A shock flash breaking out of a dusty red supergiant.

Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.

Deafness-associated tRNAPhe mutation impaired mitochondrial and cellular integrity.

Defects in mitochondrial RNA metabolism have been linked to sensorineural deafness that often occurs as a consequence of damaged or deficient inner ear hair cells. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAPhe 593T > C mutation that changed a highly conserved uracil to cytosine at position 17 of the DHU-loop. The m.593T > C mutation altered tRNAPhe structure and function, including increased melting temperature, resistance to S1 nuclease-mediated digestion, and conformational changes. The aberrant tRNA metabolism impaired mitochondrial translation, which was especially pronounced by decreases in levels of ND1, ND5, CYTB, CO1, and CO3 harboring higher numbers of phenylalanine. These alterations resulted in aberrant assembly, instability, and reduced activities of respiratory chain enzyme complexes I, III, IV, and intact supercomplexes overall. Furthermore, we found that the m.593T > C mutation caused markedly diminished membrane potential, and increased the production of reactive oxygen species in the mutant cell lines carrying the m.593T > C mutation. These mitochondrial dysfunctions led to the mitochondrial dynamic imbalance via increasing fission with abnormal mitochondrial morphology. Excessive fission impaired the process of autophagy including the initiation phase, formation, and maturation of the autophagosome. In particular, the m.593T > C mutation upregulated the PARKIN-dependent mitophagy pathway. These alterations promoted an intrinsic apoptotic process for the removal of damaged cells. Our findings provide critical insights into the pathophysiology of maternally inherited deafness arising from tRNA mutation-induced defects in mitochondrial and cellular integrity.

Leber's hereditary optic neuropathy-associated ND6 14484T > C mutation caused pleiotropic effects on the complex I, RNA homeostasis, apoptosis and mitophagy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mitochondrial DNA (mtDNA) mutations. LHON-linked ND6 14484T > C (p.M64V) mutation affected structural components of complex I but its pathophysiology is poorly understood. The structural analysis of complex I revealed that the M64 forms a nonpolar interaction Y59 in the ND6, Y59 in the ND6 interacts with E34 of ND4L, and L60 of ND6 interacts with the Y114 of ND1. These suggested that the m.14484T > C mutation may perturb the structure and function of complex I. Mutant cybrids constructed by transferring mitochondria from lymphoblastoid cell lines of one Chinese LHON family into mtDNA-less (ρo) cells revealed decreases in the levels of ND6, ND1 and ND4L. The m.14484T > C mutation may affect mitochondrial mRNA homeostasis, supported by reduced levels of SLIRP and SUPV3L1 involved in mRNA degradation and increasing expression of ND6, ND1 and ND4L genes. These alterations yielded decreased activity of complex I, respiratory deficiency, diminished mitochondrial ATP production and reduced membrane potential, and increased production of reactive oxygen species in the mutant cybrids. Furthermore, the m.14484T > C mutation promoted apoptosis, evidenced by elevating Annexin V-positive cells, release of cytochrome c into cytosol, levels in apoptotic proteins BAX, caspases 3, 7, 9 and decreasing levels in anti-apoptotic protein Bcl-xL in the mutant cybrids. Moreover, the cybrids bearing the m.14484T > C mutation exhibited the reduced levels of autophagy protein LC3, increased levels of substrate P62 and impaired PINK1/Parkin-dependent mitophagy. Our findings highlighted the critical role of m.14484T > C mutation in the pathogenesis of LHON.

Reversible Acid-Base Long Persistent Luminescence Switch Based on Amino-Functionalized Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) with long persistent luminescence (LPL) have attracted extensive research attention from researchers due to their potential applications in information encryption, anticounterfeiting technology, and security logic. In contrast to short-lived fluorescent materials, LPL materials offer a visible response that can be easily distinguished by the naked eye, thereby facilitating a much clearer visualization. However, there are few reports on functional LPL MOF materials as probes. In this article, two amino-functional LPL MOFs (VB4-2D and VB4-1D) were synthesized. They both exhibited adjustable fluorescence and phosphorescence from blue to green and from cyan to green, respectively. Notably, the MOFs emitted bright and adjustable LPL upon the removal of the different radiation sources. The basic amino functional groups in the MOFs exhibited acid and ammonia sensitivity, and fluorescence and phosphorescence emission intensities can be burst and restored in two atmospheres, respectively, which can be cycled multiple times. Furthermore, LPL intensity undergoes switching between two different conditions as well, which can be visually discerned by the naked eye, enabling visual sensing of volatiles by LPL. This combination of photoluminescence and the visual LPL switching behavior of acids and bases in functional MOFs may provide an effective avenue for stimulus response, anticounterfeiting, and encryption applications.

Complete Shrinking of Mixed Growth Hormone and Prolactin-Secreting Pituitary Adenoma With Bromocriptine Therapy Alone.

A 40-year-old man presented with acromegaly, reduction of visual acuity and visual field, and elevated blood sugar. Imaging examinations demonstrated a large sellar adenoma with suprasellar extension that compresses the optic chiasma upward, spreads downward to the sphenoid sinus, and invades the cavernous sinus bilaterally. Random prolactin and growth hormone were beyond the scope of normal. The patient achieved complete shrinking of the adenoma by taking bromocriptine orally. For some kinds of giant mixed growth hormone-prolactin adenomas, surgical treatment is not necessary, and drug treatment can also achieve good results.

Mouse Abdominal Aortic Aneurysm Model Induced by Periarterial Incubation of Papain.

For decades, numerous experimental animal models have been developed to examine the pathophysiologic mechanisms and potential treatments for abdominal aortic aneurysms (AAAs) in diverse species with varying chemical or surgical approaches. This study aimed to create an AAA mouse model by the periarterial incubation with papain, which can mimic human AAA with advantages such as simplicity, convenience, and high efficiency. Eighty C57BL/6J male mice were randomly assigned to 1 of the 4 groups: papain (1.0 or 2.0 mg), porcine pancreatic elastase, and phosphate-buffered solution. The aortic segment was wrapped for 20 minutes, and the diameter was measured using ultrasound preoperatively and postoperative days 7 and 14. Then, the mice were killed for histomorphometric and immunohistochemical analyses. According to ultrasound measurements and histomorphometric analyses, on postoperative day 7, 65% of mice in the 1.0-mg papain group and 60% of mice in the 2.0-mg papain group developed AAA. In both papain groups, 100% of mice developed AAA, and 65% of mice in the porcine pancreatic elastase group developed AAA on postoperative day 14. Furthermore, hematoxylin/eosin, elastin van Gieson, and Masson staining of tissues from the papain group revealed thickened media and intimal hyperplasia, collagen sediments, and elastin destruction, indicating that AAA histochemical alteration was similar to that of humans. In addition, the immunohistochemical analysis was conducted to detect infiltrated inflammatory cells, such as macrophages and leukocytes, in the aortic wall and hyperplasic adventitia. The expression of matrix metalloproteinase 2 and 9 was significantly upregulated in papain and human AAA tissues. Periarterial incubation with 1.0 mg of papain for 20 minutes can successfully create an experimental AAA model in mice for 14 days, which can be used to explore the mechanism and treatment of human AAA.

TRPC6 promotes daunorubicin-induced mitochondrial fission and cell death in rat cardiomyocytes with the involvement of ERK1/2-DRP1 activation.

Daunorubicin (DNR-) induced cardiotoxicity seriously restricts its clinical application. Transient receptor potential cation channel subfamily C member 6 (TRPC6) is involved in multiple cardiovascular physiological and pathophysiological processes. However, the role of TRPC6 anthracycline-induced cardiotoxicity (AIC) remains unclear. Mitochondrial fragmentation greatly promotes AIC. TRPC6-mediated ERK1/2 activation has been shown to favor mitochondrial fission in dentate granule cells. The aim of the present study was to elucidate the effects of TRPC6 on daunorubicin- induced cardiotoxicity and identify the mechanisms associated with mitochondrial dynamics. The sparkling results showed that TRPC6 was upregulated in models in vitro and in vivo. TRPC6 knockdown protected cardiomyocytes from DNR-induced cell apoptosis and death. DNR largely facilitated mitochondrial fission, boosted mitochondrial membrane potential collapse and damaged debilitated mitochondrial respiratory function in H9c2 cells，these effects were accompanied by TRPC6 upregulation. siTRPC6 effectively inhibited these mitochondrial adverse aspects showing a positive unexposed effect on mitochondrial morphology and function. Concomitantly, ERK1/2-DRP1 which is related to mitochondrial fission was significantly activated with amplified phosphorylated forms in DNR-treated H9c2 cells. siTRPC6 effectively suppressed ERK1/2-DPR1 over activation, hinting at a potential correlation between TRPC6 and ERK1/2-DRP1 by which mitochondrial dynamics are possibly modulated in AIC. TRPC6 knockdown also raised the Bcl-2/Bax ratio, which may help to block mitochondrial fragmentation-related functional impairment and apoptotic signaling. These findings suggested an essential role of TRPC6 in AIC by intensifying mitochondrial fission and cell death via ERK1/2-DPR1, which could be a potential therapeutic target for AIC.

Optimized allotopic expression of mitochondrial ND6 transgene restored complex I and apoptosis deficiencies caused by LHON-linked ND6 14484T > C mutation.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease due to mutations in mitochondrial DNA. However, there is no effective treatment for this disease. LHON-linked ND6 14484T > C (p.M64V) mutation caused complex I deficiency, diminished ATP production, increased production of reactive oxygen species (ROS), elevated apoptosis, and impaired mitophagy. Here, we investigated if the allotopic expression of human mitochondrial ND6 transgene corrected the mitochondrial dysfunctions due to LHON-associated m.14484T > C mutation. METHODS: Nucleus-versions of ND6 was generated by changing 6 non-universal codons with universal codons and added to mitochondrial targeting sequence of COX8. Stable transfectants were generated by transferring human ND6 cDNA expressed in a pCDH-puro vector into mutant cybrids carrying the m.14484T > C mutation and control cybrids. The effect of allotopic expression of ND6 on oxidative phosphorylation (OXPHOS) was evaluated using Blue Native gel electrophoresis and extracellular flux analyzer. Assessment of ROS production in cell lines was performed by flow cytometry with MitoSOX Red reagent. Analyses for apoptosis and mitophagy were undertaken via flow cytometry, TUNEL and immunofluorescence assays. RESULTS: The transfer of human ND6 into the cybrids carrying the m.14484T > C mutation raised the levels of ND6, ND1 and ND4L but did not change the levels of other mitochondrial proteins. The overexpression of ND6 led to 20~23% increases in the assembly and activity of complex I, and ~ 53% and ~ 33% increases in the levels of mitochondrial ATP and ΔΨm in the mutant cybrids bearing m.14484T > C mutation. Furthermore, mutant cybrids with overexpression of ND6 exhibited marked reductions in the levels of mitochondrial ROS. Strikingly, ND6 overexpression markedly inhibited the apoptosis process and restored impaired mitophagy in the cells carrying m.14484T > C mutation. However, overexpression of ND6 did not affect the ND6 level and mitochondrial functions in the wild-type cybrids, indicating that this ND6 level appeared to be the maximum threshold level to maintain the normal cell function. CONCLUSION: We demonstrated that allotopic expression of nucleus-versions of ND6 restored complex I, apoptosis and mitophagy deficiencies caused by the m.14484T > C mutation. The restoration of m.14484T > C mutation-induced mitochondrial dysfunctions by overexpression of ND6 is a step toward therapeutic interventions for LHON and mitochondrial diseases.

Diversity and Surgical Management of Intracranial Fungal Infections.

Intracranial fungal infection is a rare entity. This disease is mainly concentrated in dry and hot climates, such as India, Africa, California, and usually occurs in patients with immune deficiency. Now, we retrospectively analyzed the clinical manifestations, pathologic manifestations, imaging features, surgical methods, and prognosis of 4 patients with fungal infection who were confirmed by postoperative pathology. Intermittent pricking on the right face was presented in 2 patients, headache in 2 patients, orbital apex syndrome in 2 patients, and 1 patient presented with fever. Imaging showed the lesions of all patients were located in the right temporal, including 2 patients involving the right orbital, 1 patient involving the right trigeminal semilunar ganglion, 1 patient involving the right brainstem and tentorium cerebellum, 1 patient involving the right internal carotid artery. Craniotomy was performed in 2 patients, endoscopic biopsy in 1 patient, and stereotactic surgery in 1 patien. Aspergilloma was the most common pathogenic bacteria. One patient relapsed repeatedly and died. Secondary aneurysm complicated with subarachnoid hemorrhage occurred in 1 patient. Therefore, the author confirmed that intracranial fungal infection has diverse clinical, imaging, and pathologic manifestations. Neurosurgeons should be aware of the possibility of intracranial fungal infection when they find abnormal intracranial lesions, neurologic deficits, and inflammation of paranasal sinuses. Combining multiple clinical data may help doctors to improve the accuracy of diagnosis. Individualized and diversified surgical protocols should be selected for diverse lesions. Notably, secondary intracranial fungal vasculitis is common, with high mortality and disability rates.

Pharmacological Modulations of Nrf2 and Therapeutic Implications in Aneurysmal Subarachnoid Hemorrhage.

An aneurysmal subarachnoid hemorrhage (aSAH) is a subtype of stroke with high morbidity and mortality. The main causes of a poor prognosis include early brain injury (EBI) and delayed vasospasm, both of which play a significant role in the pathophysiological process. As an important mechanism of EBI and delayed vasospasm, oxidative stress plays an important role in the pathogenesis of aSAH by producing reactive oxygen species (ROS) through the mitochondria, hemoglobin, or enzymatic pathways in the early stages of aSAH. As a result, antioxidant therapy, which primarily targets the Nrf2-related pathway, can be employed as a potential strategy for treating aSAH. In the early stages of aSAH development, increasing the expression of antioxidant enzymes and detoxifying enzymes can relieve oxidative stress, reduce brain damage, and improve prognosis. Herein, the regulatory mechanisms of Nrf2 and related pharmacological compounds are reviewed, and Nrf2-targeted drugs are proposed as potential treatments for aSAH.

One/Two-Photon-Excited ESIPT-Attributed Coordination Polymers with Wide Temperature Range and Color-Tunable Long Persistent Luminescence.

The multiple metastable excited states provided by excited-state intramolecular proton transfer (ESIPT) molecules are beneficial to bring temperature-dependent and color-tunable long persistent luminescence (LPL). Meanwhile, ESIPT molecules are intrinsically suitable to be modulated as D-π-A structure to obtain both one/two-photon excitation and LPL emission simultaneously. Herein, we report the rational design of a dynamic CdII coordination polymer (LIFM-106) from ESIPT ligand to achieve the above goals. By comparing LIFM-106 with the counterparts, we established a temperature-regulated competitive relationship between singlet excimer and triplet LPL emission. The optimization of ligand aggregation mode effectively boost the competitiveness of the latter. In result, LIFM-106 shows outstanding one/two-photon excited LPL performance with wide temperature range (100-380 K) and tunable color (green to red). The multichannel radiation process was further elucidated by transient absorption and theoretical calculations, benefiting for the application in anti-counterfeiting systems.

Thermally Activated Fluorescence vs Long Persistent Luminescence in ESIPT-Attributed Coordination Polymer.

Excited-state intramolecular proton transfer (ESIPT) molecules demonstrating specific enol-keto tautomerism and the related photoluminescence (PL) switch have wide applications in displaying, sensing, imaging, lasing, etc. However, an ESIPT-attributed coordination polymer showing alternative PL between thermally activated fluorescence (TAF) and long persistent luminescence (LPL) has never been explored. Herein, we report the assembly of a dynamic Cd(II) coordination polymer (LIFM-101) from the ESIPT-type ligand, HPI2C (5-(2-(2-hydroxyphenyl)-4,5-diphenyl-1H-imidazol-1-yl)isophthalic acid). For the first time, TAF and/or color-tuned LPL can be achieved by controlling the temperature under the guidance of ESIPT excited states. Noteworthily, the twisted structure of the HPI2C ligand in LIFM-101 achieves an effective mixture of the higher-energy excited states, leading to ISC (intersystem crossing)/RISC (reverse intersystem crossing) energy transfer between the high-lying keto-triplet state (Tn(K*)) and the first singlet state (S1(K*)). Meanwhile, experimental and theoretical results manifest the occurrence probability and relevance among RISC, ISC, and internal conversion (IC) in this unique ESIPT-attributed coordination polymer, leading to the unprecedented TAF/LPL switching mechanism, and paving the way for the future design and application of advanced optical materials.

High magnesium mitigates the vasoconstriction mediated by different types of calcium influx from monocrotaline-induced pulmonary hypertensive rats.

NEW FINDINGS: What is the central question of this study? What is the involvement of Mg2+ in mitigating the vasoconstriction in pulmonary arteries and smaller pulmonary arteries in the monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model? What are the main finding and its importance? Both store-operated Ca2+ entry- and receptor-operated Ca2+ entry-mediated vasoconstriction were enhanced in the MCT-PAH model. High magnesium inhibited vasoconstriction by directly antagonizing Ca2+ and increasing NO release, and this was more notable in smaller pulmonary arteries. ABSTRACT: Increased extracellular magnesium concentration has been shown to attenuate the endothelin-1-induced contractile response via the release of nitric oxide (NO) from the endothelium in proximal pulmonary arteries (PAs) of chronic hypoxic mice. Here, we further examined the involvement of Mg2+ in the inhibition of vasoconstriction in PAs and distal smaller pulmonary arteries (sPAs) in a monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) rat model. The data showed that in control rats vasoconstriction in sPAs is more intense than that in PAs. In MCT-PAH rats, store-operated Ca2+ entry (SOCE)- and receptor-operated Ca2+ entry (ROCE)-mediated contraction were significantly strengthened. However, there was no upregulation of the vasoconstriction mediated by voltage-dependent calcium entry (VDCE). Furthermore, high magnesium greatly inhibited VDCE-mediated contraction in PAs rather than sPAs, which was the opposite of the ROCE-mediated contraction. Moreover, monocrotaline pretreatment partly eliminated the endothelium-dependent vasodilatation in PAs, which in sPAs, however, was still promoted by magnesium due to the increased NO release in pulmonary microvascular endothelial cells (PMVECs). In conclusion, the findings suggest that both SOCE- and ROCE-mediated vasoconstriction in the MCT-PAH model are enhanced, especially in sPAs. The inhibitory effect of high magnesium on vasoconstriction can be achieved partly by its direct role as a Ca2+ antagonist and partly by increasing NO release in PMVECs.

Early versus the traditional start of oral intake following esophagectomy for esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Nil by mouth is considered the standard of care during the first days following esophagectomy. However, with the routine implementation of enhanced recovery after surgery, early oral intake is more likely to be the preferred mode of nutrition following esophagectomy. The present study aims to evaluate the safety and effectiveness of early oral intake following esophagectomy for esophageal cancer. METHODS: Comprehensive literature searches were conducted using PubMed, Web of Science, Embase, and Cochrane Library. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (CI) were calculated as the effect sizes for continuous and dichotomous variables, respectively. RESULTS: Fourteen studies with a total of 1947 patients were included. Length of hospital stay (WMD = - 3.94, CI: - 4.98 to - 2.90; P < 0.001), the time to first flatus (WMD = - 1.13, CI: - 1.25 to - 1.01; P < 0.001) and defecation (WMD = - 1.26, CI: - 1.82 to - 0.71; P < 0.001) favored the early oral intake group. There was no statistically significant difference in mortality (OR = 1.23, CI: 0.45 to 3.36; P = 0.69). Early oral intake also did not increase the risk of pneumonia and overall postoperative complications. CONCLUSIONS: Current evidence indicates early oral intake following esophagectomy seems to be safe and effective. It may be the preferred mode of nutrition following esophagectomy. However, more high-quality studies are still needed to further validate this conclusion.

Effects of an art-based intervention in older adults with mild cognitive impairment: a randomised controlled trial.

BACKGROUND: Art-based interventions may delay cognitive decline and improve health-related outcomes in older adults with mild cognitive impairment (MCI). OBJECTIVE: To examine the effects of the Creative Expressive Arts-based Storytelling (CrEAS) program compared to active and waitlist controls on neurocognitive and other health-related outcomes in older people with MCI. DESIGN: Three-arm parallel-group, randomised controlled design. PARTICIPANTS: One-hundred and thirty-five adults with MCI (mean age: 70.93 ± 6.91 years). METHODS: Participants were randomly assigned to intervention (CrEAS, n = 45), active control (n = 45) or waitlist control (n = 45) groups. Interventions were applied once per week for 24 weeks. The primary outcome was global cognitive function; secondary outcomes were specific cognition domains (memory, executive function, language and attention) and other health-related outcomes (anxiety, depression and quality of life [QoL]). All variables were measured at baseline (T0), 24-week follow-up (T1) and 48-week follow-up (T2). RESULTS: Participants in the CrEAS group showed significantly higher global cognitive function (adjusted mean difference [MD] = -0.905, 95% confidence interval [CI] -1.748 to -0.062; P = 0.038) and QoL (adjusted MD = -4.150, 95% CI -6.447 to -1.853; P = 0.001) and lower depression symptoms (adjusted MD = 2.902, 95% CI 0.699-5.104; P = 0.011) post-intervention at the 24-week follow-up compared with the active control group. At 48-week follow-up, only the Auditory Verbal Learning Test Immediate recall score was significantly improved compared with the active control group (adjusted MD = -2.941, 95% CI -5.262 to -0.620; P = 0.014). CONCLUSIONS: Older adults with MCI who participated in the CrEAS program improved their neuropsychological outcomes and QoL and reduced their rate of cognitive deterioration.

Diagnostic value of Lipoarabinomannan antigen for detecting Mycobacterium tuberculosis in adults and children with or without HIV infection.

OBJECTIVES: Even today, tuberculosis (TB) remains a leading public health problem; yet, the current diagnostic methods still have a few shortcomings. Lipoarabinomannan (LAM) provides an opportunity for TB diagnosis, and urine LAM detection seems to have a promising and widely applicable prospect. DESIGN OR METHODS: Four databases were systematically searched for eligible studies, and the quality of the studies was evaluated using the quality assessment of diagnostic accuracy studies-2 (QUADAS-2). Graphs and tables were created to show sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), the area under the curve (AUC), and so on. RESULTS: Based on the included 67 studies, the pooled sensitivity of urine LAM was 48% and specificity was 89%. In the subgroup analyses, the FujiLAM test had higher sensitivity (69%) and specificity (92%). Furthermore, among patients infected with human immunodeficiency virus (HIV), 50% of TB patients were diagnosed using a urine LAM test. Besides, the CD4+ cell count was inversely proportional to the sensitivity. CONCLUSIONS: Urine LAM is a promising diagnostic test for TB, particularly using the FujiLAM in HIV-infected adults whose CD4+ cell count is ≤100 per µl. Besides, the urine LAM test shows various sensitivities and specificities in different subgroups in terms of age, HIV infection status, CD4+ cell count, and testing method.

Esophagectomy versus definitive chemoradiotherapy as initial treatment for clinical stage I esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Esophagectomy and definitive chemoradiotherapy are commonly used in the treatment of stage I esophageal cancer (EC). The present study aims to compare the efficacy and safety of esophagectomy and definitive chemoradiotherapy as the initial treatment for clinical stage I EC. METHODS: This study was registered with the International Prospective Register of Systematic Reviews (CRD42020197203). Relevant studies were identified through PubMed, Web of Science, EMBASE, and Cochrane Library from database inception to June 30, 2020. Hazard ratio (HR) with 95% confidence intervals (CI) was employed to compare overall survival (OS) and progression-free survival (PFS). Odds ratio (OR) with 95% CI was employed to compare treatment-related death, complications, and tumor recurrence. RESULTS: A total of 13 non-randomized controlled studies involving 3,346 patients were included. Compared with definitive chemoradiotherapy, esophagectomy showed an improved OS (HR 0.69, 95% CI 0.55-0.86; P < 0.001), PFS (HR 0.47, 95% CI 0.33-0.67; P < 0.001), and a lower risk of tumor recurrence (OR 0.43, 95% CI 0.30-0.61; P < 0.001). There was no significant difference in the incidence of complications (OR 1.11, 95% CI 0.75-1.65; P = 0.60) and treatment-related death (OR 1.15, 95% CI 0.31-4.30; P = 0.84) between the two treatments. CONCLUSIONS: Current evidence shows esophagectomy has superior survival benefits as the initial treatment for clinical stage I EC. It is still the preferred choice for patients with clinical stage I EC. However, future high-quality randomized controlled trials are needed to validate this conclusion.

Targeting translation regulators improves cancer therapy.

Deregulation of protein synthesis may be involved in multiple aspects of cancer, such as gene expression, signal transduction and drive specific cell biological responses, resulting in promoting cancer growth, invasion and metastasis. Study the molecular mechanisms about translational control may help us to find more effective anti-cancer drugs and develop novel therapeutic opportunities. Recently, the researchers had focused on targeting translational machinery to overcome cancer, and various small molecular inhibitors targeting translation factors or pathways have been tested in clinical trials and exhibited improving outcomes in several cancer types. There is no doubt that an insight into the class of translation regulation protein would provide new target for pharmacologic intervention and further provide opportunities to develop novel anti-tumor therapeutic interventions. In this review, we summarized the developments of translational control in cancer survival and progression et al, and highlighted the therapeutic approach targeted translation regulation to overcome the cancer.

[Clinical evaluation of true and false positive Z values among high-risk cases screened by non-invasive prenatal testing].

OBJECTIVE: To analyze the Z values of true and false positive cases by non-invasive prenatal testing (NIPT) in order to improve its accuracy in clinical practice. METHODS: Results of 24 384 NIPT tests were reviewed. For cases with high risks for trisomies 21, 18 and 13, the range of Z values in true and false positive cases was analyzed and discussed. RESULTS: A total of 335 high-risk cases were identified by NIPT, among which 256 had elected prenatal diagnosis, 153 (59.77%) were verified as true positives, and 103 (40.23%) were false positives, and the area under the curve (AUC) was 0.9994. For NIPT screening, the positive predictive value (PPV) for trisomy 21 was 100% when Z>13, regardless if the pregnant woman was over 35. When 335 and about 41.6% (5/12) for those<35. For trisomy 18, the PPV was 100% when Z>13, and only 14.3% (1/7) when 3

Overexpression of mitochondrial histidyl-tRNA synthetase restores mitochondrial dysfunction caused by a deafness-associated tRNAHis mutation.

The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tRNAHis structure and function, supported by decreased melting temperature, conformational changes, and instability of mutated tRNA. We show that the m.12201T>C mutation-induced alteration of aminoacylation tRNAHis causes mitochondrial translational defects and respiratory deficiency. We found that the transfer of HARS2 into the cybrids carrying the m.12201T>C mutation raises the levels of aminoacylated tRNAHis from 56.3 to 75.0% but does not change the aminoacylation of other tRNAs. Strikingly, HARS2 overexpression increased the steady-state levels of tRNAHis and of noncognate tRNAs, including tRNAAla, tRNAGln, tRNAGlu, tRNALeu(UUR), tRNALys, and tRNAMet, in cells bearing the m.12201T>C mutation. This improved tRNA metabolism elevated the efficiency of mitochondrial translation, activities of oxidative phosphorylation complexes, and respiration capacity. Furthermore, HARS2 overexpression markedly increased mitochondrial ATP levels and membrane potential and reduced production of reactive oxygen species in cells carrying the m.12201T>C mutation. These results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation. These findings provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.