Miracle-dz/UniFAR-FTUs huggingface dataset:
Synthetic viruses—Anything new?

The report of the construction of an infectious horsepox virus from synthesized DNA by Noyce, Lederman, and Evans [1] raised considerable concerns about whether this study will facilitate the construction of smallpox virus (variola) using synthetic biology [2–5]. This is a valid concern, but for a number of reasons—as explained below—no major change concerning the likelihood of a “resurrection” of smallpox emerges from this publication. Having said this, it is also evident that the scientific community, politicians, decision makers, and the lay public have to continue, and probably intensify, a discussion on benefits and risks of synthetic biology in a broader sense.
Hypertensive emergencies in diabetic patients from predominantly African American urban communities

ABSTRACT Aim: The aim of this study was to identify risk factors for hypertensive emergencies in diabetic patients presenting with severely elevated blood pressure. Methods: Using electronic medical records, this study identified diabetic patients with hypertensive crisis who presented to the emergency department of Newark Beth Israel Medical Center, Newark, NJ from June 2013 to May 2016. Diabetic patients with hypertensive emergencies were compared with non-diabetic patients based on important demographic and clinical characteristics. Results: Patients with diabetes accounted for 52.27% of all hypertensive emergencies during the study period. There were 264 diabetic patients with hypertensive emergencies and 519 diabetic patients with hypertensive urgencies. The majority of patients were African Americans (88.6%). The odds of hypertensive emergencies were strikingly higher in diabetic patients with hyperlipidemia (OR 1.66, 95% CI 1.23–2.24), coronary artery disease (OR 2.95, 95% CI 2.15–4.05), congestive heart failure (OR 6.28, 95% CI 4.49–8.80), renal insufficiency (OR 2.84, 95% CI 2.10–3.86) and low hemoglobin (OR 0.9, 95% CI 0.84–0.97). Acute or worsening heart failure was the most frequent acute target organ injury (49.6%) followed by non-ST elevation myocardial infarction (41.7%). Diabetic and non-diabetic patients had similar rates of target organ injuries. Conclusion: The development of hypertensive emergencies in patients with diabetes was not because of diabetes per se but because of coexisting highly elevated blood pressure. Tight blood pressure control may decrease the risk of hypertensive emergencies in this patient population.
Human iPS Cell-Derived Patient Tissues and 3D Cell Culture Part 1: Target Identification and Lead Optimization

Human-induced pluripotent stem cells (HiPSCs), and new technologies to culture them into functional cell types and tissues, are now aiding drug discovery. Patient-derived HiPSCs can provide disease models that are more clinically relevant and so more predictive than the currently available animal-derived or tumor cell-derived cells. These cells, consequently, exhibit disease phenotypes close to the human pathology, particularly when cultured under conditions that allow them to recapitulate the tissue architecture in three-dimensional (3D) systems. A key feature of HiPSCs is that they can be cultured under conditions that favor formation of multicellular spheroids or organoids. By culturing and differentiating in systems mimicking the human tissue in vivo, the HiPSC microenvironment further reflects patient in vivo physiology, pathophysiology, and ultimately pharmacological responsiveness. We assess the rationale for using HiPSCs in several phases of preclinical drug discovery, specifically in disease modeling, target identification, and lead optimization. We also discuss the growing use of HiPSCs in compound lead optimization, particularly in profiling compounds for their potential metabolic liability and off-target toxicities. Collectively, we contend that both approaches, HiPSCs and 3D cell culture, when used in concert, have exciting potential for the development of novel medicines.
Rational discovery of a SOD1 tryptophan oxidation inhibitor with therapeutic potential for amyotrophic lateral sclerosis

Abstract Formation of Cu, Zn superoxide dismutase 1 (SOD1) protein inclusions within motor neurons is one of the principal characteristics of SOD1-related amyotrophic lateral sclerosis (ALS). A hypothesis as to the nature of SOD1 aggregation implicates oxidative damage to a solvent-exposed tryptophan as causative. Here, we chart the discovery of a phenanthridinone based compound (Lig9) from the NCI Diversity Set III by rational methods by in silico screening and crystallographic validation. The crystal structure of the complex with SOD1, refined to 2.5 Å, revealed that Lig9 binds the SOD1 β-barrel in the β-strand 2 and 3 region which is known to scaffold SOD1 fibrillation. The phenanthridinone moiety makes a substantial π–π interaction with Trp32 of SOD1. The compound possesses a significant binding affinity for SOD1 and inhibits oxidation of Trp32; a critical residue for SOD1 aggregation. Thus, Lig9 is a good candidate from which to develop a new library of SOD1 aggregation inhibitors through protection of Trp32 oxidation. Communicated by Ramaswamy H. Sarma
Changes in cardiovascular risk and clinical outcomes in a HIV/AIDS cohort study over a 1-year period at a specialized clinic in Mexico

Introduction The third report of the National Cholesterol Education Program guidelines recommends calculating the 10-year morbidity of atherosclerotic cardiovascular disease (ASCVD) using risk calculators when treating high blood cholesterol in adults. We analyzed the changes in cardiovascular risk (CVR) among Mexican patients with HIV. Patients and methods This observational, prospective cohort study compared the CVR after 1 year of antiretroviral treatment among 460 HIV patients from a Mexican clinic. Changes using the ASCVD risk estimator and changes in clinical outcomes were analyzed. The results were categorized as low or high CVR using a cutoff of 7.5%. Results The CVR initially had a median of 2.3% (interquartile range [IQR]: 1%–4.8%), which changed to 2.4% (IQR: 1.5%–5.5%) after 1 year (P=0.001). After CVR stratification, we found that 84.3% of the patients had a low CVR, and 18% in this subgroup had metabolic syndrome (MS). Moreover, 15.7% had high CVR, and 47% in this subgroup had MS. The 4.3% of patients had an increase in CVR from the low to high subgroup, and 2.6% had a decrease in CVR from the high to low subgroup. Out of all patients, 22.3% had MS. Conclusion More than 50% of the population had an increase in CVR after 1 year. Of these patients, 4.3% changed from the low to high CVR group. Although the guidelines proposed different time periods for performing CVR estimations, this study showed that such assessments offered valuable clinical data over a relatively short-term period.
Application of insulin signaling to predict insect growth rate in Maruca vitrata (Lepidoptera: Crambidae)

Insect growth is influenced by two major environmental factors: temperature and nutrient. These environmental factors are internally mediated by insulin/insulin-like growth factor signal (IIS) to coordinate tissue or organ growth. Maruca vitrata, a subtropical lepidopteran insect, migrates to different climate regions and feeds on various crops. The objective of this study was to determine molecular tools to predict growth rate of M. vitrata using IIS components. Four genes [insulin receptor (InR), Forkhead Box O (FOXO), Target of Rapamycin (TOR), and serine-threonine protein kinase (Akt)] were used to correlate their expression levels with larval growth rates under different environmental conditions. The functional association of IIS and larval growth was confirmed because RNA interference of these genes significantly decreased larval growth rate and pupal weight. Different rearing temperatures altered expression levels of these four IIS genes and changed their growth rate. Different nutrient conditions also significantly changed larval growth and altered expression levels of IIS components. Different local populations of M. vitrata exhibited significantly different larval growth rates under the same nutrient and temperature conditions along with different expression levels of IIS components. Under a constant temperature (25°C), larval growth rates showed significant correlations with IIS gene expression levels. Subsequent regression formulas of expression levels of four IIS components against larval growth rate were applied to predict growth patterns of M. vitrata larvae reared on different natural hosts and natural local populations reared on the same diet. All four formulas well predicted larval growth rates with some deviations. These results indicate that the IIS expression analysis explains the growth variation at the same temperature due to nutrient and genetic background.
Caesarean section provision and readiness in Tanzania: analysis of cross-sectional surveys of women and health facilities over time

Objectives To describe trends in caesarean sections and facilities performing caesareans over time in Tanzania and examine the readiness of such facilities in terms of infrastructure, equipment and staffing. Design Nationally representative, repeated cross-sectional surveys of women and health facilities. Setting Tanzania. Participants Women of reproductive age and health facility staff. Main outcome measures Population-based caesarean rate, absolute annual number of caesareans, percentage of facilities reporting to perform caesareans and three readiness indicators for safe caesarean care: availability of consistent electricity, 24 hour schedule for caesarean and anaesthesia providers, and availability of all general anaesthesia equipment. Results The caesarean rate in Tanzania increased threefold from 2% in 1996 to 6% in 2015–16, while the total number of births increased by 60%. As a result, the absolute number of caesareans increased almost fivefold to 120 000 caesareans per year. The main mechanism sustaining the increase in caesareans was the doubling of median caesarean volume among public hospitals, from 17 caesareans per month in 2006 to 35 in 2014–15. The number of facilities performing caesareans increased only modestly over the same period. Less than half (43%) of caesareans in Tanzania in 2014–15 were performed in facilities meeting the three readiness indicators. Consistent electricity was widely available, and 24 hour schedules for caesarean and (less systematically) anaesthesia providers were observed in most facilities; however, the availability of all general anaesthesia equipment was the least commonly reported indicator, present in only 44% of all facilities (34% of public hospitals). Conclusions Given the rising trend in numbers of caesareans, urgent improvements in the availability of general anaesthesia equipment and trained anaesthesia staff should be made to ensure the safety of caesareans. Initial efforts should focus on improving anaesthesia provision in public and faith-based organisation hospitals, which together perform more than 90% of all caesareans in Tanzania.
Management of Wheezy Preschoolers in the Emergency Department

Objectives This study aimed to elicit pediatric emergency physician's treatment choices for preschool-aged children with wheeze, determine the characteristics of the presenting child that influence treatment choices, and determine whether there is clinical equipoise by eliciting physician willingness to enroll these children in a placebo-controlled trial of corticosteroids. Methods Discrete choice experiments varying the characteristics of the presenting child were designed to elicit Canadian emergency physician's treatment choices, both in the emergency department (ED) and at discharge, for young children presenting with wheeze and their willingness to enroll in a randomized controlled trial (RCT). Results Most physicians chose to treat children with albuterol both in the ED and at discharge for all clinical scenarios. The proportion of physicians who chose to treat children with oral corticosteroids both in the ED and at discharge varied widely (from 12% to 81%) across all scenarios. Physician preference whether preschool children with wheeze should be treated with corticosteroids varied depending on the child's age, history of atopy, and previous and continuous wheeze. Between 73% and 86% of physicians were willing to enroll these children in an RCT indicating clinical equipoise. Conclusions Physician treatment choices varied widely indicating clinical equipoise as to the effectiveness of corticosteroids in this population of patients. Management choices with respect to albuterol and corticosteroids were not consistent with published national and international guidelines. In line with this finding, physician's considerable willingness to enroll these children in an RCT may suggest that they are seeking guidance on how to manage these patients.
Development of a Stable MGAT1− CHO Cell Line to Produce Clade C gp120 With Improved Binding to Broadly Neutralizing Antibodies

The high rate of new HIV infections, particularly in Sub-Saharan Africa, emphasizes the need for a safe and effective vaccine to prevent acquired immunodeficiency syndrome (AIDS). To date, the only HIV vaccine trial that has exhibited protective efficacy in humans was the RV144 study completed in Thailand. The finding that protection correlated with antibodies to gp120 suggested that increasing the quality or magnitude of the antibody response that recognize gp120 might improve the modest yet significant protection (31.2%) achieved with this immunization regimen. However, the large-scale production of rgp120 suitable for clinical trials has been challenging due, in part, to low productivity and difficulties in purification. Moreover, the antigens that are currently available were produced largely by the same technology used in the early 1990s and fail to incorporate unique carbohydrates presented on HIV virions required for the binding of several major families of broadly neutralizing antibodies (bNAbs). Here we describe the development of a high-yielding CHO cell line expressing rgp120 from a clade C isolate (TZ97008), representative of the predominant circulating HIV subtype in Southern Africa and Southeast Asia. This cell line, produced using robotic selection, expresses high levels (1.2 g/L) of the TZ97008 rgp120 antigen that incorporates oligomannose glycans required for binding to multiple glycan dependent bNAbs. The resulting rgp120 displays a lower degree of net charge and glycoform heterogeneity as compared to rgp120s produced in normal CHO cells. This homogeneity in net charge facilitates purification by filtration and ion exchange chromatography methods, eliminating the need for expensive custom-made lectin, or immunoaffinity columns. The results described herein document the availability of a novel cell line for the large-scale production of clade C gp120 for clinical trials. Finally, the strategy used to produce a TZ97008 gp120 in the MGAT− CHO cell line can be applied to the production of other candidate HIV vaccines.
On (weak) fpc generators

Corrado Bohm once observed that if $Y$ is any fixed point combinator (fpc), then $Y(\lambda yx.x(yx))$ is again fpc. He thus discovered the first "fpc generating scheme" -- a generic way to build new fpcs from old. Continuing this idea, define an \emph{fpc generator} to be any sequence of terms $G_1,\dots,G_n$ such that $$Y \text{ is fpc } \Longrightarrow YG_1\cdots G_n \text{ is fpc}$$ In this contribution, we take first steps in studying the structure of (weak) fpc generators. We isolate several classes of such generators, and examine elementary properties like injectivity and constancy. We provide sufficient conditions for existence of fixed points of a given generator $(G_1,.,G_n)$: an fpc $Y$ such that $Y = YG_1\cdots G_n$. We conjecture that weak constancy is a necessary condition for existence of such (higher-order) fixed points. This generalizes Statman's conjecture on the non-existence of ``double fpcs'': fixed points of the generator $(G) = (\lambda yx.x(yx))$ discovered by Bohm.
Secondary failure of TNF‐α inhibitors in clinical practice

Tumor necrosis factor alpha (TNF‐α) is a leading inflammatory cytokine that plays a pivotal role in the pathogenesis of psoriasis. In case of a severe course of psoriasis and moderate‐to‐severe disease in which traditional systemic treatments are ineffective or contraindicated, TNF‐α inhibitors (iTNF‐α) are used. This class of drugs includes monoclonal antibodies and a fusion protein (etanercept) and can induce a humoral or cell‐mediated immune response, leading to formation of anti‐drug antibodies (ADAs). The immunogenicity may affect iTNF‐α drug pharmacokinetics, which would lead to hampering the clinical response (secondary drug failure), so a need to increase the drug dose arises. Antibodies against monoclonal antibodies (adalimumab, infliximab) have been associated with diminished clinical response, while against etanercept are non‐neutralizing and appear to have no significant effect on clinical response and treatment safety. Switching of biologic agents may be one strategy in ADA‐associated secondary failure of iTNF‐α. However researches are needed to identify risk factors for ADA development and investigate management strategies for optimized treatment response. The authors reviewed the literature on the effectiveness of iTNF‐α and pointed out the prevention of secondary failure in clinical practice.
A randomized controlled trial of the impact of protein supplementation on leg lean mass and integrated muscle protein synthesis during inactivity and energy restriction in older persons.

Background In older persons, muscle loss is accelerated during physical inactivity and hypoenergetic states, both of which are features of hospitalization. Protein supplementation may represent a strategy to offset the loss of muscle during inactivity, and enhance recovery on resumption of activity. Objective We aimed to determine if protein supplementation, with proteins of substantially different quality, would alleviate the loss of lean mass by augmenting muscle protein synthesis (MPS) while inactive during a hypoenergetic state. Design Participants (16 men, mean ± SD age: 69 ± 3 y; 15 women, mean ± SD age: 68 ± 4 y) consumed a diet containing 1.6 g protein · kg-1 · d-1, with 55% ± 9% of protein from foods and 45% ± 9% from supplements, namely, whey protein (WP) or collagen peptides (CP): 30 g each, consumed 2 times/d. Participants were in energy balance (EB) for 1 wk, then began a period of energy restriction (ER; -500 kcal/d) for 1 wk, followed by ER with step reduction (ER + SR; <750 steps/d) for 2 wk, before a return to habitual activity in recovery (RC) for 1 wk. Results There were significant reductions in leg lean mass (LLM) from EB to ER, and from ER to ER + SR in both groups (P < 0.001) with no differences between WP and CP or when comparing the change from phase to phase. During RC, LLM increased from ER + SR, but in the WP group only. Rates of integrated muscle protein synthesis decreased during ER and ER + SR in both groups (P < 0.01), but increased during RC only in the WP group (P = 0.05). Conclusions Protein supplementation did not confer a benefit in protecting LLM, but only supplemental WP augmented LLM and muscle protein synthesis during recovery from inactivity and a hypoenergetic state. This trial was registered at http://www.clinicaltrials. gov as NCT03285737.
Twenty-year time trends in hypertension prevalence in Yi people of China: three successive cross-sectional studies, 1996–2015

Objective To explore the trend of hypertension prevalence and related factors in Yi people from 1996 to 2015. Methods Three successive cross-sectional surveys were conducted in Liangshan Yi Autonomous Prefecture in 1996, 2007 and 2015, respectively. A total of 8448 participants aged 20–80 years (5040 Yi farmers, 3408 Yi migrants) were included in final analysis. Results Overall, the age-standardised prevalence of hypertension in migrants was significantly higher than in farmers. Furthermore, the age-standardised prevalence rates increased from 10.1% to 15.3% to 19.6% in Yi migrants and from 4.0% to 6.3% to 13.1% in Yi farmers during 1996 to 2007 to 2015. The highest 2015-to-1996 ratio of age-standardised hypertension prevalence was in male farmers (ratio=4.30), whereas despite the highest prevalence of hypertension, the equivalent figure in male migrants was 1.57. The older age, overweight and obesity were persistent risk factors of hypertension in three periods. After adjusted for age and body mass index, the difference of hypertension prevalence between 1996 and 2015 then vanished in male migrants (OR=1.335; 95% CI: 0.884 to 2.015) and female farmers (OR=1.267; 95% CI: 0.590 to 2.719). The disparities of hypertension prevalence between Yi migrants and farmers were not statistically significant in all subgroups when adjusted for age, body mass index and education. Conclusions Over the past two decades, the hypertension prevalence in Yi people has significantly increased. Yi migrants were more likely to be hypertensive than Yi farmers which was predominantly driven by the discrepancy of body mass index between them.
Agricultural research, or a new bioweapon system?

Insect-delivered horizontal genetic alteration is concerning Agricultural genetic technologies typically achieve their agronomic aims by introducing laboratory-generated modifications into target species' chromosomes. However, the speed and flexibility of this approach are limited, because modified chromosomes must be vertically inherited from one generation to the next. In an effort to remove this limitation, an ongoing research program funded by the U.S. Defense Advanced Research Projects Agency (DARPA) aims to disperse infectious genetically modified viruses that have been engineered to edit crop chromosomes directly in fields. This is genetic engineering through horizontal transfer, as opposed to vertical inheritance. The regulatory, biological, economic, and societal implications of dispersing such horizontal environmental genetic alteration agents (HEGAAs) into ecosystems are profound. Further, this program stipulates that the means of delivery of these viral HEGAAs into the environment should be insect-based dispersion (1). In the context of the stated aims of the DARPA program, it is our opinion that the knowledge to be gained from this program appears very limited in its capacity to enhance U.S. agriculture or respond to national emergencies (in either the short or long term). Furthermore, there has been an absence of adequate discussion regarding the major practical and regulatory impediments toward realizing the projected agricultural benefits. As a result, the program may be widely perceived as an effort to develop biological agents for hostile purposes and their means of delivery, which—if true—would constitute a breach of the Biological Weapons Convention (BWC).
Drunkorexia: A new term and diagnostic criteria

Abstract Individuals who restrict their caloric intake and/or exercise excessively to mitigate the calories from alcohol consumption may suffer from an eating disorder, substance abuse disorder, or both. While the term “drunkorexia” has been used in both academic articles and popular culture, issues persist with respect to diagnosing and treating this condition. Classifying the behavior as a subcategory of Other Specified Feeding and Eating Disorders (OSFED) would provide patients with an increased likelihood of receiving insurance coverage for this condition. A consistent definition of this behavior and a more medically accurate/appropriate term—such as “alcoholimia”—are both needed to advance treatment and prevention efforts.