Miracle-dz/UniFAR-FTUs huggingface dataset:
Leishmania donovani Exploits Macrophage Heme Oxygenase-1 To Neutralize Oxidative Burst and TLR Signaling–Dependent Host Defense

Suppression of host oxidative burst is essential for survival of the intracellular parasite Leishmania donovani. Screening of macrophage antioxidant enzymes during infection revealed marked upregulation of the heme-degrading enzyme, heme oxygenase-1 (HO-1). Moreover, HO-1–silenced RAW macrophages depicted increased superoxide production and decreased parasite survival. HO-1 induction decreased cellular heme content, thereby inhibiting the heme-dependent maturation of gp91phox, a catalytic component of major reactive oxygen species–producing enzyme NAD(P)H oxidase. Decreased gp91phox expression resulted in reduced stability of p22phox, another component of the catalytic center of NAD(P)H oxidase. Replenishing infected cells with exogenous heme reversed these effects and restored NAD(P)H oxidase activity. Persistent HO-1 expression at late hour of infection prompted us to investigate its effect on other host defense parameters, and inhibition study revealed a reciprocal relationship of HO-1 with host proinflammatory responses. Among all the HO-1–mediated heme degradation products (CO, Fe, and biliverdin), only CO documented potent anti-inflammatory effects. Quenching of CO during infection increased the production of disease-resolving cytokines IL-12 and TNF-α. Coimmunoprecipitation experiments revealed that CO inhibited the interaction of TLR4 with MyD88 and TIR domain–containing adapter-inducing IFN-β, thereby dampening the activation of NF-κB and IFN regulatory factor 3–mediated production of proinflammatory cytokines. Administration of HO-1 inhibitor tin protoporphyrin IX dichloride in infected BALB/c mice led to a decrease in liver and spleen parasite burden along with increased production of IL-12 and TNF-α. These results suggest that HO-1 on one hand inhibits reactive oxygen species generation and on the other hand downregulates host favorable cytokine responses, thereby facilitating intramacrophage parasite survival.
Determination of absorption dose in chemical mutagenesis in plants

Chemical mutagenesis is a useful tool for inducing mutations in plants. Seeds are often used as the material for chemical mutagenesis. The biological effect of a chemical mutagen on seeds is determined by absorption dose (the product of mutagen concentration and acting time, which starts after the mutagen is absorbed by the seeds). In practice, however, the concept of exposure dose (the product of mutagen concentration and treating time) is usually used instead because the time for absorbing mutagen is unknown. In this study, we conducted an experiment using ethyl methane sulphonate (EMS) to treat cauliflower seeds, in which five EMS concentrations (0%, 0.5%, 1.0%, 1.5% and 2.0%), three treating time lengths (4 h, 6 h and 8 h) and two pretreatments (non-presoaking and presoaking of seeds for 2 h) were set. We obtained a well-fitted nonlinear regression model for the relationship between seedling survival rate and the EMS treatment, and its marginal models for the two pretreatments. Based on the models, we determined the EMS absorption doses under the two different pretreatments and identified their 50% lethality dose (LD50). We found that presoaking could delay EMS absorption and therefore reduce the injury caused by EMS within a given treating time, but could hardly change the biological effect of EMS after it is absorbed. The conclusions about absorption dose and presoaking effect obtained in this study might be generally applicable to plant chemical mutagenesis in principle.
An Internet-Based Controlled Trial of Interpretation Bias Modification Versus Progressive Muscle Relaxation for Body Dysmorphic Disorder

Objective: The current study extended upon previous research efforts by evaluating the utility and feasibility of an 8-session Internet-based interpretation bias modification (IBM) training protocol targeting evaluation- and appearance-related threat biases characteristic of the disorder compared to a progressive muscle relaxation (PMR) condition for treatment of body dysmorphic disorder (BDD). Method: Fifty participants with BDD were recruited from across the United States and randomly assigned to eight sessions of either IBM or PMR. Assessments of interpretation bias, BDD symptoms, depression, and anxiety were administered at pretreatment, 1-week posttreatment, and 3-month follow-up. Results: Compared to the PMR group, individuals in the IBM condition reported less negative/threat interpretation biases and greater positive/benign interpretation biases at posttreatment and follow-up. There were no significant differences between groups with regard to BDD symptoms, depression, or anxiety. Clinically significant improvement was common in both conditions (IBM = 64.0%; PMR = 52.0%), though it did not differ between them. Conclusions: Contrary to our hypothesis, IBM did not outperform PMR with regard to BDD symptom reduction, though both treatments yielded significant improvements on symptom outcomes. Findings suggest that IBM and/or PMR may be promising treatment strategies for BDD, perhaps adjunctively. Overall, these findings provide helpful future directions for IBM research and provide an additional lens through which to examine its potential effectiveness for BDD.
Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome

Objective To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. Methods Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. Results All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. Conclusions GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.
Effect of Dome-Shaped Titanium Mesh Cages on Cervical Endplate Under Cyclic Loading: An In Vitro Biomechanics Study

Background This study aimed to verify the anti-subsidence ability of dome-shaped titanium mesh cage (TMC) used in anterior cervical corpectomy and fusion (ACCF). Material/Methods Thirty fresh human cervical vertebrae specimens were collected and randomly harvested into 2 groups: the traditional TMC group and the dome-shaped TMC group. The bone mineral density (BMD) of the specimens was recorded. Each group was biomechanically tested in axial compression with a cyclically loading range from 60 to 300 N at 0.5Hz for 10 000 cycles. The displacement data of the 2 groups were recorded every 10 cycles. Results There was no significant difference in bone mineral density between the 2 groups of cervical specimens. The traditional TMC group stabilized at 535±35 cycles while the dome-shaped TMC group stabilized at 1203±57 cycles, which showed that the rate of subsidence of the dome-shaped TMC group was significantly slower than that of the traditional TMC group (p<0.05). After reaching stability, both groups had a more gradual and sustained growth. The peak displacement during fatigue testing was −2.064±0.150mm in the traditional TMC group and −0.934±0.086mm in the dome-shaped TMC group, which showed a significant difference (p<0.05). Conclusions The dome-shaped TMC showed a smaller subsidence displacement and a gentler subsidence tendency following the same cyclic loading (compared to the traditional TMC). From a biomechanical point of view, the dome-shaped TMC has stronger anti-subsidence ability due to its unique structural design that closely matches the vertebral endplate.
Preoperative Risk Stratification in Spine Tumor Surgery - A Comparison of the Modified Charlson Index, Frailty Index, and ASA Score.

STUDY DESIGN Retrospective review of prospectively collected data. OBJECTIVE The purpose of this study is to compare and validate several preoperative scores for predicting outcomes following spine tumor resection. SUMMARY OF BACKGROUND DATA Preoperative risk assessment for patients undergoing spinal tumor resection remains challenging. At present, few risk assessment tools have been validated in this high-risk population. METHODS The 2008-2014 National Surgical Quality Improvement database was used to identify all patients undergoing surgical resection of spinal tumors, stratified as extradural, intradural extramedullary, and intramedullary based on CPT codes. ASA score, modified Charlson Comorbidity Index (CCI), and modified Frailty Index (mFI) were computed. A binary logistic regression model was used to explore the relationship between these variables and postoperative outcomes including mortality, major and minor adverse events, and hospital length of stay (LOS). Other significant variables such as demographics, operative time, and tumor location were controlled for in each model. RESULTS 2,170 patients met the inclusion criteria. Higher CCI scores were independent predictors of mortality (OR = 1.24, 95%CI: 1.14-1.36, P < 0.001), major adverse events (OR = 1.07, 95%CI: 1.01-1.31, P = 0.018), minor adverse events (OR = 1.15, 95%CI: 1.10-1.20, P < 0.001), and prolonged LOS (OR = 1.14, 95%CI: 1.09-1.19, P < 0.001). Patients' mFI scores were significantly associated with mortality and LOS, but not major or minor adverse events. ASA scores were not associated with any outcome metric when controlling for other variables. CONCLUSIONS The CCI demonstrated superior predictive capacity compared to mFI and ASA scores and may be valuable as a preoperative risk assessment tool for patients undergoing surgical resection of spinal tumors. The validation of assessment scores is important for preoperative risk stratification and improving outcomes in this high-risk group. LEVEL OF EVIDENCE 3.
Borderline personality disorder or a disorder within the schizophrenia spectrum? A psychopathological study

109 analyzed through dependent t-tests with bootstrapping to test for effects of potential outliers and reliability of results. These revealed significant temporal differences in basic symptoms (mean delta=3.45, t(28)=2.38, p=0.024) and positive symptoms sum scores (mean delta=2.00, t(28)=2.48, p=0.021). In contrast, differences in WSS scores remained non-significant: physical anhedonia (mean delta=1.55, t(28)=1.79, p=0.106), social anhedonia (mean delta=1.35, t(28)=1.68, p=0.107), magical ideation (mean delta=0.28, t(28)=0.40, p=0.691), and perceptual aberration (mean delta=0.62, t(28)=0.92, p=0.360). Furthermore, examining Pearson’s correlations between the scales difference scores, we found a significant strong correlation only between magical ideation and perceptual aberration (r=0.506, p=0.005), and trend-level moderate correlations between physical anhedonia and both magical ideation (r=0.337, p=0.091) and perceptual aberration (r=0.319, p=0.073), as well as between the two CHR symptoms difference scores (r=0.328, p=0.083). Difference scores of WSS and CHR symptoms never correlated (r=0.012 to 0.306; p=0.969 to 0.106). In linear regression analyses, WSS difference scores were not predictive of CHR symptom difference scores, which, in turn, did not predict WSS difference scores. Our results strengthen the distinction between CHR symptoms and schizotypy in terms of independent state and trait factors and, thus, the notion that CHR symptoms occur on top of a heightened schizotypy, as suggested by the model by Debbané et al. Furthermore, their independence support notions that the prediction of psychosis might be improved by their combination. To this aim, physical anhedonia and social anhedonia, that constitute the negative schizotypy dimension, might be especially promising candidates. Negative schizotypy might be able to detect those people most likely to progress to a severe mental disorder among those at an already increased risk to experience psychotic or psychoticlike symptoms – detected by CHR criteria. This might explain why both anhedonia scales showed greater, though still nonsignificant, variation over time. Future studies on larger samples with longer follow-up and more assessment times are needed to explore the reliability of our findings, the potential specific relationships between trait and state factors, the potential patterns related to conversion to psychosis, and, ultimately, the role of these likely important risk factors of psychoses in their aetiology. Chantal Michel, Rahel Flückiger, Jochen Kindler, Daniela Hubl, Michael Kaess, Frauke Schultze-Lutter University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland; Translational Research Center, University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland; Department of Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany; Department of Psychiatry and Psychotherapy, Heinrich-Heine-University, Düsseldorf, Germany
Pregnancy and oncologic outcomes after fertility-sparing management for early stage endometrioid endometrial cancer

Objective Hormonal management is an alternative treatment for preserving fertility in patients with presumed early stage endometrioid endometrial cancer. This study aimed to define the pregnancy and oncologic outcomes and factors of successful conception after hormone therapy for endometrioid endometrial cancer. Methods We retrospectively analyzed patients presumed to have stage IA, grade 1–2 endometrioid endometrial cancer who underwent fertility-sparing treatment. Concurrent medroxyprogesterone and levonorgestrel-release intra-uterine devices were used for treatment. The pregnancy outcomes and oncologic outcomes were compared between the pregnant and non-pregnant groups. Results Seventy-one patients presumed to have stage IA, grade 1–2 endometrioid endometrial cancer had complete remission, and 49 of them tried to conceive. Twenty-two (44.9%) patients became pregnant; the total number of pregnancies was 30. These pregnancies resulted in seven abortions (23.3%), one pre-term birth (3.3%), and 20 full-term births (66.6%). The total live birth rate was 66.6 % (20/30). The median duration of hormonal treatment was 11.9 months (range 4–49) and 12.0 months (range 3–35) in the pregnant and non-pregnant groups, respectively. On multivariate analysis, age, body mass index, treatment duration, medroxyprogesterone dose, and number of dilatation and curettage biopsies were not significantly associated with pregnancy failure, but the association with grade (OR 6.2, 95% CI 1.0 to 38.9; P<0.05) was statistically significant. The median disease-free survival duration was 26 months (range 20–38) and 12 months (range 4–48) in the pregnant and non-pregnant groups, respectively (P<0.05, log-rank test). Conclusions A lower grade might be a positive factor for future pregnancy. Moreover, successful pregnancy might be a factor in preventing recurrence.
Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model

There is a pressing need for drug development for gonorrhea. Here we describe a pharmacokinetic (PK)/pharmacodynamic (PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. ABSTRACT There is a pressing need for drug development for gonorrhea. Here we describe a pharmacokinetic (PK)/pharmacodynamic (PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. The PK determined in uninfected mice displayed a clear dose-response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESC-susceptible (ESCs) strain FA1090 were 5 mg/kg of body weight (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (the time that the free drug concentration remains above the MIC [fTMIC]) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against ESC-resistant (ESCr) strain H041. However, fractionation (three times a day every 8 h [TIDq8h]) of a 120-mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to the findings for gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤50% of mice, with the therapeutic times estimated from single-dose PK data being 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships observed in mice reflected those observed in humans, with in vivo efficacy against an ESCs strain requiring doses that yielded an fTMIC in excess of 20 to 24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCr strain and were useful in designing effective dosing regimens.
An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence

ABSTRACT Introduction: Pulmonary hypertension is a severe condition that can develop during childhood due to several different etiologies. During the last two decades, based on a better understanding of the underlying pathobiology leading to pulmonary arterial hypertension, targeted therapies have been developed and have improved the dreadful prognosis of the condition. However, curative therapy remains elusive. Areas covered: In this article, we will review the currently available drugs in pediatric pulmonary arterial hypertension and discuss the recommended management strategies. Expert commentary: Most of the drugtrials in pulmonary hypertension have been performed in adults, with extrapolation of the results to children. Most of the pediatric studies are non-controlled. The rarity of the disease and the lack of identifiable pediatric treatment goals and satisfactory trial end-points could explain the paucity of specific pediatric studies. An evolution has been made in the last few years regarding the treatment strategy of pulmonary arterial hypertension, with evidence that early combination therapy with at least two pulmonary vasodilators was beneficial on the survival. Children with pulmonary hypertension should be referred to experienced centers early, to benefit from a comprehensive initial assessment. Serial clinical and hemodynamic re-evaluation should assess treatment response and guide potential change in therapy.
Genetic and in silico analysis of plantaricin EFI locus in indigenous isolates of lactobacillus plantarum

Genetic investigation and in silico analysis of plantaricin EFI (plnEFI) locus was performed in three indigenous isolates of Lactobacillus plantarum EL3, L28 and BL1. Amplification with plnEFI specific primers and production of ~ 10 KDa size protein suggested the existence of class II bacteriocins. The analysis demonstrated that the studied fragment included structural bacteriocin, immunity, partial transporter and potential regulatory encoding regions. Based on the results, there was one DNA polymorphic site in plnE as well as plnF of the studied sequences. One nucleotide substitution in plnE of BL1 isolate lead to replacement of Glycin with Valine. These two are of non‐polar type which did not affect instability index of plnE protein. The only nucleotide variation in plnF of EL3 isolate did not change the amino acid sequence since the modified nucleotide constituted alternative codon of the original amino acid. The highest DNA polymorphism occurred in the region with immunity function which in BL1 resulted in the conversion of start codon to amino acid codon. In the partial transporter sequence, one variable nucleotide site caused amino acid replacement in all the isolates which elevated stability of N‐terminal domain in the transporter protein compared to nominated reference isolate L. plantarum C11. The region with possible regulatory function was identical in all three isolates. © 2018 American Institute of Chemical Engineers Biotechnol Progress, 35: e2773, 2019.
Real-Time Pure Shift HSQC NMR for Untargeted Metabolomics.

Sensitivity and resolution are key considerations for NMR applications in general and for metabolomics in particular, where complex mixtures containing hundreds of metabolites over a large range of concentrations are commonly encountered. There is a strong demand for advanced methods that can provide maximal information in the shortest possible time frame. Here, we present the optimization and application of the recently introduced 2D real-time BIRD 1H-13C HSQC experiment for NMR-based metabolomics of aqueous samples at 13C natural abundance. For mouse urine samples, it is demonstrated how this real-time pure shift sensitivity-improved heteronuclear single quantum correlation method provides broadband homonuclear decoupling along the proton detection dimension and thereby significantly improves spectral resolution in regions that are affected by spectral overlap. Moreover, the collapse of the scalar multiplet structure of cross-peaks leads to a sensitivity gain of about 40-50% over a traditional 2D HSQC-SI experiment. The experiment works well over a range of magnetic field strengths and is particularly useful when resonance overlap in crowded regions of the HSQC spectra hampers accurate metabolite identification and quantitation.