Mitochondrial ribosomes mitoribosomes synthesize a critical set of proteins essential for oxidative phosphorylation Therefore, mitoribosomal function is vital to the cellular energy supply Mitoribosome biogenesis follows distinct molecular pathways that remain poorly understood Here, we determine the cryo-EM structures of mitoribosomes isolated from human cell lines with either depleted or overexpressed mitoribosome assembly factor GTPBP5, allowing us to capture consecutive steps during mitoribosomal large subunit mt-LSU biogenesis Our structures provide essential insights into the last steps of 16S rRNA folding, methylation and peptidyl transferase centre PTC completion, which require the coordinated action of nine assembly factors We show that mammalian-specific MTERF4 contributes to the folding of 16S rRNA, allowing 16 S rRNA methylation by MRM2, while GTPBP5 and NSUN4 promote fine-tuning rRNA rearrangements leading to PTC formation Moreover, our data reveal an unexpected involvement of the elongation factor mtEF-Tu in mt-LSU assembly, where mtEF-Tu interacts with GTPBP5, similar to its interaction with tRNA during translational elongationClear cell renal cell carcinomas ccRCC reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine Recently, sirtuin 4 SIRT4, a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment However, the role of SIRT4 in ccRCC remains poorly understood Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species ROS Heme oxygenase-1 HO-1 is part of an endogenous defense system against oxidative stress Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel-Lindau VHL-proficient cells and repressed its expression in VHL-deficient cells This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1 Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1 Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCsIt has long been known that bacteria coordinate their physiology with their nutrient environment, yet our current understanding offers little intuition for how bacteria respond to the second-to-minute scale fluctuations in nutrient concentration characteristic of many microbial habitats To investigate the effects of rapid nutrient fluctuations on bacterial growth, we couple custom microfluidics with single-cell microscopy to quantify the growth rate of E coli experiencing 30 s to 60 min nutrient fluctuations Compared to steady environments of equal average concentration, fluctuating environments reduce growth rate by up to 50 However, measured reductions in growth rate are only 38 of the growth loss predicted from single nutrient shifts This enhancement derives from the distinct growth response of cells grown in environments that fluctuate rather than shift once We report an unexpected physiology adapted for growth in nutrient fluctuations and implicate nutrient timescale as a critical environmental parameter beyond nutrient identity and concentrationAccumulated evidence shows that OGT-mediated O-GlcNAcylation plays an important role in response to DNA damage repair However, it is unclear if the "eraser" O-GlcNAcase OGA participates in this cellular process Here, we examined the molecular mechanisms and biological functions of OGA in DNA damage repair, and found that OGA was recruited to the sites of DNA damage and mediated deglycosylation following DNA damage The recruitment of OGA to DNA lesions is mediated by O-GlcNAcylation events Moreover, we have dissected OGA using deletion mutants and found that C-terminal truncated OGA including the pseudo HAT domain was required for the recruitment of OGA to DNA lesions Using unbiased protein affinity purification, we found that the pseudo HAT domain was associated with DNA repair factors including NONO and the Ku70/80 complex Following DNA damage, both NONO and the Ku70/80 complex were O-GlcNAcylated by OGT The pseudo HAT domain was required to recognize NONO and the Ku70/80 complex for their deglycosylation Suppression of the deglycosylation prolonged the retention of NONO at DNA lesions and delayed NONO degradation on the chromatin, which impaired non-homologus end joining NHEJ Collectively, our study reveals that OGA-mediated deglycosylation plays a key role in DNA damage repairProteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction Osteocrin OSTN acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy DCM Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin STZ, 50 mg/kg for consecutive 5 days to generate diabetic models Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro Mechanistically, OSTN treatment restored protein kinase G PKG-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro  https//wwwselleckchemcom/products/phycocyanobilinhtml  Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCMMotoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disordersCore binding factor acute myelogenous leukemia CBF-AML, characterized by the presence of either t8;21 q22;q22 or inv16 p13q22/t16;16, is considered good-risk AML in the context of cytarabine based intensive chemotherapy Still, outcome can be improved significantly through the effective implementation of available therapeutic measures and appropriate disease monitoring The incorporation of gemtuzumab ozogamicin into frontline therapy should be standard Cytarabine based induction/consolidation regimen may be combined with anthracycline 3 + 7 standard or antimetabolite, fludarabine Serial quantitative polymerase chain reaction QPCR monitoring of unique fusion transcripts allows monitoring for measurable residual disease clearance; this allows for better prognostication and well as treatment modificationsFusion genes FGs are important genetic abnormalities in acute leukemias, but their variety and occurrence in acute leukemias remain to be systematically described Whole transcriptome sequencing WTS provides a powerful tool for analyzing FGs Here we report the FG map revealed by WTS in a consecutive cohort of 1000 acute leukemia cases in a single center, including 539 acute myeloid leukemia AML, 437 acute lymphoblastic leukemia ALL, and 24 mixed-phenotype acute leukemia MPAL patients Bioinformatic analysis identified 792 high-confidence in-frame fusion events 296 distinct fusions which were classified into four tiers Tier A pathogenic, B likely pathogenic, and C uncertain significance FGs were identified in 618 cases of the total cohort 597 in AML, 645 in ALL, and 636 in MPAL FGs involving protein kinase, transcription factor, and epigenetic genes were detected in 107, 485, and 151 cases, respectively A considerable amount of novel FGs 82 in AML, 88 in B-ALL, 13 in T-ALL, and 9 in MPAL was identified This comprehensively described real map of FGs in acute leukemia revealed multiple FGs with clinical relevance that have not been previously recognized WTS is a valuable tool and should be widely used in the routine diagnostic workup of acute leukemiaAs demonstrated during the COVID-19 pandemic, advanced deep ultraviolet DUV light sources 200-280 nm, such as AlGaN-based light-emitting diodes LEDs show excellence in preventing virus transmission, which further reveals their wide applications from biological, environmental, industrial to medical However, the relatively low external quantum efficiencies mostly lower than 10 strongly restrict their wider or even potential applications, which have been known related to the intrinsic properties of high Al-content AlGaN semiconductor materials and especially their quantum structures Here, we review recent progress in the development of novel concepts and techniques in AlGaN-based LEDs and summarize the multiple physical fields as a toolkit for effectively controlling and tailoring the crucial properties of nitride quantum structures In addition, we describe the key challenges for further increasing the efficiency of DUV LEDs and provide an outlook for future developmentsAlthough methotrexate MTX is the most widely used therapy for central nervous system CNS prophylaxis in patients with diffuse large B-cell lymphoma DLBCL, the optimal regimen remains unclear We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP or R-CHOP-like regimens from 2001 to 2017, of whom 295 50 received prophylaxis Intrathecal IT MTX was given to 253 86 and high-dose MTX HD-MTX to 42 14 After a median follow-up of 68 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not 2 vs 71 However, the difference became less significant over time 5-year risk 56 vs 75, indicating prophylaxis tended to delay CNS relapse rather than prevent it Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX 5-year risk 5