Miracle-dz/UniFAR-FTUs huggingface dataset:
An incoherent HIFU transducer for treatment of the medial branch nerve: Numerical study and in vivo validation

Abstract Background Chronic back pain due to facet related degenerative changes affects 4-6 million patients a year in the United States. Patients refractory to conservative therapy may warrant targeted injections of steroids into the joint or percutaneous medial branch nerve denervation with radiofrequency ablation. We numerically tested a novel noninvasive high intensity focused ultrasound transducer to optimize nerve ablation near a bone-soft tissue interface. Methods A transducer with 4 elements operating in an incoherent mode was modeled numerically and tested pre-clinically under fluoroscopic guidance. After 6 lumbar medial branch nerve ablations were performed in 2 pigs, they were followed clinically for 1 week and then sacrificed for pathological evaluation. Results Simulations show that the acoustic spot size in water at 6 dB was 14mm axial x 1.6mm lateral and 52mm axial x 1.6mm lateral for coherent and incoherent modes, respectively. We measured the size of N = 6 lesions induced in vivo in a pig model and compared them to the size of the simulated thermal dose. The best match between the simulated and measured lesion size was found with a maximum absorption coefficient in the cortical bone adjusted to 30 dB/cm/MHz. This absorption was used to simulate clinical scenarios in humans to generate lesions with no potential side effects at 1000 and 1500 J. Conclusion The elongated spot obtained with the incoherent mode facilitates the targeting during fluoroscopic-guided medial branch nerve ablation.
Predicting the protein composition of human urine in normal and pathological states: Quantitative description based on Dent1 disease (CLCN5 mutation)

The presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both. Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, α1‐microglobulin (α1‐m), β2‐microglobulin (β2‐m) and retinol‐binding protein 4 (RBP4) urine concentrations. Our results indicate that the urinary excretion of β2‐m and RBP4 differs from that of albumin and α1‐m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption. The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria. Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease.
Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

The hyperpolarization-activated cyclic nucleotide-gated channel (HCN), which underlies the hyperpolarization-activated cation current (Ih), has diverse roles in regulating neuronal excitability across cell types and brain regions. Recently, HCN channels have been implicated in preclinical models of substance abuse including alcohol. In the prefrontal cortex of rodents, HCN expression and Ih magnitude are developmentally regulated during adolescence and may be vulnerable to alcohol’s effects. In mice, binge alcohol consumption during the adolescent period results in a sustained reduction in Ih that coincides with increased alcohol consumption in adulthood, yet the direct role HCN channels have on alcohol consumption are unknown. Here, we show that the genetic deletion of Hcn1 causes an increase in alcohol preference on intermittent 2-bottle choice task in homozygous null (HCN1−/−) male mice compared to wild-type littermates without affecting saccharine or quinine preference. The targeted viral deletion of HCN1 in pyramidal neurons of the medial prefrontal cortex resulted in a gradual loss of Hcn1 expression and a reduction in Ih magnitude during adolescence, however, this did not significantly affect alcohol consumption or preference. We conclude that while HCN1 regulates alcohol preference, the genetic deletion of Hcn1 in the medial prefrontal cortex does not appear to be the locus for this effect.
The President’s Emergency Plan for AIDS Relief and adult mortality: A replication study of HIV development assistance effects in Sub-Saharan African countries

The US budget for global health funding, which was by far the largest of similar funding in the world, increased from US $1.3 billion in 2001 to more than US $10 billion in recent years. More than 54% of this funding was allocated to the Global Fund to Fight HIV/AIDS through the US President’s Emergency Plan for AIDS Relief (PEPFAR) in Africa. However, recent studies indicate contradictory results regarding the effectiveness of PEPFAR. One by Bendavid, Holmes, Bhattacharya, and Miller shows positive effects of PEPFAR in reducing adult mortality in Africa, while another by Duber, Coates, Szekeras, Kaji, and Lewis finds that there are no significant differences in reducing adult mortality in countries that received PEPFAR funding vs countries that did not. Due to their potential impact on policy decisions regarding critical global health funding, we wanted to assess why the results are discrepant. To do this, we replicated the Bendavid study. The replication provides verification that the study replicable and that the analytic choices of the authors are robust to different assumptions or restrictions. This allows us to assess the different choices and data available to the two research groups and draw some conclusions about why the results may be different. Then, focusing on two of the prominently discrepant studies, i.e., the Bendavid study (1998–2008) and the Duber study (2000–2006), we establish why the two studies are in disagreement. We apply appropriate individual-level and country-level analytical methodology as used by Bendavid over the analytical time period used for the Duber study (2000–2006), which originally focused on nationally aggregated data and differed in some key focus countries. For our first objective, we replicated the original Bendavid study findings and our findings support their conclusion that between 1998–2008 all-cause mortality decreased significantly more (OR = 0.84, CI, 0.72–0.99) in countries that implemented PEPFAR. For our second objective (Bendavid’s data and methodology applied to Duber’s study period), we found reduction in all cause adult mortality to be borderline insignificant (OR = 0.87 CI, 0.75–1.01, p = 0.06), most possibly reflecting the abbreviated fewer number of events and sample size over a shorter period. Therefore, our overall analyses are consistent with the conclusion of positive impact of the PEPFAR program in reducing adult mortality. We believe that the discrepancy observed in the original studies mainly a reflection of shortcomings in the analytical approach necessitated by the Duber study’s nationally aggregated dataset or “may reflect a lack of data quality” in the Duber study (Duber, et al. 2010).
The perceived impact of fluency on personalities of adults who stutter: implicit evidence of self-stigma

Abstract Purpose The NEO-FFI is an extensively used instrument that has been used to identify personality differences between those who stutter and matched controls or group norms. The goal of this study was to use the NEO-FFI to implicitly capture and quantify self-stigma related to personality in persons who stutter (PWS). Methods Thirty PWS completed the NEO-FFI twice; once as themselves and once while mentalizing (using theory of mind) to respond as though they did not stutter and had never stuttered, thus comparing their true personality to their perceived personality if they were fluent speakers. Compared to their true personalities, PWS perceived their fluent counterparts to be significantly less neurotic and more extroverted. Results The differences observed are somewhat analogous, though considerably larger in magnitude than personality differences that have previously been reported when comparing PWS to fluent controls or norms. Differences were interpreted to be due to “contrast effects” influencing the comparison. That is, PWS cognitively separated themselves from their fluent counterparts, seeing their true selves in a negative light compared to their fluent counterparts. This “us” vs. “them” separation is considered evidence of self-stigma related to personality in PWS. Conclusions The finding that the perceived differences were in the domains of Neuroticism and Extraversion is consistent with prevailing stereotypes about PWS and exemplifies how public stigma can become internalized. Clinical implications are discussed with respect to how similar theory of mind/social comparison exercises can be used in cognitive behavioral therapy to help identify and restructure negative thoughts and beliefs about stuttering.
Uncovering the basis of protein-protein interaction specificity with a combinatorially complete library

Protein-protein interaction specificity is often encoded at the primary sequence level. However, the contributions of individual residues to specificity are usually poorly understood and often obscured by mutational robustness, sequence degeneracy, and epistasis. Using bacterial toxin-antitoxin systems as a model, we screened a combinatorially complete library of antitoxin variants at three key positions against two toxins. This library enabled us to measure the effect of individual substitutions on specificity in hundreds of genetic backgrounds. These distributions allow inferences about the general nature of interface residues in promoting specificity. We find that positive and negative contributions to specificity are neither inherently coupled nor mutually exclusive. Further, a wild-type antitoxin appears optimized for specificity as no substitutions improve discrimination between cognate and non-cognate partners. By comparing crystal structures of paralogous complexes, we provide a rationale for our observations. Collectively, this work provides a generalizable approach to understanding the logic of molecular recognition.
Reconsidering the relation between parental functioning and child externalizing behaviors: A meta-analysis on child-driven effects.

Guided by multiple theories illustrating the transactional nature of the relation between parents' and children's behaviors, the present meta-analysis provides synthesized evidence on the strength of child-driven effects in eliciting changes in parents' psychological stress and parenting practices. A meta-analysis of 45 independent samples with 640 effect sizes found significant positive associations between children's externalizing behaviors and parents' subsequent functioning (r = .087, 95% CI [.07, .10]). These associations were net of parents' functioning at baseline, and the strength of these associations was statistically comparable with the effects of parents on children's externalizing behaviors (r = .075, 95% CI [.06, .09]). In addition, the strength of the child-driven effects did not vary as a function of child gender, age, or the time interval between assessments. The implications of these findings with respect to research on the dynamic relation between parenting functioning and children's adjustment are discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Intensive Care Unit-Acquired Weakness: Not Just Another Muscle Atrophying Condition

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models.
GPD1L is negatively associated with HIF1α expression and predicts lymph node metastasis in oral and HPV- oropharyngeal cancer.

OBJECTIVE The study is to determine if Glycerol-3-phosphate dehydrogenase 1-like(GPD1L) and hypoxia-inducible factor-1α(HIF1α) can identify high-risk patients with delayed lymph node metastasis in early-stage head and neck squamous cell carcinoma(HNSCC). MATERIALS AND METHODS The mRNA and protein expressions of markers were analyzed using fresh and paraffin embedded HNSCC specimens. The statistical analyses included chi-square test, t test, correlation analysis, univariate and multivariate analyses, etc. RESULTS: GPD1L(down-regulated) and HIF1α(up-regulated) mRNA expression had a negative correlation (r=-0.496, P=0.001) in cT1-2N0 HNSCC. The low GPD1L+high HIF1α expression group(22.6%) showed a significant decrease in disease-free survival compared with the high GPD1L+low HIF1α expression group(71.4%) in the neck dissection group. The low GPD1L+high HIF1α expression(39.4%) resulted in a significantly higher delayed metastasis rate than the high GPD1L+low HIF1α expression(5.6%) for cT1-2N0 HNSCC in the neck observation group. GPD1L and HIF1α protein expression more accurately predicted lymph node metastasis than the WINTER hypoxia gene panel (false negative rate in predicting metastasis:8.1% vs. 26.4%). Cox regression analyses found that the combined protein expression of GPD1L and HIF1α could predict delayed metastasis (HR:0.118, 95% CI:0.027-0.525). CONCLUSIONS Low GPD1L+high HIF1α expression can serve as candidate biomarkers for high-risk populations with lymph node metastases in early-stage HNSCC.
Metabolomics and Proteomics to Understand Fuel Use in Rat Model of High and Low Exercise Capacity.

x Chapter 1 Introduction 1 1.1 Aim and Scope 2 1.2 Study overview 3 Chapter 2 Importance of fuel preference 5 2.1 A brief history 5 2.1.1 Studies linking fuel use and high exercise capacity 6 2.1.2 Fuel selection and metabolic health 8 2.1. 3 Fuel selection and longevity 10 2.2 Mechanisms for adaptive fuel selection 11 2.2.1 Fuel availability 12 2.2.2 Substrate entry into the cell 15 2.2.3 Glycogenolysis and glycolysis 16 2.2.4 Substrate entry into the mitochondria 19 2.2. 5 Mitochondrial enzyme activity 20 2.3 Model for high and low exercise capacity 21 2.3. 1 Beginnings of the HCR-LCR model 22 2.3. 2 Fuel selection in HCR and LCR 24 2.4 Summary 25 Chapter 3 Metabolomics to define fuel use during exercise 26
Functional aspects of primary cilium in signaling, assembly and microenvironment in cancer

The primary cilium is an antennae‐like structure extent outside the cell surface. It has an important role in regulating cell‐signaling transduction to affect proliferation, differentiation and migration. Evidence is accumulating that ciliary defects lead to ciliopathies and ciliary deregulation also play crucial roles in cancer formation and progression. Interestingly, restoring the cilia can suppress proliferation in some cancer cell. However, t he role of primary cilia in cancer still be debated. In this article, we review the role of the primary cilium in cancer through architecture, signaling pathways, cilia assembly and disassembly regulators, and summarized the new findings of the primary cilium in tumor microenvironments and different cancers, highlighting novel possibilities for therapeutic target in cancer.
Optimal Design of TSM Langasite Resonator for High-Temperature Applications: A Review

In this review article, we address two vital design considerations that govern the high-temperature operation of a thickness–shear mode langasite resonator: 1) electrode design and 2) electrode material. Optimal electrode designs to mitigate unwanted spurious modes and achieve a high Q-factor for fundamental and higher overtone modes have been discussed in great detail. Governing equations that determine the size, shape, and orientation of these electrodes have also been presented. In addition, the suitability of six platinum-group metals as electrode materials for high-temperature resonators have been assessed and summarized. Furthermore, the adhesion to the substrate, electrical conductivity, thermal stability, and various other temperature-dependent properties of these metals have been discussed. Finally, several combinations and operating ranges of these electrode materials have been thoroughly evaluated.
Heat Stress Triggers Differential Protein Accumulation in the Extracellular Matrix of Sorghum Cell Suspension Cultures

Plants reprogram gene expression as an adaptive response to survive high temperatures. While the identity and functions of intracellular heat stress-responsive proteins have been extensively studied, the heat response of proteins secreted to the extracellular matrix is unknown. Here, we used Sorghum bicolor, a species adapted for growth in hot climates, to investigate the extracellular heat-induced responses. When exposed to 40 °C for 72 h, heat-sensitive Arabidopsis cell suspension cultures died, while ICSB338 sorghum cell cultures survived by activation of a transcriptional response characterized by the induction of HSP70 and HSP90 genes. Quantitative proteomic analysis of proteins recovered from cell culture medium revealed specific heat stress-induced protein accumulation within the sorghum secretome. Of the 265 secreted proteins identified, 31 responded to heat (≥2-fold change), with 84% possessing a predicted signal peptide for targeting to the classical secretory pathway. The differentially accumulated proteins have putative functions in metabolism, detoxification, and protein modifications. A germin (SORBI_3003G427700) was highly heat-inducible at both protein and gene level. Overall, our study reveals new insights into sorghum responses to heat and provides a useful resource of extracellular proteins that could serve as targets for developing thermotolerant crops. Data are available via ProteomeXchange with identifier PXD021536.
A genomic and historical synthesis of plague in 18th century Eurasia

Significance The spread and evolution of plague have been under debate in the past few years. However, very little is known of the dynamics of the plague pathogen, Yersinia pestis, during the last phase of the Second Plague Pandemic in Europe (18th and 19th century). We present nine ancient Y. pestis genomes from the Second Plague Pandemic. CHE1 is the first Second Plague Pandemic genome from the Caucasus region, an area that houses plague wildlife reservoirs to this day, making it a key strain to help elucidate the origin of Medieval and Early Modern plague. Our study documents the importance of a noneurocentric approach to historical plague dynamics and proposes an origin of plague introductions outside of Europe. Plague continued to afflict Europe for more than five centuries after the Black Death. Yet, by the 17th century, the dynamics of plague had changed, leading to its slow decline in Western Europe over the subsequent 200 y, a period for which only one genome was previously available. Using a multidisciplinary approach, combining genomic and historical data, we assembled Y. pestis genomes from nine individuals covering four Eurasian sites and placed them into an historical context within the established phylogeny. CHE1 (Chechnya, Russia, 18th century) is now the latest Second Plague Pandemic genome and the first non-European sample in the post-Black Death lineage. Its placement in the phylogeny and our synthesis point toward the existence of an extra-European reservoir feeding plague into Western Europe in multiple waves. By considering socioeconomic, ecological, and climatic factors we highlight the importance of a noneurocentric approach for the discussion on Second Plague Pandemic dynamics in Europe.
Mitochondrial medicine therapies: rationale, evidence, and dosing guidelines

Purpose of review Primary mitochondrial disease is a highly heterogeneous but collectively common inherited metabolic disorder, affecting at least one in 4300 individuals. Therapeutic management of mitochondrial disease typically involves empiric prescription of enzymatic cofactors, antioxidants, and amino acid and other nutrient supplements, based on biochemical reasoning, historical experience, and consensus expert opinion. As the field continues to rapidly advance, we review here the preclinical and clinical evidence, and specific dosing guidelines, for common mitochondrial medicine therapies to guide practitioners in their prescribing practices. Recent findings Since publication of Mitochondrial Medicine Society guidelines for mitochondrial medicine therapies management in 2009, data has emerged to support consideration for using additional therapeutic agents and discontinuation of several previously used agents. Preclinical animal modeling data have indicated a lack of efficacy for vitamin C as an antioxidant for primary mitochondrial disease, but provided strong evidence for vitamin E and N-acetylcysteine. Clinical data have suggested L-carnitine may accelerate atherosclerotic disease. Long-term follow up on L-arginine use as prophylaxis against or acute treatment for metabolic strokes has provided more data supporting its clinical use in individuals with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and Leigh syndrome. Further, several precision therapies have been developed for specific molecular causes and/or shared clinical phenotypes of primary mitochondrial disease. Summary We provide a comprehensive update on mitochondrial medicine therapies based on current evidence and our single-center clinical experience to support or refute their use, and provide detailed dosing guidelines, for the clinical management of mitochondrial disease. The overarching goal of empiric mitochondrial medicines is to utilize therapies with favorable benefit-to-risk profiles that may stabilize and enhance residual metabolic function to improve cellular resiliency and slow clinical disease progression and/or prevent acute decompensation.