0.89, p = 0.004), AML (OR = 0.76, 95% CI = 0.59–0.98, p = 0.034), and CML (OR = 0.72 95% CI = 0.51–1.0, ns). We observed the same trend for NHL (OR = 0.47 95% CI = 0.26–0.88 p = 0.017). For ALL, the protective effect of the KIR AA genotype was greater in the presence of KIR ligands C1 (Pc = 0.01) and Bw4 (Pc = 0.001), which are tightly linked in East Asians. By contrast, the C2 ligand strengthened protection from CML (Pc = 0.004). NK cells isolated from KIR AA individuals were significantly more cytotoxic toward leukemic cells than those from other KIR genotypes (p < 0.0001). These data suggest KIR allotypes encoded by East Asian KIR A haplotypes are strongly inhibitory, arming NK cells to respond to leukemogenic cells having altered HLA expression. Thus, the study of populations with distinct KIR and HLA distributions enlightens understanding of immune mechanisms that significantly impact leukemia pathogenesis.

Sensory axon development requires concerted actions of growth factors for the precise control of axonal outgrowth and target innervation. How developing sensory neurons integrate different cues is poorly understood. We demonstrate here that Smad1 activation is required for neurotrophin-mediated sensory axon growth in vitro and in vivo. Through differential phosphorylation, Smad1 exerts transcriptional selectivity to regulate the expression and activity of Erk1 and Erk2—two key neurotrophin effectors. Specifically, bone morphogenetic proteins (BMPs) signal through carboxy-terminal phosphorylation of Smad1 (pSmad1C) to induce Erk1/2 transcription for enhanced neurotrophin responsiveness. Meanwhile, neurotrophin signaling results in linker phosphorylation of Smad1 (pSmad1L), which in turn upregulates an Erk-specific dual-specificity phosphatase, Dusp6, leading to reduced pErk1/2 and constituting a negative-feedback loop for the prevention of axon overgrowth. Together, the BMP and neurotrophin pathways form a tightly regulated signaling network with a balanced ratio of Erk1/2 and pErk1/2 to direct the precise connections between sensory neurons and peripheral targets.

Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP) signaling, results in neuroprotection in an ischemia-reperfusion (I/R) stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS (Smad1 cKO) displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1(-/-) astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO), Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.

BACKGROUND: End-Stage Renal Disease (ESRD) is a worldwide public health problem. Currently, many genome-wide association studies have suggested a potential association between human leukocyte antigen (HLA) and ESRD by uncovering a causal relationship between HLA and glomerulonephritis. However, previous studies, which investigated the HLA polymorphism and its association with ESRD, were performed with the modest data sets and thus might be limited. On the other hand, few researches were conducted to tackle the Chinese population with ESRD. Therefore, this study aims to detect the susceptibilities of HLA polymorphism to ESRD within the Cantonese community, a representative southern population of China. METHODS: From the same region, 4541 ESRD patients who were waiting for kidney transplantation and 3744 healthy volunteer bone marrow donors (controls) were randomly chosen for this study. Polymerase chain reaction-sequence specific primer method was used to analyze the HLA polymorphisms (including HLA-A, HLA-B and HLA-DRB1 loci) in both ESRD patients and controls. The frequencies of alleles at these loci and haplotypes were compared between ESRD patients and controls. RESULTS: A total of 88 distinct HLA alleles and 1361 HLA A-B-DRB1 haplotypes were detected. The frequencies of five alleles, HLA-A*24, HLA-B*55, HLA-B*54, HLA-B*40(60), HLA-DRB1*04, and one haplotype (HLA-A*11-B*27-DRB1*04) in ESRD patients are significantly higher than those in the controls, respectively. CONCLUSIONS: Five HLA alleles and one haplotype at the HLA-A, HLA-B and HLA-DRB1 loci appear to be associated with ESRD within the Cantonese population.

This article discusses the application of metagenomic next-generation sequencing (mNGS) and targeted metagenomic next-generation sequencing in diagnosing pulmonary infections in both immunocompetent and immunocompromised patients. The study found that bacteria were the most common pathogens in single infections, followed by fungi and viruses. Additionally, the article provides a summary of the most common bacterial, fungal, and viral pathogens detected through mNGS. This information can be valuable for researchers and healthcare professionals studying and treating pulmonary infections. [Extracted from the article]