Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of longevity by depolarization-induced activation of PLC-β–IP3R signaling in neurons

Significance We demonstrate that depolarization of Drosophila glutamatergic neurons augmented inositol trisphosphate receptor (IP3R)-dependent release of endoplasmic reticulum (ER) Ca2+, which in turn potentiated mitochondrial Ca2+ uptake and ATP production. Perturbations that induced chronic depolarization, including the expression of neurodegeneration-related transgenes, led to the diversion of released ER Ca2+ into lysosomes and an attendant shortening of animal lifespan. Thus, genetic disruption of PLC-β–IP3R signaling or lysosomal Ca2+ uptake restored longevity in animals with chronically depolarized glutamatergic neurons. Our findings point to aberrant Ca2+ signaling between the ER and lysosomes as a mechanism by which hyperexcitable glutamatergic neurons shorten animal lifespan. Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.
Contribution of the peroneus longus neuromuscular compartments to eversion and plantarflexion of the ankle

Compartmentalization of animal and human skeletal muscle by multiple motor nerve branches known as the neuromuscular compartment (NMC) has been observed primarily in muscles that participate in a plane of motion. In this context, the peroneus longus muscle contributes to eversion and plantarflexion of the ankle and the presence of NMCs has been reported. However, no research has reported the selective activation of the compartments of the peroneus longus during the performance of different ankle movements. The purpose of this research was to determine the contribution of peroneus longus NMCs, through multi-channel surface electromyography (sEMG), to eversion and plantarflexion movements. Multi-channel sEMG was recorded from the peroneus longus muscle by using an electrode grid during eversion and plantarflexion of the ankle at 10%, 30%, 50%, and 70% of maximal voluntary isometric contraction (MVIC). The root mean square and displacement of the center of mass position in the X (COMx) and Y (COMy) components were calculated. The primary finding was that eversion showed significantly higher sEMG amplitude than plantarflexion in the posterior compartment in low, moderate, and high percentages of MVIC. However, no significant difference in sEMG amplitude was observed in the anterior compartment between eversion and plantarflexion. In addition, a posterior displacement of the COMx in eversion compared to plantarflexion in all MVIC percentages, with greater topographic distancing of the COMx at higher levels of activation. In conclusion, the peroneus longus muscle presented NMCs; the anterior compartment contributed to both eversion and plantarflexion movements, whereas the posterior compartment mainly contributed to the eversion movement of the ankle in low, moderate, and high percentages of MVIC.
Structural and thermodynamic analysis of factors governing the stability and thermal folding/unfolding of SazCA

Molecular basis of protein stability at different temperatures is a fundamental problem in protein science that is substantially far from being accurately and quantitatively solved as it requires an explicit knowledge of the temperature dependence of folding free energy of amino acid residues. In the present study, we attempted to gain insights into the thermodynamic stability of SazCA and its implications on protein folding/unfolding. We report molecular dynamics simulations of water solvated SazCA in a temperature range of 293-393 K to study the relationship between the thermostability and flexibility. Our structural analysis shows that the protein maintains the highest structural stability at 353 K and the protein conformations are highly flexible at temperatures above 353 K. Larger exposure of hydrophobic surface residues to the solvent medium for conformations beyond 353 K were identified from H-bond analysis. Higher number of secondary structure contents exhibited by SazCA at 353 K corroborated the conformations at 353 K to exhibit the highest thermal stability. The analysis of thermodynamics of protein stability revealed that the conformations that denature at higher melting temperatures tend to have greater maximum thermal stability. Our analysis shows that 353 K conformations have the highest melting temperature, which was found to be close to the experimental optimum temperature. The enhanced protein stability at 353 K due the least value of heat capacity at unfolding suggested an increase in folding. Comparative Gibbs free energy analysis and funnel shaped energy landscape confirmed a transition in folding/unfolding pathway of SazCA at 353 K.
达沙替尼联合多药化疗方案治疗成人初诊Ph+急性淋巴细胞白血病：一项单中心前瞻性研究

目的 评价达沙替尼联合多药化疗方案在Ph染色体阳性急性淋巴细胞白血病（Ph+ ALL）患者中的疗效及安全性。 方法 前瞻性、单臂、开放的临床研究。 2016年1月至2018年4月中国医学科学院血液病医院收治的30例初诊成人Ph+ ALL患者入组。 采用多药化疗方案，标准诱导化疗为期4周，自诱导化疗第8天开始口服达沙替尼（商品名依尼舒，正大天晴药业集团股份有限公司产品）100 mg/d，持续应用至整体治疗结束。 有条件和意愿进行移植者，可进行异基因造血干细胞移植或自体造血干细胞移植。 结果 所有30例患者在诱导治疗4周后均达到血液学完全缓解（HCR），累积完全分子学反应（MCR）率为70. 0％（21/30）。 中位随访时间为37. 8（32.0～46.6）个月。 3年总生存（OS）率为68. 1％，3年无血液学复发生存（HRFS）率为61. 6％。 63.3％的患者在治疗3个月时达到主要分子学反应（MMR）（其中有43. 3％患者达到MCR）。 6个月时60. 0％的患者达到MCR，达到MCR的患者具有更好的OS（P＝0.004）、HRFS（P＝0.049）和EFS（P＝0.001）。 15例（50.0％）患者在第1次HCR期内进行移植，移植组患者HRFS（P＝0.030）和EFS（P＝0.010）优于化疗组。 结论 达沙替尼联合多药化疗方案治疗初诊Ph+ALL安全有效。 临床试验注册 ClinicalTrials.gov，NCT02523976。
Scaffold-Free Engineering of Human Cartilage Implants

Objective Despite new strategies in tissue engineering, cartilage repair remains a major challenge. Our aim is to treat patients with focal lesions of articular cartilage with autologous hyaline cartilage implants using a scaffold-free approach. In this article, we describe experiments to optimize production of scaffold-free cartilage discs. Design Articular chondrocytes were expanded in vitro, seeded in transwell inserts and redifferentiated using established chondrogenic components. Experimental variables included testing 2 different expansion media, adding bone morphogenetic protein 2 (BMP2), insulin-like growth factor 1 (IGF1), growth/differentiation factor 5 (GDF5), or fibroblast growth factor 18 (FGF18) to the differentiation medium and allowing the disc to float freely in large wells. Cartilage discs were analyzed by weight and thickness, real-time RT-qPCR (reverse transcriptase qualitative polymerase chain reaction), fluorescence immunostaining, transmission electron microscopy, second harmonic generation imaging, and measurement of Young’s modulus. Results Addition of BMP2 to the chondrogenic differentiation medium (CDM) was essential for stable disc formation, while IGF1, GDF5, and FGF18 were redundant. Allowing discs to float freely in CDM on a moving platform increased disc thickness compared with discs kept continuously in transwell inserts. Discs cultured for 6 weeks reached a thickness of almost 2 mm and Young’s modulus of >200 kPa. There was abundant type II collagen. Collagen fibrils were 25 nm thick, with a tendency to be organized perpendicular to the disc surface. Conclusion Scaffold-free engineering using BMP2 and providing free movement in CDM produced firm, elastic cartilage discs with abundant type II collagen. This approach may potentially be used in clinical trials.
Nitric oxide production inhibitory activity of clerodane diterpenes from Monoon membranifolium

Abstract A new clerodane diterpene, 2β-methoxyhardwickiic acid (1), and four known compounds (2–5) were isolated from the twigs of Monoon membranifolium. The structure of the new compound was determined by extensive spectroscopic methods and ESITOFMS data. The absolute configuration of 1 was established by a comparison of its ECD spectrum and specific rotation with those of related previously reported compounds. All compounds were evaluated for their nitric oxide (NO) production inhibitory activities in RAW264.7 macrophage cells. Compounds 3 and 5 inhibited NO production with IC50 values of 16.1 and 28.9 μM, respectively, which were better than that of standard compound, indomethacin (IC50 = 32.2 μM). Graphical Abstract
Carbon monoxide activates large-conductance calcium-activated potassium channels of human cardiac fibroblasts through various mechanisms

Carbon monoxide (CO) is a cardioprotectant and potential cardiovascular therapeutic agent. Human cardiac fibroblasts (HCFs) are important determinants of myocardial structure and function. Large-conductance Ca2+-activated K+ (BK) channel is a potential therapeutic target for cardiovascular disease. We investigated whether CO modulates BK channels and the signaling pathways in HCFs using whole-cell mode patch-clamp recordings. CO-releasing molecules (CORMs; CORM-2 and CORM-3) significantly increased the amplitudes of BK currents (IBK). The CO-induced stimulating effects on IBK were blocked by pre-treatment with specific nitric oxide synthase (NOS) blockers (L-NG-monomethyl arginine citrate and L-NG-nitroarginine methyl ester). 8-bromo-cyclic GMP increased IBK. KT5823 (inhibits PKG) or ODQ (inhibits soluble guanylate cyclase) blocked the CO-stimulating effect on IBK. Moreover, 8-bromo-cyclic AMP also increased IBK, and pre-treatment with KT5720 (inhibits PKA) or SQ22536 (inhibits adenylate cyclase) blocked the CO effect. Pre-treatment with N-ethylmaleimide (a thiol-alkylating reagent) also blocked the CO effect on IBK, and DL-dithiothreitol (a reducing agent) reversed the CO effect. These data suggest that CO activates IBK through NO via the NOS and through the PKG, PKA, and S-nitrosylation pathways.
Command Voices and Aggression in a Lebanese Sample Patients with Schizophrenia.

BACKGROUND The impact of command voices (CV) on violent behaviors in patients with schizophrenia remains unclear. The literature has produced mixed results, with no research existing on CV and violence among the Lebanese population. The study objecttives were to (1) evaluate the association between voice beliefs, psychosis severity, treatment, demographic factors and command voices, and (2) evaluate the association between command voices and violence among patients with schizophrenia in Lebanon. METHODS A cross-sectional study, conducted between April and August 2019, enrolled 280 patients with schizophrenia. RESULTS The results showed that 111 (39.6%) patients with schizophrenia had auditory hallucinations, among whom 93 (83.8%) patients had command voices; from these 93 patients, 53 (57.0%) were compliant with voices. Higher positive (ORa=1.09) and general psychopathology (ORa=1.04) PANSS subscales scores were significantly associated with higher compliance to voices. A higher resistance to beliefs about voices (ORa=0.91) was significantly associated with lower compliance to voices. CONCLUSIONS The prevalence of CV in patients with schizophrenia that report auditory hallucinations, was high in our sample. The vast majority of violent acts committed by patients was in compliance to CV, with a significantly high rate of the violence committed being directed towards property. Our findings were able to connect positive symptoms to higher probability of compliance to CV.
Time-dependent association between selective serotonin reuptake inhibitors and hospitalization due to hyponatremia

Background: Selective serotonin reuptake inhibitors (SSRIs) have a wide and increasing use for the treatment of depression and anxiety. Previous studies have indicated an increased risk of hyponatremia during the first months of treatment. We aimed to investigate the detailed time-course of SSRI-associated hyponatremia with a high temporal resolution, using registry data encompassing the total Swedish population. Methods: This was a population-based case control study using several national registers. Patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) were compared with matched controls (n = 44,801). Multivariable regression was applied to explore time-dependent associations between SSRIs and hospitalization due to hyponatremia. Results: Individuals initiating treatment with SSRIs were exposed to an immediately increased risk for hospitalization at week 1, reaching an adjusted odds ratio (aOR) (95% confidence interval) of 29 (19–46). The associations then gradually declined, reaching an aOR of 2.1 (1.0–4.2) by week 13. The aOR for individuals treated for longer than 13 weeks was 0.78 (0.71–0.85). Conclusions: This study revealed a dramatically increased risk of hyponatremia exclusively related to newly initiated treatment. Consequently, even subtle symptoms consistent with hyponatremia during the first weeks of SSRI treatment should prompt analysis of sodium levels. In patients treated with SSRIs for several months or years, other causes should primarily be sought in the event of hyponatremia.
Adolescents’ dietary polyphenol intake in relation to serum total antioxidant capacity: the HELENA study

Abstract We evaluated the association between intake of total polyphenols, polyphenol classes and the 10 most consumed individual polyphenols with serum total antioxidant capacity (TAC) in 749 European adolescents (53% girls; 15% overweight; 12.5–17.5 years-old) from the cross-sectional HELENA study of 2006–2007. Dietary polyphenol intake was calculated from two non-consecutive 24-h recalls matched with the Phenol-Explorer database. Multilevel linear models examined the associations between dietary polyphenols and TAC. Polyphenol intake was rather low (median = 321mg/day; p25 = 158; p75 = 536) and TAC was comparable to other literature findings (median = 1.57 mmol/L; p25 = 1.45; p75 = 1.74). Total polyphenol intake, polyphenol classes and the top 10 compounds were not associated with TAC in a linear, quadratic or cubic way in partially or fully confounder-adjusted models. A direct anti-oxidative effect of dietary polyphenol intake was not observed in European adolescents. Polyphenol biomarkers and additional antioxidant measures are needed in future prospective studies to confirm these results.
In vitro and in vivo synergistic effects of tigecycline combined with aminoglycosides on carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES Carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections represent severe threats to public health worldwide. The aim of this study was to assess potential synergistic interaction between tigecycline and aminoglycosides via in vitro and in vivo studies. METHODS Antibiotic resistance profiles and molecular characteristics of 168 CR-KP clinical isolates were investigated by susceptibility testing, PCR and MLST. Chequerboard tests and time-kill assays were performed for 20 CR-KP isolates to evaluate in vitro synergistic effects of tigecycline combined with aminoglycosides. A tissue-cage infection model of rats was established to evaluate in vivo synergistic effects. Different doses of tigecycline and aminoglycosides alone or in combination were administered for 7 days via tail vein injection. Antibiotic efficacy was evaluated in tissue-cage fluid and emergence of resistance was screened. RESULTS The chequerboard tests showed that this combination displayed synergistic or partial synergistic activity against CR-KP. The time-kill assays further demonstrated that strong synergistic effects of such a combination existed against isolates that were susceptible to both drugs but for resistant isolates no synergy was observed if clinical pharmacokinetics were taken into consideration. The in vivo study showed that the therapeutic effectiveness of combination therapies was better than that of monotherapy for susceptible isolates, suggesting in vivo synergistic effects. Furthermore, combinations of tigecycline with an aminoglycoside showed significant activity in reducing the occurrence of tigecycline-resistant mutants. CONCLUSIONS Compared with single drugs, tigecycline combined with aminoglycosides could exert synergistic effects and reduce the emergence of tigecycline resistance. Such a combination might be an effective alternative when treating CR-KP infections in clinical practice.
Advancements of nature nanocage protein: preparation, identification and multiple applications of ferritins

Abstract Ferritin is an important iron storage protein, which is widely existed in all forms of life. Ferritin can regulate iron homeostasis when iron ions are lacking or enriched in the body, so as to avoid iron deficiency diseases and iron poisoning. Ferritin presents a hollow nanocage, which can store ions or other small molecular substances in the cavity. Therefore, ferritin shows its potential as a functional nanomaterial that can deliver nutrients or drugs in a targeted manner to improve bioavailability. Due to the special structure, the research on ferritin has attracted more and more attention in recent years. In this paper, the structural characteristics of ferritin were introduced, and the natural purification and prokaryotic expression methods of ferritin from different sources were described. At the same time, ferritin can bind to small molecules, so that it has the activity of small molecules, to construct a new type of ferritin. As a result, ferritin plays an important role as a nutrient substance, in targeted transport, and disease monitoring, etc. In conclusion, the yield of ferritin can be improved by means of molecular biology. Meanwhile, molecular modification can be used to make ferritin have unique activity and function, which lays a foundation for subsequent research. Highlights The molecular and structural properties of ferritins were clearly described. Isolation and purification technologies of ferritin were compared. Characterization, functions and molecular modifications mechanism of ferritin were reviewed. The applications of ferritin in pharmaceutical and food industry were prospected.
In‐circuit high‐frequency jet ventilation to reduce organ motion in a child undergoing sarcoma ablation

Patients with primary or metastatic solid tumours can be treated with minimally invasive image‐guided procedures as an alternative to surgical resection. Reducing organ motion during these procedures is crucial so that tumours can be accurately targeted and treatment delivered within a small margin, limiting potential damage to adjacent structures. As ventilation is the main cause of motion, there has been a shift from conventional ventilation towards the use of in‐circuit high‐frequency jet ventilation techniques for these procedures. We present the case of a 7‐year‐old who required computed tomography‐guided microwave ablation of a right lung metastatic nodule under general anaesthesia. The patient's lungs were ventilated with in‐circuit high‐frequency jet ventilation in order to provide optimum conditions for ablation. The treatment was successfully completed and she was discharged home the following day. High‐frequency jet ventilation is regularly used in our institution for adult computed tomography‐guided treatments and to our knowledge, this application has not been described yet in a child this young. Our experience suggests that this technique can be safely used in paediatric patients, though further investigation of the optimum parameters for in‐circuit high‐frequency jet ventilation in this population is warranted.
Superficial Siderosis: A Clinical Review

Superficial siderosis of the central nervous system results from subpial hemosiderin deposition due to chronic low‐grade bleeding into the subarachnoid space. The confluent and marginal subpial hemosiderin is best appreciated on iron‐sensitive magnetic resonance imaging sequences. With widespread use of magnetic resonance imaging, the disorder is increasingly being recognized, including in asymptomatic individuals. Gait ataxia, often with hearing impairment is a common clinical presentation. A clinical history of subarachnoid hemorrhage is generally not present. A macrovascular pathology is generally not causative. The most common etiology is dural disease, often dural tears. Prior or less commonly ongoing symptoms of craniospinal hypovolemia may be present. Common etiologies for dural tears include disc disease and trauma, including surgical trauma. Patients with dural tears due to herniated and calcified discs often have a ventral intraspinal fluid collection due to cerebrospinal fluid leak. A precise identification of the dural tear relies on multimodality imaging. It has been speculated that chronic bleeding from fragile blood vessels around the dural tear may be the likely underlying mechanism. Surgical correction of the bleeding source is a logical therapeutic strategy. Clinical outcomes are variable, although neuroimaging evidence of successful dural tear repair is noted. The currently available data regarding use of deferiprone in patients with superficial siderosis is insufficient to recommend its routine use in patients. ANN NEUROL 2021;89:1068–1079