Protein folding as a jamming transition.

Proteins fold to a specific functional conformation with a densely packed hydrophobic core that controls their stability. We develop a geometric, yet all-atom model for proteins that explains the universal core packing fraction of ϕc=0.55 found in experimental measurements. We show that as the hydrophobic interactions increase relative to the temperature, a novel jamming transition occurs when the core packing fraction exceeds ϕc. The model also recapitulates the global structure of proteins since it can accurately refold to native-like structures from partially unfolded states.

Identifying the minimal sets of distance restraints for FRET-assisted protein structural modeling.

Proteins naturally occur in crowded cellular environments and interact with other proteins, nucleic acids, and organelles. Since most previous experimental protein structure determination techniques require that proteins occur in idealized, non-physiological environments, the effects of realistic cellular environments on protein structure are largely unexplored. Recently, Förster resonance energy transfer (FRET) has been shown to be an effective experimental method for investigating protein structure in vivo. Inter-residue distances measured in vivo can be incorporated as restraints in molecular dynamics (MD) simulations to model protein structural dynamics in vivo. Since most FRET studies only obtain inter-residue separations for a small number of amino acid pairs, it is important to determine the minimum number of restraints in the MD simulations that are required to achieve a given root-mean-square deviation (RMSD) from the experimental structural ensemble. Further, what is the optimal method for selecting these inter-residue restraints? Here, we implement several methods for selecting the most important FRET pairs and determine the number of pairs Nr that are needed to induce conformational changes in proteins between two experimentally determined structures. We find that enforcing only a small fraction of restraints, Nr/N≲0.08, where N is the number of amino acids, can induce the conformational changes. These results establish the efficacy of FRET-assisted MD simulations for atomic scale structural modeling of proteins in vivo. Significance: Determining protein structure in vivo is essential for understanding protein function. Most protein structures have been studied in non-physiological conditions using x-ray crystallography, NMR spectroscopy, and cryo-electron microscopy. Thus, we do not know whether the cellular environment significantly affects protein structure. We emphasize the benefits of FRET-assisted molecular dynamics simulations in characterizing protein structure in vivo at the atomic scale. We identify the minimum number of FRET pairs that can induce conformational changes in several proteins, including one that has been characterized using in-cell NMR.

The transcriptional control of LcIDL1-LcHSL2 complex by LcARF5 integrates auxin and ethylene signaling for litchi fruitlet abscission.

At the physiological level, the interplay between auxin and ethylene has long been recognized as crucial for the regulation of organ abscission in plants. However, the underlying molecular mechanisms remain unknown. Here, we identified transcription factors involved in indoleacetic acid (IAA) and ethylene (ET) signaling that directly regulate the expression of INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) and its receptor HAESA (HAE), which are key components initiating abscission. Specifically, litchi IDA-like 1 (LcIDL1) interacts with the receptor HAESA-like 2 (LcHSL2). Through in vitro and in vivo experiments, we determined that the auxin response factor LcARF5 directly binds and activates both LcIDL1 and LcHSL2. Furthermore, we found that the ETHYLENE INSENSITIVE 3-like transcription factor LcEIL3 directly binds and activates LcIDL1. The expression of IDA and HSL2 homologs was enhanced in LcARF5 and LcEIL3 transgenic Arabidopsis plants, but reduced in ein3 eil1 mutants. Consistently, the expressions of LcIDL1 and LcHSL2 were significantly decreased in LcARF5- and LcEIL3-silenced fruitlet abscission zones (FAZ), which correlated with a lower rate of fruitlet abscission. Depletion of auxin led to an increase in 1-aminocyclopropane-1-carboxylic acid (the precursor of ethylene) levels in the litchi FAZ, followed by abscission activation. Throughout this process, LcARF5 and LcEIL3 were induced in the FAZ. Collectively, our findings suggest that the molecular interactions between litchi AUXIN RESPONSE FACTOR 5 (LcARF5)-LcIDL1/LcHSL2 and LcEIL3-LcIDL1 signaling modules play a role in regulating fruitlet abscission in litchi and provide a long-sought mechanistic explanation for how the interplay between auxin and ethylene is translated into the molecular events that initiate abscission.

O-sialoglycoprotein Endopeptidase (OSGEP) Suppresses Hepatic Ischemia-Reperfusion Injury-Induced Ferroptosis Through Modulating the MEK/ERK Signaling Pathway.

Hepatic ischemia-reperfusion injury (HIRI) was widely accepted as a critical complication of liver resection and transplantation. A growing body of evidence suggested that O-sialoglycoprotein endopeptidase (OSGEP) was involved in cell proliferation and mitochondrial metabolism. However, whether OSGEP could mediate the pathogenesis of HIRI has still remained unclarified. This study investigated whether OSGEP could be protective against HIRI and elucidated the potential mechanisms. The OSGEP expression level was detected in cases undergoing ischemia-related hepatectomy and a stable oxygen-glucose deprivation/reoxygenation (OGD/R) condition in hepG2 cells. Additionally, it was attempted to establish a mouse model of HIRI, thus, the function and mechanism of OSGEP could be analyzed. At one day after hepatectomy, the negative association of OSGEP expression level with the elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted. Moreover, it was attempted to carry out gain- and loss-of-function analyses of OSGEP in hepG2 cells to reveal its influences on OGD/R-induced injury and relevant signaling pathways. The findings suggested that OSGEP overexpression significantly protected hepG2 cells against ferroptotic cell death, while OSGEP consumption had opposite effects. Consistent with in vitro studies, OSGEP deficiency exacerbated liver functions and ferroptotic cell death in a mouse model of HIRI. The results also revealed that OSGEP mediated the progression of HIRI by regulating the MEK/ERK signaling pathway. Rescue experiments indicated that ERK1/2 knockdown or overexpression reversed the effects of OSGEP overexpression or knockdown on hepG2 cells under OGD/R condition. Taken together, the findings demonstrated that OSGEP could contribute to alleviate HIRI by mediating the MEK-ERK signaling pathway, which may serve as a potential prognostic marker and a therapeutic target for HIRI.

The L-shaped association of mid-upper arm circumference with all-cause and cause-specific mortality in US adults: a population-based prospective cohort study.

BACKGROUND: The arm circumference is a feasible and reliable indicator in evaluating the nutritional status of children. However, its application in general adults has yet to be thoroughly investigated. OBJECTIVE: This study aimed to evaluate the association between mid-upper arm circumferences (MUACs) and mortality in general adults. METHODS: The nationally representative cohort from the National Health and Nutrition Examination Survey (1999-2018) was analyzed with mortality information obtained through linkage to the National Death Index. The baseline MUACs were collected as exposure. Survey-weighted Cox proportional hazard regressions were performed to estimate the hazard ratios (HRs) and 95% confidential intervals (CIs) of mortality risk for individuals with different MUACs. Restricted cubic spline analyses were performed to examine the nonlinear association of MUAC with all-cause and cause-specific mortality. RESULTS: A total of 52,159 participants were included in this study. During a median follow-up time of 117 months, 7157 deaths were documented, with leading causes of cardiovascular disease (CVD), cancer, and respiratory disease. Individuals in the first quartile (Q1) of MUAC tended to have higher all-cause mortality risk than the rest after full adjustment. Similarly, CVD mortality risk in Q1 was higher than that in the second quartile (Q2) and the third quartile (Q3); respiratory mortality risk in Q1 was higher than in Q2. MUAC was non-linearly associated with all-cause mortality and CVD mortality. Individuals in Q1 MUAC (≤ 29.3) tended to have higher all-cause mortality risk, with HRs (95% CIs) estimated to be 0.76 (0.67-0.87) for Q2 (29.4, 32.5), 0.69 (0.59-0.81) for Q3 (32.6, 36.0), and 0.59 (0.46-0.75) for Q4 (≥ 36.1) after adjustment of demographic, lifestyle, and comorbidity covariates. Similarly, compared with Q1, HRs (95% CIs) for CVD mortality were estimated to be 0.73 (0.58-0.93) for Q2 and 0.57 (0.43-0.47) for Q3; HRs (95% CIs) for respiratory mortality was estimated to be 0.57 (95% CI, 0.37-0.87) for Q2 with other differences not significant. CONCLUSION: The MUAC was inversely associated with long-term mortality in general adults in the United States and may serve as a valuable measurement in adult health evaluations.

LncRNA-MEG3 attenuates hyperglycemia-induced damage by enhancing mitochondrial translocation of HSP90A in the primary hippocampal neurons.

The diabetic cognitive impairments are associated with high-glucose (HG)-induced mitochondrial dysfunctions in the brain. Our previous studies demonstrated that long non-coding RNA (lncRNA)-MEG3 alleviates diabetic cognitive impairments. However, the underlying mechanism has still remained elusive. Therefore, this study was designed to investigate whether the mitochondrial translocation of HSP90A and its phosphorylation are involved in lncRNA-MEG3-mediated neuroprotective effects of mitochondrial functions in HG-treated primary hippocampal neurons and diabetic rats. The primary hippocampal neurons were exposed to 75 mM glucose for 72 h to establish a HG model in vitro. Firstly, the RNA pull-down and RNA immunoprecipitation (RIP) assays clearly indicated that lncRNA-MEG3-associated mitochondrial proteins were Annexin A2, HSP90A, and Plectin. Although HG promoted the mitochondrial translocation of HSP90A and Annexin A2, lncRNA-MEG3 over-expression only enhanced the mitochondrial translocation of HSP90A, rather than Annexin A2, in the primary hippocampal neurons treated with or without HG. Meanwhile, Plectin mediated the mitochondrial localization of lncRNA-MEG3 and HSP90A. Furthermore, HSP90A threonine phosphorylation participated in regulating mitochondrial translocation of HSP90A, and lncRNA-MEG3 also enhanced mitochondrial translocation of HSP90A through suppressing HSP90A threonine phosphorylation. Finally, the anti-apoptotic role of mitochondrial translocation of HSP90A was found to be associated with inhibiting death receptor 5 (DR5) in HG-treated primary hippocampal neurons and diabetic rats. Taken together, lncRNA-MEG3 could improve mitochondrial functions in HG-exposed primary hippocampal neurons, and the underlying mechanisms were involved in enhanced mitochondrial translocation of HSP90A via suppressing HSP90A threonine phosphorylation, which may reveal a potential therapeutic target for diabetic cognitive impairments.

Chrysophanol postconditioning attenuated cerebral ischemia-reperfusion injury induced NLRP3-related pyroptosis in a TRAF6-dependent manner.

Individuals who suffer from post-CA (cardiac arrest) brain injury experience higher mortality and more severe functional disability. Neuroinflammation has been identified as a vital factor in cerebral ischemia-reperfusion injury (CIRI) following CA. Pyroptosis induces neuronal death by triggering an excessive inflammatory injury. Chrysophanol possesses robust anti-inflammatory features, and it is protective against CIRI. The purpose of this research was to assess the effect of Chrysophanol postconditioning on CIRI-induced pyroptotic cell death, and to explore its underlying mechanisms. CIRI was induced in rats by CA and subsequent cardiopulmonary resuscitation, and PC12 cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to imitate CIRI in vitro. It was found that post-CA brain injury led to a notable cerebral damage revealed by histopathological changes and neurological outcomes. The existence of pyroptosis was also confirmed in in vivo and in vitro CIRI models. Moreover, we further confirmed that Chrysophanol, the main bioactive ingredient of Rhubarb, significantly suppressed expressions of pyroptosis-associated proteins, e.g., NLRP3, ASC, cleaved-caspase-1 and N-terminal GSDMD, and inhibited the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6). Furthermore, NLRP3 overexpression neutralized the neuroprotection of Chrysophanol postconditioning, suggesting that pyroptosis was the major neuronal death pathway modulated by Chrysophanol postconditioning in OGD/R. Additionally, the neuroprotection of Chrysophanol postconditioning was also abolished by gain-of-function analyses of TRAF6. Finally, the results demonstrated that Chrysophanol postconditioning suppressed the interaction between TRAF6 and NLRP3. Taken together, our findings revealed that Chrysophanol postconditioning was protective against CIRI by inhibiting NLRP3-related pyroptosis in a TRAF6-dependent manner.

Core packing of well-defined X-ray and NMR structures is the same.

Numerous studies have investigated the differences and similarities between protein structures determined by solution NMR spectroscopy and those determined by X-ray crystallography. A fundamental question is whether any observed differences are due to differing methodologies or to differences in the behavior of proteins in solution versus in the crystalline state. Here, we compare the properties of the hydrophobic cores of high-resolution protein crystal structures and those in NMR structures, determined using increasing numbers and types of restraints. Prior studies have reported that many NMR structures have denser cores compared with those of high-resolution X-ray crystal structures. Our current work investigates this result in more detail and finds that these NMR structures tend to violate basic features of protein stereochemistry, such as small non-bonded atomic overlaps and few Ramachandran and sidechain dihedral angle outliers. We find that NMR structures solved with more restraints, and which do not significantly violate stereochemistry, have hydrophobic cores that have a similar size and packing fraction as their counterparts determined by X-ray crystallography at high resolution. These results lead us to conclude that, at least regarding the core packing properties, high-quality structures determined by NMR and X-ray crystallography are the same, and the differences reported earlier are most likely a consequence of methodology, rather than fundamental differences between the protein in the two different environments.

Burden of brain and other central nervous system cancer in China, 1990-2019: a systematic analysis of observational data from the global burden of disease study 2019.

OBJECTIVE: To evaluate the trends in disease burden and the epidemiological features of central nervous system (CNS) cancer in China from 1990 to 2019. DESIGN: A population-based observational study. SETTING: The incidence, prevalence, death and disability-adjusted life years (DALYs) due to CNS cancer in China, stratified by sex, age and provincial region, were collected from the Global Burden of Disease Study 2019. PARTICIPANTS: Data were publicly available and individuals were not involved. RESULTS: In 2019, the incident cases of CNS cancer in China were 347 992 (95% UI 262 084-388 896), and the age-standardised rate (ASR) of incidence was 5.69 (95% UI 4.36-6.78) per 100 000 person-years increased by 27.9% compared with that in 1990; meanwhile, CNS cancer caused 63 527 (95% UI 47 793-76 948) deaths in China in 2019, and the ASR of death was 3.5 (95% UI 2.62-4.21) per 100 000 person-years decreased by 9.6%. The ASRs of incidence and prevalence of CNS cancer in China increased more rapidly than the global average; meanwhile, the ASRs of DALYs owing to CNS cancer declined more rapidly. The burden of CNS cancer showed no significant differences between men and women, but was more pronounced in early childhood and old adulthood. The ASRs of incidence and prevalence were higher in high-income provinces, confirmed by the positive correlation with Sociodemographic Index (SDI), with correlation coefficient r of 0.322 and 0.767, respectively (both p<0.0001). However, the ASRs of death and DALYs demonstrated a negative correlation with SDI, with r of -|0.319 and -0.642, respectively (both p<0.0001). CONCLUSIONS: From a global perspective, China has been bearing a substantial burden of CNS cancer. More attention should be paid to children and elderly populations for CNS cancer. The disease burden varied significantly at the subnational level of China, which was associated with socioeconomic development.

Prognostic Factors and Treatment Strategies for Elderly Patients with Malignant Meningioma: A SEER Population-Based Study.

Objective: Malignant meningioma (MM) is a relatively rare disease with poor survival. Few studies had focused on MM in the elderly population. This study aims to explore the prognostic factors and optimal therapeutic strategy in elderly patients with MM. Methods: We took advantage of the Surveillance, Epidemiology, and End Results (SEER) database to include 275 adult patients with histologically confirmed MM between 2011 and 2018. The Kaplan-Meier curves were plotted by different covariates to reveal the survival probability. Univariate and multivariable Cox proportional hazard regression analyses were applied to identify prognostic factors for cancer-specific survival (CSS). Results: The multivariable analysis in the elderly group revealed that when compared with patients receiving gross total resection (GTR), patients receiving biopsy had significantly worse CSS (HR = 3.72; 95% CI: 1.35-10.21; P = 0.011), whereas patients receiving subtotal resection (STR) had nearly the same CSS (HR = 0.83; 95% CI: 0.37-1.86; P = 0.653). Meanwhile, postoperative radiotherapy (PORT) showed no significant association with CSS in the elderly patient group (HR = 0.94; 95% CI: 0.42-2.12; P = 0.888). Conclusion: Surgical resection is recommended for elderly patients with MM in the absence of surgical contraindications, but GTR does not present survival benefit in the elderly patients compared with STR. Additional large-scale clinical studies are needed to explore the survival benefit of PORT applied in patients with MM.

Genome-Wide Identification and Expression Analysis of Chitinase-like Genes in Petunia axillaris.

Chitinase (EC 3.2.1.14) is a kind of chitin-degrading glycosidase, which plays important roles in the abiotic and biotic defense of plants. In this study, we conducted whole-genome annotation, molecular evolution, and gene expression analyses on the chitinase-like (CTL) gene family members of Petunia axillaris. Thirty-three Petunia axillarischitinase-like genes (PaCTLs) were identified from the latest Petunia genome database. According to the phylogenetic analyses, these genes were divided into GH18 and GH19 subgroups and further subdivided into five classes (Class I to Class V). Conserved motif arrangements indicated their functional relevance within each group. The expansion and homeology analyses showed that gene replication events played an important role in the evolution of PaCTLs and the increase of the GH18 subgroup members was the main reason for the expansion of the PaCTL gene family in the evolution progress. By qRT-PCR analysis, we found that most of the PaCTLs showed a very low expression level in the normal growing plants. But lots of PaCTLs showed upregulated expression profiles when the plants suffered different abiotic stress conditions. Among them, five PaCTLs responded to high temperature and exhibited significantly upregulate expression level. Correspondingly, many hormone responses, as well as biotic and abiotic stress elements were found in the promoters of PaCTLs by using cis-acting element analysis. These results provide a foundation for the exploration of PaCTLs' function and enrich the evolutionary process of the CTL gene family.

L-shaped association of serum calcium with all-cause and CVD mortality in the US adults: A population-based prospective cohort study.

Background: Calcium is involved in many biological processes, but the impact of serum calcium levels on long-term mortality in general populations has been rarely investigated. Methods: This prospective cohort study analyzed data from the National Health and Nutrition Examination Survey (1999-2018). All-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality were obtained through linkage to the National Death Index. Survey-weighted multivariate Cox regression was performed to compute hazard ratios (HRs) and 95% confidential intervals (CIs) for the associations of calcium levels with risks of mortality. Restricted cubic spline analyses were performed to examine the non-linear association of calcium levels with all-cause and disease-specific mortality. Results: A total of 51,042 individuals were included in the current study. During an average of 9.7 years of follow-up, 7,592 all-cause deaths were identified, including 2,391 CVD deaths and 1,641 cancer deaths. Compared with participants in the first quartile (Q1) of serum calcium level [≤2.299 mmol/L], the risk of all-cause mortality was lower for participants in the second quartile (Q2) [2.300-2.349 mmol/L], the third quartile (Q3) [2.350-2.424 mmol/L] and the fourth quartile (Q4) [≥2.425 mmol/L] with multivariable-adjusted HRs of 0.81 (95% CI, 0.74-0.88), 0.78 (95% CI, 0.71-0.86), and 0.80 (95% CI, 0.73, 0.88). Similar associations were observed for CVD mortality, with HRs of 0.82 (95% CI, 0.71-0.95), 0.87 (95% CI, 0.74-1.02), and 0.83 (95% CI, 0.72, 0.97) in Q2-Q4 quartile. Furthermore, the L-shaped non-linear associations were detected for serum calcium with the risk of all-cause mortality. Below the median of 2.350 mmol/L, per 0.1 mmol/L higher serum calcium was associated with a 24% lower risk of all-cause mortality (HR: 0.76, 95% CI, 0.70-0.83), however, no significant changes were observed when serum calcium was above the median. Similar L-shaped associations were detected for serum calcium with the risk of CVD mortality with a 25% reduction in the risk of CVD death per 0.1 mmol/L higher serum calcium below the median (HR: 0.75, 95% CI, 0.65-0.86). Conclusion: L-shaped associations of serum calcium with all-cause and CVD mortality were observed in US adults, and hypocalcemia was associated with a higher risk of all-cause mortality and CVD mortality.

The Survival Benefits of Surgical Resection and Adjuvant Therapy for Patients With Brainstem Glioma.

PURPOSE: The role of surgical resection in the treatment of brainstem glioma (BSG) is poorly understood. For pediatric low-grade (LGBSG) group, several monocentric small-scale retrospective studies reported contradictory conclusions. And there was no clinical study focused on surgical resection for adult or pediatric high-grade (HG) patient groups. This study aims to illustrate whether surgical resection and adjuvant therapy provide survival benefits for patients with histologically confirmed BSG. PATIENTS AND METHODS: This retrospective cohort study included 529 patients with histologically confirmed BSG in Surveillance Epidemiology and End Results (SEER) database from 2006-2015. Patients were divided into four groups by age and World Health Organization (WHO) grade. Kaplan-Meier curves of CSS were plotted by different treatment options to compare the survival probability. Univariate and multivariable analyses were then conducted to determine the prognosis effects of surgical resection and adjuvant therapy on cancer specific survival (CSS). All analyses were done in four different groups separately. RESULTS: The final sample included 529 patients. The entire study population was divided into groups of pediatric LG (n=236, 44.6%), pediatric HG (n=37, 7.0%), adult LG (n=204, 38.6%) and adult HG (n=52, 9.8%). 52.7% (n=144) of pediatric patients had pilocytic astrocytoma and 45.3% (n=116) of adult patients had ependymoma. Pediatric LGBSG group had the highest gross total resection (GTR) rate (61.4%) and 5-year CSS rate (88.6%). Kaplan-Meier curves of pediatric LGBSG group revealed that patients treated with GTR had significantly better survival probability (P=0.033). Multivariable analysis identified GTR as independently significant predictor for prolonged CSS in pediatric LGBSG group (HR0.29, 95%CI 0.11-0.78, P=0.015); Surgical resection showed no relation to CSS in other patient groups. Kaplan-Meier curves of adult HGBSG group showed that patients treated with both RT and CT in adult HGBSG group had the best survival probability (P=0.02). However, multivariable analysis showed the combination of radiotherapy (RT) and chemotherapy (CT) was not significantly related to better CSS in adult HGBSG group (HR0.35, 95%CI 0.11-1.09, P=0.070). Adjuvant therapy didn't associate with better CSS in other patient groups. CONCLUSION: Pediatric LGBSG group had the highest GTR rate and the most favorable clinical outcome. GTR can provide significant survival benefits for pediatric LGBSG group.

Competing risk model to determine the prognostic factors and treatment strategies for elderly patients with glioblastoma.

The prognostic factors and optimal treatment for the elderly patient with glioblastoma (GBM) were poorly understood. This study extracted 4975 elderly patients (≥ 65 years old) with histologically confirmed GBM from Surveillance, Epidemiology and End Results (SEER) database. Firstly, Cumulative incidence function and cox proportional model were utilized to illustrate the interference of non-GBM related mortality in our cohort. Then, the Fine-Gray competing risk model was applied to determine the prognostic factors for GBM related mortality. Age ≥ 75 years old, white race, size > 5.4 cm, frontal lobe tumor, and overlapping lesion were independently associated with more GBM related death, while Gross total resection (GTR) (HR 0.87, 95%CI 0.80-0.94, P = 0.010), radiotherapy (HR 0.64, 95%CI 0.55-0.74, P < 0.001), chemotherapy (HR 0.72, 95%CI 0.59-0.90, P = 0.003), and chemoRT (HR 0.43, 95%CI 0.38-0.48, P < 0.001) were identified as independently protective factors of GBM related death. Based on this, a corresponding nomogram was conducted to predict 3-, 6- and 12-month GBM related mortality, the C-index of which were 0.763, 0.718, and 0.694 respectively. The calibration curve showed that there was a good consistency between the predicted and the actual mortality probability. Concerning treatment options, GTR followed by chemoRT is suggested as optimal treatment. Radiotherapy and chemotherapy alone also provide moderate clinical benefits.

Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis.

OBJECTIVE: To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS). METHODS: We searched PubMed, EMBASE and Cochrane Library for eligible studies. Annualized relapse rate, discontinuation due to adverse events (AEs) were assessed as primary outcomes. Sensitivity analysis and inconsistency detection were performed to evaluated whether exclusion of high-risk studies affected the validity. Risk of bias was assessed using Cochrane's Risk-of-Bias Tool 2. Surface under the cumulative ranking curve (SUCRA) was used to estimate the rankings among different DMTs. RESULTS: 21 studies were included for main report. Seven studies were evaluated as "high risk" and were therefore excluded. Exclusion of high-risk studies did not affect the validity of evidence. The risk of relapses for most DMTs except Betaseron 50 µg was significantly lower comparing to placebo. Incompliance in patients treated with DMTs was not significantly increased comparing to placebo. Dimethyl fumarate and ocrelizumab had superiority in improving MRI outcomes. Ocrelizumab and ofatumumab had the largest reduction of risk in disability progression at 3 months. Referring to SUCRA, ofatumumab, alemtuzumab and natalizumab showed the best efficacy and compliance. CONCLUSION: The present study demonstrated the hierarchy of DMTs treating RRMS. Ofatumumab, alemtuzumab and natalizumab have superiority with respect to effectiveness and compliance. More studies are required to explore the long-term effect of DMTs. Our findings could provide helpful information and contribute to clinical treatment decision-making.

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

Sugar and Hormone Dynamics and the Expression Profiles of SUT/SUC and SWEET Sweet Sugar Transporters during Flower Development in Petunia axillaris.

Flowering is the first committed step of plant sexual reproduction. While the developing flower is a strong sink requiring large quantity of sugars from photosynthetic source tissues, this process is under-temper-spatially controlled via hormone signaling pathway and nutrient availability. Sugar transporters SUT/SUC and SWEET mediate sugars movement across membranes and play a significant role in various physiological processes, including reproductive organ development. In Petunia axillaris, a model ornamental plant, 5 SUT/SUC and 36 SWEET genes are identified in the current version of the genome. Analysis of their gene structure and chromosomal locations reveal that SWEET family is moderately expanded. Most of the transporter genes are abundantly expressed in the flower than in other organs. During the five flower developmental stages, transcript levels of PaSUT1, PaSUT3, PaSWEET13c, PaSWEET9a, PaSWEET1d, PaSWEET5a and PaSWEET14a increase with the maturation of the flower and reach their maximum in the fully open flowers. PaSWEET9c, the nectar-specific PhNEC1 orthologous, is expressed in matured and fully opened flowers. Moreover, determination of sugar concentrations and phytohormone dynamics in flowers at the five developmental stages shows that glucose is the predominant form of sugar in young flowers at the early stage but depletes at the later stage, whereas sucrose accumulates only in maturated flowers prior to the corolla opening. On the other hand, GA3 content and to a less extent IAA and zeatin decreases with the flower development; however, JA, SA and ABA display a remarkable peak at mid- or later flower developmental stage.

The Epidemiological Characteristics and Prognostic Factors of Low-Grade Brainstem Glioma: A Real-World Study of Pediatric and Adult Patients.

Purpose: Our current understanding of low-grade brainstem glioma (LGBSG) is still limited. This study aimed to conduct a large-scale population-based real-world study to understand the epidemiological characteristics of LGBSG and determine the predictive factors of cancer-specific survival (CSS) and overall survival (OS) of LGBSG patients. Patients and Methods: We used Surveillance Epidemiology and End Results database to conduct this study of patients with histologically confirmed LGBSG. Patient demographics, tumor characteristics, and treatment options were compared between pediatric and adult patients. Univariate and multivariate analyses were employed to determine prognostic factors of CSS and OS. Kaplan-Meier curve and decision tree were used to confirm the prognostic factors. All variables were further identified by L1-penalized (Lasso) regression and then a nomogram was established to predict the 5- and 8-year CSS and OS rate. The precision of the nomogram was evaluated by calibration plots, Harrell's concordance index, and time-dependent receiver operating characteristic curve. The clinical use of nomogram was estimated by decision curve analysis. Results: A cohort of 305 patients with LGBSG, including 165 pediatric and 140 adult patients, was analyzed. Adult and pediatric patients showed different patterns concerning tumor size, tumor extension, adjuvant therapy, and survival rate. Univariate analysis revealed that pediatric group, gross total resection (GTR), World Health Organization grade II, radiotherapy, extension to ventricular system, and diffuse astrocytic and oligodendroglial tumor (DAOT) were significantly associated with CSS. Multivariate analysis showed that pediatric group, metastasis, ventricular system involvement, and DAOT were independently associated with CSS. The prognostic factors were further confirmed by Kaplan-Meier curve and decision tree. Kaplan-Meier curve also showed that adjuvant therapy added no benefits in patients with GTR and non-GTR. In addition, the nomogram was developed and the C-index of internal validation for CSS was 0.87 (95% CI, 0.78-0.96). Conclusion: This study shows that pediatric and adult patients have different tumor characteristics, treatment options, and survival rate. Pediatric group, DAOT, ventricular system involvement, and metastasis were identified as independent prognostic factors for CSS by multivariate analysis. Adjuvant therapy showed no benefits on CSS in patients with GTR and non-GTR. The nomogram was discriminative and clinically useful.