BAG5 regulates HSPA8-mediated protein folding required for sperm head-tail coupling apparatus assembly.

Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8.

hnRNPA2B1 represses the disassembly of arsenite-induced stress granules and is essential for male fertility.

Although the composition and assembly of stress granules (SGs) are well understood, the molecular mechanisms underlying SG disassembly remain unclear. Here, we identify that heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) is associated with SGs and that its absence specifically enhances the disassembly of arsenite-induced SGs depending on the ubiquitination-proteasome system but not the autophagy pathway. hnRNPA2B1 interacts with many core SG proteins, including G3BP1, G3BP2, USP10, and Caprin-1; USP10 can deubiquitinate G3BP1; and hnRNPA2B1 depletion attenuates the G3BP1-USP10/Caprin-1 interaction but elevates the G3BP1 ubiquitination level under arsenite treatment. Moreover, the disease-causing mutation FUSR521C also disassembles faster from SGs in HNRNPA2B1 mutant cells. Furthermore, knockout of hnRNPA2B1 in mice leads to Sertoli cell-only syndrome (SCOS), causing complete male infertility. Consistent with this, arsenite-induced SGs disassemble faster in Hnrnpa2b1 knockout (KO) mouse Sertoli cells as well. These findings reveal the essential roles of hnRNPA2B1 in regulating SG disassembly and male mouse fertility.

A regulatory module comprising G3BP1-FBXL5-IRP2 axis determines sodium arsenite-induced ferroptosis.

Arsenic contamination is extremely threatening to the global public health. It was reported that sodium arsenite exposure induces serious kidney injury. However, the underlying mechanism is unclear. Ferroptosis is a newly characterized form of iron-dependent programmed cell death, which is implicated in the pathogenesis of various human diseases, including kidney injury. The lethal accumulation of iron-catalyzed lipid peroxidation is the fundamental biochemical characteristic of ferroptosis. Herein we report that sodium arsenite exposure initiates ferroptosis in mammalian HEK293, MEF and HT1080 cells, and induces ferroptosis-associated acute kidney injury in mice. RNA-binding protein G3BP1, the switch component of stress granules, is indispensable for sodium arsenite-induced ferroptosis in a stress granule-independent manner. Mechanistically, G3BP1 stabilizes IRP2, the master regulator of cellular iron homeostasis, through binding to and suppressing the translation of FBXL5 mRNA, which encodes the E3 ligase component to mediate IRP2 ubiquitination and proteasomal degradation. Sodium arsenite intoxication expedites this G3BP1-FBXL5-IRP2 axis and elevates cellular labile free iron, which is responsible for sodium arsenite exposure-induced lipid peroxidation and ferroptotic cell death. In summary, this study highlights a regulatory module comprising G3BP1-FBXL5-IRP2 axis in determining sodium arsenite-induced ferroptosis and ferroptosis-associated acute kidney injury in mice.

Construction of an index system of core competence assessment for otolaryngology nurse specialists in China: A Delphi study.

BACKGROUND: Clinical nurse specialists play a vital role in the work quality, patient safety and team development of nurses. However, there is currently no prior study constructing the index of core competence assessment for otolaryngology Nurse Specialists. OBJECTIVES: To establish an index system for the evaluation of Chinese otolaryngology Nurse Specialists' core competence. DESIGN: A Delphi study. SETTINGS: The study was mainly conducted in a university-affiliated hospital in China. PARTICIPANTS: Twenty-two experts with otolaryngology knowledge and practical experience from different regions and organizations in China. METHODS: We used literature reviews and expert meetings to establish a draft index system . Subsequently, a two-round Delphi survey was utilized to consult opinions from 22 experts about the index for the evaluation of otolaryngology nurse specialists' core competence and provide qualitative comments on their ratings. Consensus was predefined as a mean important score of 4.0 or above and a coefficient of variation is not above 0.25 among the participants. RESULTS: The final evaluation indexes of the core competencies for otolaryngology Nurse Specialists included 5 first-level indexes (clinical competence, critical thinking competence, leadership, professional development competence, professionalism), 19 second-level indexes, and 85 third-level indexes. The effective response rates of the two expert consultation rounds were 100 %. The expert authority coefficients were 0.864 and 0.859 in the first and second rounds of consultation, respectively. In the second round of consultation, the first, second and third indexes of Kendall's coefficient of concordance were 0.357, 0.330, and 0.232, respectively (P < 0.001). CONCLUSIONS: The constructed evaluation indexes of the core competencies of otolaryngology Nurse Specialists are scientific, reasonable, comprehensive, and specific and may provide references for the training and evaluation of otolaryngology Nurse Specialists.

Targeting histone deacetylases for cancer therapy: Trends and challenges.

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

SERBP1 Promotes Stress Granule Clearance by Regulating 26S Proteasome Activity and G3BP1 Ubiquitination and Protects Male Germ Cells from Thermostimuli Damage.

Stress granules (SGs) are membraneless cytoplasmic condensates that dynamically assemble in response to various stressors and reversibly disassemble after stimulus removal; however, the mechanisms underlying SG dynamics and their physiological roles in germ cell development are elusive. Here, we show that SERBP1 (SERPINE1 mRNA binding protein 1) is a universal SG component and conserved regulator of SG clearance in somatic and male germ cells. SERBP1 interacts with the SG core component G3BP1 and 26S proteasome proteins PSMD10 and PSMA3 and recruits them to SGs. In the absence of SERBP1, reduced 20S proteasome activity, mislocalized valosin containing protein (VCP) and Fas associated factor family member 2 (FAF2), and diminished K63-linked polyubiquitination of G3BP1 during the SG recovery period were observed. Interestingly, the depletion of SERBP1 in testicular cells in vivo causes increased germ cell apoptosis upon scrotal heat stress. Accordingly, we propose that a SERBP1-mediated mechanism regulates 26S proteasome activity and G3BP1 ubiquitination to facilitate SG clearance in both somatic and germ cell lines.

Occlusion preconditioned mice are resilient to hypobaric hypoxia-induced myocarditis and arrhythmias due to enhanced immunomodulation, metabolic homeostasis, and antioxidants defense.

Background: Sea-level residents experience altitude sickness when they hike or visit altitudes above ~2,500 m due to the hypobaric hypoxia (HH) conditions at such places. HH has been shown to drive cardiac inflammation in both ventricles by inducing maladaptive metabolic reprogramming of macrophages, which evokes aggravated proinflammatory responses, promoting myocarditis, fibrotic remodeling, arrhythmias, heart failure, and sudden deaths. The use of salidroside or altitude preconditioning (AP) before visiting high altitudes has been extensively shown to exert cardioprotective effects. Even so, both therapeutic interventions have geographical limitations and/or are inaccessible/unavailable to the majority of the population as drawbacks. Meanwhile, occlusion preconditioning (OP) has been extensively demonstrated to prevent hypoxia-induced cardiomyocyte damage by triggering endogenous cardioprotective cascades to mitigate myocardial damage. Herein, with the notion that OP can be conveniently applied anywhere, we sought to explore it as an alternative therapeutic intervention for preventing HH-induced myocarditis, remodeling, and arrhythmias. Methods: OP intervention (6 cycles of 5 min occlusion with 200 mmHg for 5 min and 5 min reperfusion at 0 mmHg - applying to alternate hindlimb daily for 7 consecutive days) was performed, and its impact on cardiac electric activity, immunoregulation, myocardial remodeling, metabolic homeostasis, oxidative stress responses, and behavioral outcomes were assessed before and after exposure to HH in mice. In humans, before and after the application of OP intervention (6 cycles of 5 min occlusion with 130% of systolic pressure and 5 min reperfusion at 0 mmHg - applying to alternate upper limb daily for 6 consecutive days), all subjects were assessed by cardiopulmonary exercise testing (CPET). Results: Comparing the outcomes of OP to AP intervention, we observed that similar to the latter, OP preserved cardiac electric activity, mitigated maladaptive myocardial remodeling, induced adaptive immunomodulation and metabolic homeostasis in the heart, enhanced antioxidant defenses, and conferred resistance against HH-induce anxiety-related behavior. Additionally, OP enhanced respiratory and oxygen-carrying capacity, metabolic homeostasis, and endurance in humans. Conclusions: Overall, these findings demonstrate that OP is a potent alternative therapeutic intervention for preventing hypoxia-induced myocarditis, cardiac remodeling, arrhythmias, and cardiometabolic disorders and could potentially ameliorate the progression of other inflammatory, metabolic, and oxidative stress-related diseases.

First Report of Youcai Mosaic Virus Infecting Yam in China.

Yam (Dioscorea opposita Thunb.) is cultivated mainly as a functional food and for nutritional and medicinal purposes in China (1). It is propagated through tubers and this facilitates the spread and accumulation of viruses in the crop, eventually leading to yield losses (2). At present, different virus species belonging to the genera Aureusvirus, Badnavirus, Carlavirus, Comovirus, Cucumovirus, Fabavirus, Macluravirus, Potexvirus and Potyvirus have been reported in yams (3) and fifteen viruses in these genera have been detected in China. In July 2020, a survey of viral diseases on yam was conducted in plantations of Wenxian and Mengzhou counties in Henan Province, China. Fifty-four leaf samples of Dioscorea opposite showing mosaic and leaf discoloration (Supplementary Fig1) were collected from eight fields (five to ten plants per field). These leaf samples were ground in liquid nitrogen and total RNA was extracted from a portion of the mixed powder using RNAprep Pure Plant Plus Kit (TIANGEN Biotech, Beijing, China). A cDNA library was constructed using NEBNext Ultra RNA Library Prep Kit for Illumina (NEB, USA) after ribosomal RNA depletion using Ribo-off rRNA Depletion Kit (Vazyme Biotech, Nanjing, China), and sequenced on the Illumina NovaSeq 6000 system at the Berry Genomics Corporation (Beijing, China). A total of 87,075 contigs (>200 bp) were generated from de novo assembly (CLC Genomic Workbench 10.0) from a total of 34,656,172 paired-end reads. After BLASTn analysis, three contigs with the length of 1009, 1340 and 1859 nucleotides shared 96.33%, 96.72% and 96.29% nt identity respectively with youcai mosaic virus SX isolate, a tobamovirus (YoMV GenBank accession no. JX422022). In addition to YoMV, broad bean wild virus 2 and yam latent virus were also identified, which had previously been reported in yams in China. To confirm the NGS result, total RNAs were extracted from fifty-four above-mentioned samples and RT-PCR was carried out to amplify a 528 bp fragment of the coat protein (CP) of YoMV by using a pair of specific primers CP gene. PCR products with expected size were obtained from 26 out of 54 samples, and seventeen amplicons of YoMV-CP were sequenced (accession nos. ON052726 to ON052742). The nt sequence identities of CP gene among these seventeen isolates were 99.6%-100%. Furthermore, the near-full-length genomic sequence of YoMV-Do41 isolate was obtained from sample 41 by RT-PCR amplification of four overlapping fragments using the following primer pairs: YoMV-15F/YoMV-1910R, YoMV-1770F/YoMV-3750R, YoMV-3645F/YoMV-5404R and YoMV-4921F/YoMV-6280R (Supplementary Table1). The YoMV-Do41 isolate was 6, 274 nt in length (accession no. ON149803) and shared 89.65% and 97.31% nt identities to As1-2 isolate (GenBank accession no. MW307290) and to SX isolate (accession no. JX422022), respectively.To the best of our knowledge, this is the first report of YoMV infecting yam in China. YoMV has a wide host range including genera Impatiens, Rehmannia, Brassica, Chelidonium, Trifolium, Crossandro, Alstroemeria, Stellaria. This study will serve as an important reference for the host range of YoMV. According to the detection rate infections with YoMV in yam are common in these producing regions. Further studies will be required to determine the infection rate in other producing regions and the potential threat posed by YoMV on yam production should be considered.

Cardiopulmonary exercise testing to observe subclinical abnormalities in cardiopulmonary function in patients undergoing peritoneal dialysis.

BACKGROUND: Decreased cardiorespiratory fitness (CRF) related to cardiopulmonary function increases the risk of cardiovascular disease in patients with end-stage kidney disease. Thus, early detection of the cause of impaired cardiopulmonary function in patients undergoing peritoneal dialysis (PD) is of important clinical significance. METHODS: In this cross-sectional study, symptom-restricted cardiopulmonary exercise testing (CPET) was performed in 30 patients undergoing PD and in 23 age- and sex-matched healthy control subjects. A fixed workload was added every minute until fatigue, and breath-by-breath respiratory gas was analysed with an automated gas analyzer at 10-s intervals. RESULTS: The peak oxygen uptake (16.39 ± 0.83 vs. 25.77 ± 1.33 ml/kg/min p < 0.001) and the oxygen uptake at the anerobic threshold of patients undergoing PD (9.61 ± 0.34 vs. 14.55 ± 0.64 ml/kg/min; p < 0.001) were lower than in healthy control subjects, and both of these parameters correlated with body mass index and left atrial dimension. A steeper minute ventilation/carbon dioxide production slope (27.20 ± 0.68 vs. 24.29 ± 0.69；p < 0.01) and a lower end-tidal carbon dioxide partial pressure (37.93 ± 0.54 vs. 41.27 ± 0.83 mmHg；p < 0.05) were observed in patients undergoing PD. The oxygen pulse and oxygen uptake efficiency slope was smaller in patients undergoing PD. The Maximum heart rate (126.07 ± 4.01 vs. 149.96 ± 5.29 bpm；p < 0.01) and 1-min heart rate recovery (13.93 ± 1.52 vs. 24.39 ± 1.61 bpm；p < 0.01) were also lower in patients undergoing PD. CONCLUSION: Subclinical cardiopulmonary dysfunction may exist in patients with PD, and a reduction in CRF in patients undergoing PD is affected by both central and peripheral functions. CPET has potential value in revealing the mechanism of impaired CRF and in discovering subclinical abnormalities in cardiopulmonary function.

First Report of Tobacco Mild Green Mosaic Virus Infecting Rehmannia glutinosa in China.

Rehmannia glutinosa (family Scrophulariaceae) is an important traditional medicinal plant, whose root is used to treat anemia, hemoptysis, and gynecological diseases in China (Matsumoto et al. 1989). This plant is native to China and cultivated in China, Korea, Japan, and northern Vietnam (Kwak et al. 2020). Viral diseases caused remarkable loss in the yield and quality of R. glutinosa (Ling et al. 2009). To date, ten viruses have been identified globally to infect R. glutinosa and seven of these viruses reported in China (Liu et al. 2018; Zhang et al. 2021). Most plants of R. glutinosa are infected with one or more of these viruses (Kwak et al. 2018; Zhang et al. 2004). In July 2020, a survey of the viral disease infecting R. glutinosa was conducted in commercial plantations of Wenxian, Wuzhi, Mengzhou, and Yuzhou counties in Henan Province, China. The disease symptoms included mosaic, chlorosis, leaf distortion, and the percentage of symptomatic plants was over 70% in the surveyed fields (n=9). Sixty leaf samples of symptomatic R. glutinosa plants were collected from nine cultivation fields in Wenxian, Wuzhi, Mengzhou, and Yuzhou counties (five to seven plants for each field). Total RNA was extracted from one pooled sample containing a portion of all above-mentioned leaf samples using RNAprep Pure Plant Plus Kit (TIANGEN Biotech, Beijing, China) and analyzed by high-throughput sequencing (HTS) to identify viral pathogens. A transcriptome library was generated using NEBNext Ultra RNA Library Prep Kit for Illumina (NEB, USA), and sequenced on an Illumina NovaSeq6000 sequencing system at Berry Genomics Corporation (Beijing, China). A total of 27,664,949 high-quality clean reads were obtained after trimming and used for contig assembly. The assembled contigs (n=109,180) were searched using Basic Local Alignment Search Tool (BLAST) at GenBank. BLASTn analysis showed that the R. glutinosa plants were infected with known viruses, including broad bean wilt virus, rehmannia mosaic virus, youcai mosaic virus, and cucurbit chlorotic yellows virus. In addition, one contig (6,418 nt in length) had a nucleotide sequence identity of 99.64% with the TN29 isolate of tobacco mild green mosaic virus (TMGMV, GenBank accession no. MF139550). To confirm the presence of this virus, sixty above-mentioned samples were screened by reverse transcription-polymerase chain reaction (RT-PCR) using the specific primer pairs (Supplementary Table1) TMGMG-CPF/TMGMG-CPR targeting a 545-nt fragment within the CP gene. Amplicons with expected sizes were detected from 47 of 60 samples but not from the negative control (virus-free healthy plant through the tip meristem culture). Seventeen amplicons (11#, 13#, 14#, 21#, 22#, 23#, 25#, 26#, 27#, 31#, 32#, 33#, 37#, 52#, 57#, 59#, and 60#) of TMGMV-CP were selected, and purified. The PCR products were cloned into the pMD19-T vector (TAKARA Biotech, Dalian, China) and sequenced. The sequences were deposited into the GenBank (accession nos. MZ395944 to MZ395960). The near-full-length genomic sequence of TMGMV-Rg14 isolate was obtained from one positive sample (sample no. 14) by RT-PCR amplification of two overlapping fragments using the following primer pairs: TMGMV-40F/TMGMV-3570R and TMGMV-3220F/TMGMV-6400R. The near-full-length genomic sequence of the TMGMV-Rg14 isolate was 6 304 nucleotides (nt) in length and deposited into GenBank (accession no. MZ395975). BLASTn analysis demonstrated that the TMGMV-Rg14 isolate shared a sequence identity ranging from 96.89% (AB078435) to 99.60% (MF139550) with the other TMGMV isolates. Furthermore, the virus-free healthy R. glutinosa plants were inoculated with sap from the positive sample (14#) to confirm the infection of TMGMV. Mosaic symptoms were induced on the systemically infected leaves of the inoculated plants 14 days post inoculation. The systemically infected leaves of inoculated plants were assayed by RT-PCR using the primer pairs TMGMV-CPF/CPR. Amplicons of expected size were detected from the inoculated plants but not from non-inoculated plants. To our knowledge, this is the first report of TMGMV infection on R. glutinosa. Further studies are necessary to select a suitable indicator plant for this TMGMV, its host range, and the symptoms it induces in single infection. Since R. glutinosa is cultivated by vegetative propagation, production of virus-free healthy plants is necessary. This study will help to generate virus-free healthy plants and prevent viral disease on R. glutinosa. Further study is needed to determine its pathological implications and economic impact on R. glutinosa in China.

Sesquiterpenoids from Ixeris sonchifolia and their neuroprotective activities.

The phytochemical investigation of the methanol extract of Ixeris sonchifolia led to the isolation and identification of nine analogs, including one new guaiane-type sesquiterpenoid, named ixerinoid A (1). The structure of 1 was determined by extensive analysis of the 1 D and 2 D nuclear magnetic resonance spectroscopic data, as well as quantum chemical calculations. Additionally, all the isolates were tested for their neuroprotective activity using the oxygen-glucose deprivation/reperfusion-induced SH-SY5Y cell injury model. Compounds 3, 5, 6, 8, and 9 displayed remarkable protective effects at concentrations of 1, 5, and 10 µM, respectively.

hnRNPU in Sertoli cells cooperates with WT1 and is essential for testicular development by modulating transcriptional factors Sox8/9.

Background: Sertoli cells are essential regulators of testicular fate in the differentiating gonad; however, its role and underlying molecular mechanism of regulating testicular development in prepubertal testes are poorly understood. Although several critical regulatory factors of Sertoli cell development and function have been identified, identifying extrinsic factors that regulate gonocyte proliferation and migration processes during neonatal testis development remains largely unknown. Methods: We used the Sertoli cell-specific conditional knockout strategy (Cre/Loxp) in mice and molecular biological analyses (Luciferase assay, ChIP-qPCR, RNA-Seq, etc.) in vitro and in vivo to study the physiological roles of hnRNPU in Sertoli cells on regulating testicular development in prepubertal testes. Results: We identified a co-transcription factor, hnRNPU, which is highly expressed in mouse and human Sertoli cells and required for neonatal Sertoli cell and pre-pubertal testicular development. Conditional knockout of hnRNPU in murine Sertoli cells leads to severe testicular atrophy and male sterility, characterized by rapid depletion of both Sertoli cells and germ cells and failure of spermatogonia proliferation and migration during pre-pubertal testicular development. At molecular levels, we found that hnRNPU interacts with two Sertoli cell markers WT1 and SOX9, and enhances the expression of two transcriptional factors, Sox8 and Sox9, in Sertoli cells by directly binding to their promoter regions. Further RNA-Seq and bioinformatics analyses revealed the transcriptome-wide of key genes essential for Sertoli cell and germ cell fate control, such as biological adhesion, proliferation and migration, were deregulated in Sertoli cell-specific hnRNPU mutant testes. Conclusion: Our findings demonstrate an essential role of hnRNPU in Sertoli cells for prepubertal testicular development and testis microenvironment maintenance and define a new insight for our understanding of male infertility therapy.

GSK-3ß manipulates ferroptosis sensitivity by dominating iron homeostasis.

Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3ß acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3ß by selective inhibitor LY2090314 or genetic KD of GSK-3ß by shRNA potently promotes ferroptotic resistance. GSK-3ß KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3ß in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3ß as a target for cancer chemotherapy.

A Novel Lipoprotein Lipase Mutation in an Infant With Glycogen Storage Disease Type-Ib and Severe Hypertriglyceridemia.

Glycogen storage disease (GSD) Ib is a rare genetic metabolic disorder caused by gene mutation in the glucose 6-phosphate transport gene SLC37A4 (OMIM# 602671). This study aimed to explore the association between a novel lipoprotein lipase (LPL) mutation and severe hypertriglyceridemia in a GSD Ib infant with severe hypertriglyceridemia. A 5-month-old girl was admitted to our hospital because of repeated episodes of low-grade fever over the past month and because of neutropenia. The patient was diagnosed with GSD Ib and severe hypertriglyceridemia based on clinical manifestations and laboratory test results. Next-generation sequencing and Sanger sequencing were then applied to DNA from the peripheral blood of the patient and her parents to analyze gene mutations. Pathogenicity prediction analysis was performed using Sorting Intolerant From Tolerant (SIFT) and PolyPhen-2 platforms. The results revealed that this infant carried a compound heterozygous variation in the SLC37A4 gene, a c.1043T > C (p.L348P) mutation derived from her mother and a c.572C > T (p.P191L) mutation derived from her father. In addition, a novel c.483delA (p. A162Pfs*10) frameshift mutation was found in the patient's LPL gene exon 4, which was derived from the heterozygous carrier of her father. The SIFT and PolyPhen-2 prediction programs indicated that these mutations were likely harmful. Medium-chain triglyceride milk and granulocyte colony-stimulating factor subcutaneous injection alleviated the symptoms. Our findings identified a novel LPL gene frameshift mutation combined with SLC37A4 gene compound heterozygous mutations in a GSD Ib infant with severe hypertriglyceridemia.

Factors affecting the efficacy and safety of docetaxel combined with platinum in the treatment of advanced non-small cell lung cancer.

BACKGROUND: This study aimed to quantitatively evaluate factors influencing the efficacy and safety of the docetaxel-platinum regimen to provide reliable information for optimizing chemotherapy regimens. RESEARCH DESIGN AND METHODS: A parametric survival function model was used to describe the time course of overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) receiving a docetaxel-platinum regimen. A random-effects model in a single-arm meta-analysis was used to analyze the objective response rate and grade 3-4 adverse event rates based on various docetaxel-platinum regimens. RESULTS: The model revealed that the risk of death in East Asians was approximately 1.5-fold higher than that in non-East Asians, with a median OS of 13.7 (95% confidence interval [CI]: 12.8-14.7) months and 9.3 (95% CI: 7.7-11.1) months, respectively. No significant impact of different administration regimens on OS was found. However, when drug exposure increased, the incidence of grade 3-4 anemia or neutropenia significantly increased. CONCLUSIONS: The docetaxel-platinum regimen has different efficacies in the treatment of advanced NSCLC between East Asian and non-East Asian populations. A better benefit-risk ratio can be obtained with a lower exposure regimen of docetaxel combined with platinum.

Low-dose exposure to black carbon significantly increase lung injury of cadmium by promoting cellular apoptosis.

Particulate matter 2.5 (PM2.5) has adverse biological effects on major living organs in the body, including lungs. The complex composition of PM2.5, including carbon black and heavy metals, cause toxic effects to the lung. Nonetheless, there exists considerable knowledge gaps regarding the impact of carbon black (CB) on environmental health and safety (EHS). Thus far, the synergistic effects of CB have not gained much attention in past decades. Here, we showed that combined exposure of CB and Cadmium (Cd) enhance the cytotoxicity by altering the state of cell membrane. Specially, CB caused cell membrane collapse and increased the permeability of cells, and remarkedly enhanced the metal Cd toxicity. Furthermore, upon pre-treatment sublethal-dose CB, the increased intracellular Cd brought about a significantly amount of lactate dehydrogenase (LDH) and high expression of metallothionein-1 (MT-1) in human lung epithelial cell line (BEAS-2B) cells, and ultimately resulted an increased cellular toxicity. The lung of mice exposed CBs and Cd presented remarkably inflammation than Cd alone. Mechanistic exploration deciphered that CB pre-treatment triggered cell damage via apoptosis due to Cd exposure. Collectively, our findings reveal a novel path for understanding the impact of CB on EHS with its synergistic effects, through which nanomaterials might exert detrimental effects on organisms.

Computational design of ultrashort peptide inhibitors of the receptor-binding domain of the SARS-CoV-2 S protein.

Targeting the interaction between severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) is believed to be an effective strategy for drug design to inhibit the infection of SARS-CoV-2. Herein, several ultrashort peptidase inhibitors against the RBD-ACE2 interaction were obtained by a computer-aided approach based on the RBD-binding residues on the protease domain (PD) of ACE2. The designed peptides were tested on a model coronavirus GX_P2V, which has 92.2 and 86% amino acid identity to the SARS-CoV-2 spike protein and RBD, respectively. Molecular dynamics simulations and binding free energy analysis predicted a potential binding pocket on the RBD of the spike protein, and this was confirmed by the specifically designed peptides SI5α and SI5α-b. They have only seven residues, showing potent antiviral activity and low cytotoxicity. Enzyme-linked immunosorbent assay result also confirmed their inhibitory ability against the RBD-ACE2 interaction. The ultrashort peptides are promising precursor molecules for the drug development of Corona Virus Disease 2019, and the novel binding pocket on the RBD may be helpful for the design of RBD inhibitors or antibodies against SARS-CoV-2.

Response to stress in biological disorders: Implications of stress granule assembly and function.

It is indispensable for cells to adapt and respond to environmental stresses, in order for organisms to survive. Stress granules (SGs) are condensed membrane-less organelles dynamically formed in the cytoplasm of eukaryotes cells to cope with diverse intracellular or extracellular stress factors, with features of liquid-liquid phase separation. They are composed of multiple constituents, including translationally stalled mRNAs, translation initiation factors, RNA-binding proteins and also non-RNA-binding proteins. SG formation is triggered by stress stimuli, viral infection and signal transduction, while aberrant assembly of SGs may contribute to tissue degenerative diseases. Recently, a growing body of evidence has emerged on SG response mechanisms for cells facing high temperatures, oxidative stress and osmotic stress. In this review, we aim to summarize factors affecting SGs assembly, present the impact of SGs on germ cell development and other biological processes. We particularly emphasize the significance of recently reported RNA modifications in SG stress responses. In parallel, we also review all current perspectives on the roles of SGs in male germ cells, with a particular focus on the dynamics of SG assembly.

MicroRNA-325 inhibits the proliferation and induces the apoptosis of T cell acute lymphoblastic leukemia cells in a BAG2-dependent manner.

The inhibitory effect of microRNA (miR)-325 in multiple different types of cancer cell has been identified; however, its biological function in T cell acute lymphoblastic leukemia (T-ALL) remains unknown. Moreover, Bcl-2-associated athanogene (BAG)2 is highly expressed in a various types of tumors and is regarded as an anti-apoptotic gene. In the present study, the roles of miR-325 and BAG2 in a T-ALL cell line (Jurkat cells) were investigated. BAG2 and miR-325 expression levels in clinical blood samples from healthy donors and pediatric patients with T-ALL, as well as in T-ALL cell lines was detected using western blot analysis and/or reverse transcription-quantitative PCR. Dual-luciferase reporter gene assays and TargetScan were used to evaluate the interaction between BAG2 and miR-325. Small interfering RNA technology was applied to knockdown BAG2 expression in Jurkat cells. The effects of miR-325 mimic and BAG2 downregulation on the proliferation and apoptosis were assessed by an MTT assay, flow cytometry and western blot analysis. The results revealed that the expression of miR-325 was downregulated in blood samples from pediatric patients and in T-ALL cell lines, and its expression was lowest in Jurkat cells. The expression levels of BAG2 exhibited the opposite results. The knockdown of BAG2 markedly induced the apoptosis and inhibited the proliferation of Jurkat cells. In addition, the overexpression of miR-325 significantly inhibited the growth and promoted the apoptosis of Jurkat cells, with these effects being eliminated by BAG2 overexpression. In conclusion, the findings of the present study demonstrated that miR-325 directly targets the BAG2 gene and that the introduction of miR-325 can accelerate apoptosis and suppress the proliferation of Jurkat cells by silencing BAG2 expression.