Natural selection and genetic variation in a promising Chagas disease drug target: Trypanosoma cruzi trans-sialidase

Rational drug design is a powerful method in which new and innovative therapeutics can be designed based on knowledge of the biological target aiming to provide more efficacious and responsible therapeutics. Understanding aspects of the targeted biological agent is important to optimize drug design and preemptively design to slow or avoid drug resistance. Chagas disease, an endemic disease for South and Central America and Mexico is caused by Trypanosoma cruzi, a protozoan parasite known to consist of six separate genetic clusters or DTUs (discrete typing units). Chagas disease therapeutics are problematic and a call for new therapeutics is widespread. Many researchers are working to use rational drug design for developing Chagas drugs and one potential target that receives a lot of attention is the T. cruzi trans-sialidase protein. Trans-sialidase is a nuclear gene that has been shown to be associated with virulence. In T. cruzi, trans-sialidase (TcTS) codes for a protein that catalyzes the transfer of sialic acid from a mammalian host coating the parasitic surface membrane to avoid immuno-detection. Variance in disease pathology depends somewhat on T. cruzi DTU, as well, there is considerable genetic variation within DTUs. However, the role of TcTS in pathology variance among and within DTU’s is not well understood despite numerous studies of TcTS. These previous studies include determining the crystalline structure of TcTS as well as the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. In order to understand the role of natural selection in TcTS DNA sequence and protein variation, we sequenced 540 bp of the TcTS gene from 48 insect vectors. Because all 48 sequences had multiple polymorphic bases, we examined cloned sequences from two of the insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target

Associations among osteocalcin, leptin and metabolic health in children ages 9-13 years in the United States

BACKGROUND: This study aimed to investigate the relationships among osteocalcin, leptin and metabolic health outcomes in children ages 9-13 years. METHODS: This was a cross-sectional analysis of baseline data from 161 boys and 157 girls (ages 9-13 years) who previously participated in a double-blinded randomized placebo controlled trial of vitamin D supplementation. Relationships among fasting serum total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC), leptin, and metabolic health outcomes were analyzed. RESULTS: Approximately 52% of study participants were obese based on percent body fat cutoffs (>25% for boys and >32% for girls) and about 5% had fasting serum glucose within the prediabetic range (i.e. 100 to 125 mg/dL). Serum tOC was not correlated with leptin, glucose, insulin, HOMA-IR, or HOMA-β after adjusting for percent body fat. However, serum ucOC negatively correlated with leptin (partial r = -0.16; p = 0.04) and glucose (partial r = -0.16; p = 0.04) after adjustment for percent body fat. Leptin was a positive predictor of insulin, glucose, HOMA-IR, and HOMA-β after adjusting for age, sex and percent body fat (all p < 0.001). CONCLUSIONS: These data depict an inverse relationship between leptin and various metabolic health outcomes in children. However, the notion that tOC or ucOC link fat with energy metabolism in healthy children was not supported

Insulin Resistance and the IGF-I-Cortical Bone Relationship in Children Ages 9-13 Years

IGF-I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF-I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF-I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass-dependent relationship between IGF-I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR). Cortical bone at the tibia diaphysis (66% site) and total body fat-free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA), respectively. IGF-I, insulin, and glucose were measured in fasting sera and HOMA-IR was calculated. Children with high HOMA-IR had greater unadjusted IGF-I (p < 0.001). HOMA-IR was a negative predictor of cortical bone mineral content, cortical bone area (Ct.Ar), and polar strength strain index (pSSI; all p ≤ 0.01) after adjusting for race, sex, age, maturation, fat mass, and FFST. IGF-I was a positive predictor of most musculoskeletal endpoints (all p < 0.05) after adjusting for race, sex, age, and maturation. However, these relationships were moderated by HOMA-IR (pInteraction < 0.05). FFST positively correlated with most cortical bone outcomes (all p < 0.05). Path analyses demonstrated a positive relationship between IGF-I and Ct.Ar via FFST in the total cohort (βIndirect Effect = 0.321, p < 0.001). However, this relationship was moderated in the children with high (βIndirect Effect = 0.200, p < 0.001) versus normal (βIndirect Effect = 0.408, p < 0.001) HOMA-IR. These data implicate insulin resistance as a potential suppressor of IGF-I-dependent cortical bone development, though prospective studies are needed

Mechanisms of SARS-CoV-2 neutralization by shark variable new antigen receptors elucidated through X-ray crystallography

Acknowledgements This work was supported by the Chief Scientist Office, Scottish Government, Grant COV/ABN/20/01 (Elasmogen, Ltd.), a 2018 Prostate Cancer Foundation Challenge Award (AML), a 2013 Prostate Cancer Foundation Young Investigator Award (AML), NCI R01s CA237272, CA233562, and CA245922 (AML). WEM was supported by the NIH T32 HL007741 and JMT by the NIH T32 AI055433. JSM was funded by NIGMS R01 GM088790. HA was funded by NIGMS R35 GM118047 and NCI P01 CA234228. X-ray diffraction data were collected at the Northeastern Collaborative Access Team beamlines, which are funded by the US National Institutes of Health (NIGMS P30 GM124165). The Pilatus 6M detector on 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). We thank the Marco Pravetoni lab for providing training and access to the OctetRED96e for BLI experiments.Peer reviewedPublisher PD

Geotechnical Reconnaissance: The 28 September 2018 M7.5 Palu-Donggala, Indonesia Earthquake

The Mw7.5 Palu-Donggala earthquake occurred on 28 September 2018 at 6:02 PM local time, and was caused by strike-slip faulting along the north-south trending Palu-Koro fault that extends through Palu City and the Central Sulawesi region of Indonesia. The United States Geological Survey (USGS) reports the epicenter was approximately 72 km north of Palu City at a depth of 10 km, and geodetic evidence indicates rupture of the fault over a length of 150 km. The earthquake triggered a series of massive landslides, resulted in the collapse of both unreinforced and reinforced structures, and generated tsunami waves that impacted coastal areas in Palu Bay, devastating Central Sulawesi. This report contains information about the geotechnical reconnaissance performed by the Geotechnical Extreme Events Reconnaissance (GEER) during November 2018 following the damaging earthquake and tsunami. Particular attention is devoted to a series of large liquefaction-induced flowslides that occurred after earthquake shaking ceased

Increased Risk of Fragility Fractures among HIV Infected Compared to Uninfected Male Veterans

BACKGROUND: HIV infection has been associated with an increased risk of fragility fracture. We explored whether or not this increased risk persisted in HIV infected and uninfected men when controlling for traditional fragility fracture risk factors. METHODOLOGY/PRINCIPAL FINDINGS: Cox regression models were used to assess the association of HIV infection with the risk for incident hip, vertebral, or upper arm fracture in male Veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC). We calculated adjusted hazard ratios comparing HIV status and controlling for demographics and other established risk factors. The sample consisted of 119,318 men, 33% of whom were HIV infected (34% aged 50 years or older at baseline, and 55% black or Hispanic). Median body mass index (BMI) was lower in HIV infected compared with uninfected men (25 vs. 28 kg/m²; p<0.0001). Unadjusted risk for fracture was higher among HIV infected compared with uninfected men [HR: 1.32 (95% CI: 1.20, 1.47)]. After adjusting for demographics, comorbid disease, smoking and alcohol abuse, HIV infection remained associated with an increased fracture risk [HR: 1.24 (95% CI: 1.11, 1.39)]. However, adjusting for BMI attenuated this association [HR: 1.10 (95% CI: 0.97, 1.25)]. The only HIV-specific factor associated with fragility fracture was current protease inhibitor use [HR: 1.41 (95% CI: 1.16, 1.70)]. CONCLUSIONS/SIGNIFICANCE: HIV infection is associated with fragility fracture risk. This risk is attenuated by BMI