The Mitogen-Activated Protein Kinase Hog1 Regulates Fungal Development, Pathogenicity, and Stress Response in Botryosphaeria dothidea.

The high-osmolarity glycerol mitogen-activated protein kinase (HOG-MAPK) pathway plays a central role in environmental stress adaptation in eukaryotes. However, the biological function of the HOG-MAPK pathway varies in different fungi. In this study, we investigated the HOG-MAPK pathway by inactivation of the core element Hog1 in Botryosphaeria dothidea, the causal agent of Botryosphaeria canker and apple ring rot. Targeted deletion of BdHOG1 resulted in the loss of conidiation ability and significant reduction of virulence. In addition, the ΔBdHog1 mutant exhibited hypersensitivity to osmotic stress but resistance to phenylpyrrole and dicarboximide fungicides. Comparative transcriptome analysis revealed that inactivation of BdHog1 influenced multiple metabolic pathways in B. dothidea. Taken together, our results suggest that BdHog1 plays a crucial role in development, virulence, and stress tolerance in B. dothidea, which provides a theoretical basis for the development of target-based fungicides.

Effects of posterior scleral reinforcement in pathological myopia: a 3-year follow-up study.

PURPOSE: To assess the effects of posterior sclera reinforcement (PSR) in refractive outcomes, choroidal thickness (CT), and retinal thickness (RT) during a 3-year follow-up in eyes with pathological myopia. METHODS: Thirty-eight eyes of 26 adults with pathological myopia who underwent PSR (the PSR group) and 30 eyes of 18 adults with matched age and myopia who did not receive PSR treatment (the control group) were followed up with measurements of axial length (AL), spherical equivalent (SE), best corrected visual acuity (BCVA), CT, and RT at baseline, 1 and 3 months, and 1, 2, and 3 years postoperatively. Data were analyzed by repeated measures analysis of variance and independent-samples t test. RESULTS: In the PSR group, AL, SE, BCVA, and CT were tending to be relatively stable and no statistically significant changes were found during the follow-up (all P > 0.05). In contrast, in the control group, compared with the measurements taken at baseline, AL, SE, BCVA, and CT altered gradually from 1 month onward to 3 years postoperatively. At 2-year and 3-year follow-ups, significant differences in AL, SE, BCVA, and CT were noted between the PSR group and the control group (all P < 0.05). RTs of the center subfield and the inner ring were equal to the baseline in the control group; however, RTs of the center subfield at 1 year, 2 years, and 3 years postoperatively significantly slightly reduced compared with those at the baseline in the PSR group (all P < 0.05). CONCLUSIONS: The effects of PSR in restraining eyeball elongation, stabilizing vision, and strengthening the structure of posterior pole are more prominent 2 years or more postoperatively compared with the natural progression of pathological myopia.

Lean Path for High-Quality Development of Chinese Logistics Enterprises Based on Entropy and Gray Models.

According to literature review and the data of China's logistics listed companies, this paper firstly designs the high-quality development evaluation system of logistics enterprises and establishes the panel data model group. Secondly, the method of entropy weight-Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS method) is used to synthesize and regress the indexes, and obtains that the fitting degree of the model is low, which is caused by the lack of data of some indicators in the logistics enterprises. Due to the gray nature of data information, the improved gray relational model and the three-dimensional gray relational model are constructed to study, in-depth, the strategic focus and breakthrough of high-quality development of Chinese logistics enterprises. The research finds that the innovation and the operation ability of Chinese logistics enterprises are weak, which shows specifically in the following aspects: (1) The irrational structure of the employees, the proportion of employees with a bachelor degree or above is small, and the high-education personnel fail to significantly promote the corporate performance; (2) R&D expenditure has little effect on the high-quality development of enterprises. The proportion of R&D expenses is small and cannot be translated into actual benefits, and the ability of enterprise management innovation is insufficient. According to these findings, this paper gives three lean paths for the high-quality development of China's logistics enterprises.

[Effects of serine/threonine-protein kinase B-Raf-activated long-chain non-coding RNA on apoptosis and autophagy in thyroid carcinoma cells].

OBJECTIVE: To investigate the effect of serine/threonine-protein kinase B-Raf (BRAF)-activated long-chain non-coding RNA (lncRNA-BANCR) on apoptosis and autophagy in thyroid carcinoma cells and the underlying mechanisms.
 Methods: RT-PCR was used to detect the expression of lncRNA-BANCR in thyroid carcinoma and normal thyroid tissues. The association between lncRNA-BANCR and clinicopathological data was analyzed in patients with thyroid cancer. Cell counting kit-8 (CCK-8) was used to detect the effect of lncRNA-BANCR on the proliferation of thyroid cancer cells. The effect of lncRNA-BANCR on the apoptosis of thyroid carcinoma cells was detected by flow cytometry. Transwell invasion assay was used to detect the effect of lncRNA-BANCR on the invasive ability of thyroid cancer cells. Western blot was used to detect the changes of autophagy proteins LC3-I and LC3-II after the lncRNA-BANCR expression was suppressed.
 Results: Compared with normal thyroid tissues, the expression level of lncRNA-BANCR in thyroid carcinoma tissues was elevated (P<0.05). The expression of lncRNA-BANCR was positively related to the pathological stage of thyroid carcinoma and the lymph node metastasis. Inhibition of lncRNA-BANCR expression attenuated the proliferation and invasion ability of thyroid cancer cells (both P<0.05); but the apoptosis was enhanced (P<0.05); the expression levels of autophagy protein LC3-I and LC3-II were also increased (P<0.05).
 Conclusion: The expression level of lncRNA-BANCR affects the proliferation, invasion and apoptosis of thyroid cancer cells through modulation of autophagy behavior.

The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients.

Pulsed low-dose cyclophosphamide (CTX) therapy has become a very effective approach in improving the clinical outcomes of lupus nephritis (LN) patients. However, variations of CTX therapeutic outcomes in LN patients are incompletely understood. We investigated the contributions of known allelic variants to CTX therapy outcomes in 77 LN patients. Then, 22 out of the 77 patients were randomly enrolled to evaluate the pharmacokinetic profiles. LN patients with a GSTA1*A mutation (CT heterozygous) had more risk of non-remission (44% vs. 20%, P=0.005). Pharmacokinetic data indicated that patients with a GSTA1*A heterozygous variant had a lower exposure to 4-hydroxycyclophosphamide (4OHCTX) compared to wild-type patients (AUC4OHCTX: 12.8 (9.8, 19.5) vs. 27.5 (18.1, 32.8) h mg/l, P=0.023). Clinical remission was significantly related to higher exposure of 4OHCTX (P=0.038). In conclusion, LN patients with GSTA1*A heterozygous genotypes had poor CTX treatment remission due to less exposure to activated metabolites of CTX.

Dynamic adjustment of echolocation pulse structure of big-footed myotis (Myotis macrodactylus) in response to different habitats.

Studying relationships between characteristics of sonar pulses and habitat clutter level is important for the understanding of signal design in bat echolocation. However, most studies have focused on overall spectral and temporal parameters of such vocalizations, with focus less on potential variation in frequency modulation rates (MRs) occurring within each pulse. In the current study, frequency modulation (FM) characteristics were examined in echolocation pulses recorded from big-footed myotis (Myotis macrodactylus) bats as these animals searched for prey in five habitats differing in relative clutter level. Pulses were analyzed using ten parameters, including four structure-related characters which were derived by dividing each pulse into three elements based on two knees in the FM sweep. Results showed that overall frequency, pulse duration, and MR all varied across habitat. The strongest effects were found for MR in the body of the pulse, implying that this particular component plays a major role as M. macrodactylus, and potentially other bat species, adjust to varying clutter levels in their foraging habitats.

The host mannose-6-phosphate pathway and viral infection.

Viruses, despite their simple structural composition, engage in intricate and complex interactions with their hosts due to their parasitic nature. A notable demonstration of viral behavior lies in their exploitation of lysosomes, specialized organelles responsible for the breakdown of biomolecules and clearance of foreign substances, to bolster their own replication. The man-nose-6-phosphate (M6P) pathway, crucial for facilitating the proper transport of hydrolases into lysosomes and promoting lysosome maturation, is frequently exploited for viral manipulation in support of replication. Recently, the discovery of lysosomal enzyme trafficking factor (LYSET) as a pivotal regulator within the lysosomal M6P pathway has introduced a fresh perspective on the intricate interplay between viral entry and host factors. This groundbreaking revelation illuminates unexplored dimensions of these interactions. In this review, we endeavor to provide a thorough overview of the M6P pathway and its intricate interplay with viral factors during infection. By consolidating the current understanding in this field, our objective is to establish a valuable reference for the development of antiviral drugs that selectively target the M6P pathway.

Advances in Drug Discovery Targeting Lysosomal Membrane Proteins.

Lysosomes are essential organelles of eukaryotic cells and are responsible for various cellular functions, including endocytic degradation, extracellular secretion, and signal transduction. There are dozens of proteins localized to the lysosomal membrane that control the transport of ions and substances across the membrane and are integral to lysosomal function. Mutations or aberrant expression of these proteins trigger a variety of disorders, making them attractive targets for drug development for lysosomal disorder-related diseases. However, breakthroughs in R&D still await a deeper understanding of the underlying mechanisms and processes of how abnormalities in these membrane proteins induce related diseases. In this article, we summarize the current progress, challenges, and prospects for developing therapeutics targeting lysosomal membrane proteins for the treatment of lysosomal-associated diseases.

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway.

Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 µM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.

An integrative analysis of lncRNAs and mRNAs highlights the potential roles of lncRNAs in the process of follicle selection in Taihang chickens.

Taihang chickens are a domestic breed distributed throughout Hebei province in the Taihang Mountains of China and are characterized by their high meat and egg quality. However, the relatively limited egg production by this breed constrains their more widespread commercial utilization. The follicle selection process is closely linked to oocyte development and ovulation, making it a key determinant of laying performance and fecundity in hens. To understand the biological basis for such follicle selection and to identify the associated regulatory pathways, we conducted a genome-wide analysis of long noncoding RNAs (lncRNAs) and mRNAs from the pre-hierarchical follicles and hierarchical follicles of Taihang laying hens. We identified 81 lncRNAs and 528 mRNAs that were differentially expressed during follicle selection, and integrated network analyses suggested that these RNAs were associated with the cell cycle, focal adhesion, oocyte meiosis, peroxisome proliferator-activated receptor signaling, and steroid hormone biosynthesis pathways. The identified lncRNAs were also predicted to influence a series of target genes in cis and trans, suggesting that they may be important regulators of ovarian follicular development. Overall, the present analysis of lncRNA and mRNA expression patterns associated with ovarian follicle development offers a new foundation for future studies of reproductive physiology in Taihang chickens, highlighting new opportunities to improve the laying performance of this important domestic breed.

Autophagy-Inflammation Interplay During Infection: Balancing Pathogen Clearance and Host Inflammation.

Inflammation is an essential immune response of the host against infections but is often over-activated, leading to a variety of disorders. Autophagy, a conserved degradation pathway, also protects cells by capturing intracellular pathogens that enter the cell and transporting them to the lysosome for clearance. Dysfunctional autophagy is often associated with uncontrolled inflammatory responses during infection. In recent years, more and more research has focused on the crosstalk between autophagy and inflammation. In this paper, we review the latest research advances in this field, hoping to gain insight into the mechanisms by which the body balances autophagy and inflammation in infections and how this mechanism can be used to fight infections better.

Mitophagy in Antiviral Immunity.

Mitochondria are important organelles whose primary function is energy production; in addition, they serve as signaling platforms for apoptosis and antiviral immunity. The central role of mitochondria in oxidative phosphorylation and apoptosis requires their quality to be tightly regulated. Mitophagy is the main cellular process responsible for mitochondrial quality control. It selectively sends damaged or excess mitochondria to the lysosomes for degradation and plays a critical role in maintaining cellular homeostasis. However, increasing evidence shows that viruses utilize mitophagy to promote their survival. Viruses use various strategies to manipulate mitophagy to eliminate critical, mitochondria-localized immune molecules in order to escape host immune attacks. In this article, we will review the scientific advances in mitophagy in viral infections and summarize how the host immune system responds to viral infection and how viruses manipulate host mitophagy to evade the host immune system.

ER-Phagy and Microbial Infection.

The endoplasmic reticulum (ER) is an essential organelle in cells that synthesizes, folds and modifies membrane and secretory proteins. It has a crucial role in cell survival and growth, thus requiring strict control of its quality and homeostasis. Autophagy of the ER fragments, termed ER-phagy or reticulophagy, is an essential mechanism responsible for ER quality control. It transports stress-damaged ER fragments as cargo into the lysosome for degradation to eliminate unfolded or misfolded protein aggregates and membrane lipids. ER-phagy can also function as a host defense mechanism when pathogens infect cells, and its deficiency facilitates viral infection. This review briefly describes the process and regulatory mechanisms of ER-phagy, and its function in host anti-microbial defense during infection.

Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection.

Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as HMGB1 and ATF3, which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1-/- mice and RNA-seq data from mouse liver tissue overexpressing ATF3, we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.

Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. Thus, novel therapeutic targets are needed to be sought for the successful treatment of HCC. Peptaibols, a family of peptides synthesized non-ribosomally by the Trichoderma species and other fungi, exhibit antibiotic activities against bacteria and fungi. Few studies recently showed that peptaibols exerted cytotoxicity toward human lung epithelial and breast carcinoma cells. However, the mechanism involved in peptaibol-induced cell death remains poorly understood. RESULTS: Here, we showed that Trichokonin VI (TK VI), a peptaibol from Trichoderma pseudokoningii SMF2, induced growth inhibition of HCC cells in a dose-dependent manner. It did not obviously impair the viability of normal liver cells at lower concentration. Moreover, the suppression of cell viability resulted from the programmed cell death (PCD) with characteristics of apoptosis and autophagy. An influx of Ca2+ triggered the activation of mu-calpain and proceeded to the translocation of Bax to mitochondria and subsequent promotion of apoptosis. On the other hand, typically morphological characteristics consistent with autophagy were also observed by punctate distribution of MDC staining and the induction of LC3-II, including extensive autophagic vacuolization and enclosure of cell organelles by these autophagosomes. More significantly, specific depletion of Bak expression by small RNA interfering (siRNA) could partly attenuate TK VI-induced autophagy. However, siRNA against Bax led to increased autophagy. CONCLUSION: Taken together, these findings showed for the first time that peptaibols were novel regulators involved in both apoptosis and autophagy, suggesting that the class of peptaibols might serve as potential suppressors of tumor cells.

Effects of intracoronary injection of nicorandil and tirofiban on myocardial perfusion and short-term prognosis in elderly patients with acute ST-segment elevation myocardial infarction after emergency PCI.

BACKGROUND: This study investigated the effects of the intracoronary injection of nicorandil and tirofiban on myocardial perfusion and short-term prognosis in elderly patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). METHODS: Seventy-eight STEMI patients with age >65 years who underwent emergency PCI were consecutively enrolled. These patients received conventional PCI and were randomly divided into a control group and a treatment group (n=39 per group). The control group received an intracoronary injection of tirofiban followed by a maintenance infusion for 36 hours after surgery. The treatment group received intracoronary injection of tirofiban and nicorandil, and then intravenous infusion of tirofiban and nicorandil 36 hours after surgery. The following parameters were measured: TIMI grade, corrected TIMI frame count (cTFC), TIMI myocardial perfusion grade (TMPG), ST-segment resolution (STR) rate 2 hours post-operatively, resolution of ST-segment elevation (STR) at 2 hours postoperatively, peak level of serum CK-MB, left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) at 7-10 days postoperatively, and major adverse cardiac events (MACEs) in-hospital and within 30 days post-operatively. RESULTS: Compared with the control group, more patients in the treatment group had TIMI 3 and TMPG 3, and STR after PCI was significantly higher. The treatment group also had significantly lower cTFC, lower infarction relative artery (IRA), lower peak CK-MB, and no reflow ratio after PCI. The treatment group had significantly higher LVEDD and LVEF but lower incidence of MACEs than the control group. CONCLUSION: The intracoronary injection of nicorandil combined with tirofiban can effectively improve myocardial reperfusion in elderly STEMI patients after emergency PCI and improve short-term prognoses.

Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells.

TIP30 (Tat-interacting protein 30), a newly found proapoptotic factor, appears to be involved in multiple functions including metabolic suppression, apoptosis induction, and diminishing angiogenic properties. In the present study, we reported that mitochondrial events were required for apoptosis induced by TIP30 in hepatocellular carcinoma cells (HCC cells). Translocation of Bax was essential for TIP30-induced apoptosis, whereas overexpression of the anti-apoptotic protein Bcl-xL delayed both second mitochondria-derived activator of caspases (Smac/DIABLO) release and onset of apoptosis. Furthermore, TIP30-induced apoptosis was dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (z-VAD-fmk) blocked DNA fragmentation. Release of Smac/DIABLO from the mitochondria through the TIP30-P53-Bax cascade was required to remove the inhibitory effect of XIAP (X-linked Inhibitor of Apoptosis) and allowed apoptosis to proceed. Our results showed for the first time that Bax-dependent release of Smac/DIABLO, cytochrome c and AIF from the mitochondria mediated the contribution of the mitochondrial pathway to TIP30-mediated apoptosis. Our data suggested that adenovirus-mediated overexpression of TIP30 was capable of inducing therapeutic programmed cell death in vitro by activating the mitochondrial pathway of apoptosis. On the basis of these studies, elucidating the mechanism by which TIP30 induces cell death might establish it as an anticancer approach.

Preparation and modification of high dietary fiber flour: A review.

Dietary fiber, consisting of soluble dietary fiber and insoluble dietary fiber, has beneficial functional effects on the human body that are receiving increasingly attention. Refined flour lacks dietary fiber and poses potential risks to human health. Therefore, improving the nutritional value and processing performance of flour in the preparation and modification of high dietary fiber flour is of great importance. Whole-wheat flour, a high dietary fiber flour obtained by crushing whole-wheat grains, is rich in nutritional value. High dietary fiber flour obtained by adding bran back into the flour makes full use of the bran, which increases the utilization of wheat-milling byproducts. The addition of dietary fiber to flour is a direct method for obtaining high dietary fiber flour, and which has evolved with the development of the dietary fiber extraction industry. Further modifications of whole-wheat flour, bran, and dietary fiber, such as milling, extrusion, heat treatment, and biological treatment, can diminish the effect that bran materials on the quality of flour and flour products. This review summarizes methods used for the preparation and modification of three kinds of high dietary fiber flour and the effects of these different methods on the quality of flour and flour products, with the aim to provide guidance for the industrial preparation of high dietary fiber flour.

Autophagy is required for ectoplasmic specialization assembly in sertoli cells.

The ectoplasmic specialization (ES) is essential for Sertoli-germ cell communication to support all phases of germ cell development and maturity. Its formation and remodeling requires rapid reorganization of the cytoskeleton. However, the molecular mechanism underlying the regulation of ES assembly is still largely unknown. Here, we show that Sertoli cell-specific disruption of autophagy influenced male mouse fertility due to the resulting disorganized seminiferous tubules and spermatozoa with malformed heads. In autophagy-deficient mouse testes, cytoskeleton structures were disordered and ES assembly was disrupted. The disorganization of the cytoskeleton structures might be caused by the accumulation of a negative cytoskeleton organization regulator, PDLIM1, and these defects could be partially rescued by Pdlim1 knockdown in autophagy-deficient Sertoli cells. Altogether, our works reveal that the degradation of PDLIM1 by autophagy in Sertoli cells is important for the proper assembly of the ES, and these findings define a novel role for autophagy in Sertoli cell-germ cell communication.

Autophagy regulates spermatid differentiation via degradation of PDLIM1.

Spermiogenesis is a complex and highly ordered spermatid differentiation process that requires reorganization of cellular structures. We have previously found that Atg7 is required for acrosome biogenesis. Here, we show that autophagy regulates the round and elongating spermatids. Specifically, we found that Atg7 is required for spermatozoa flagella biogenesis and cytoplasm removal during spermiogenesis. Spermatozoa motility of atg7-null mice dropped significantly with some extra-cytoplasm retained on the mature sperm head. These defects are associated with an impairment of the cytoskeleton organization. Functional screening revealed that the negative cytoskeleton organization regulator, PDLIM1 (PDZ and LIM domain 1 [elfin]), needs to be degraded by the autophagy-lysosome-dependent pathway to facilitate the proper organization of the cytoskeleton. Our results thus provide a novel mechanism showing that autophagy regulates cytoskeleton organization mainly via degradation of PDLIM1 to facilitate the differentiation of spermatids.