Theoretical insights into the stabilities,detonation performance,and electrostatic potentials of cocrystals containing α- or β-HMX and TATB,FOX-7, NTO,or DMF in various molar ratios

A molecular dynamics method was employed to study the binding energies associated with the cocrystallization (at selected crystal planes) of either 1,3,5-triamino-2,4,6-trinitro-benzene (TATB), 1,1-diamino-2,2-dinitroethylene, 3-nitro-1,2,4-triazol-5-one (TATB, FOX-7, and NTO, respectively, all of which are explosives), or N,N-dimethylformamide (DMF, a nonenergetic solvent) in various molar ratios with 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane in its α and β conformations (α-HMX and β-HMX, respectively). The results showed that the cocrystals with low molar ratios (2:1, 1:1, 1:2, and 1:3) were the most stable. The binding energies of HMX/NTO and HMX/DMF were larger than those of HMX/TATB and HMX/FOX-7. According to the calculated stabilities, HMX prefers to adopt its α form in HMX/TATB and its β form in HMX/NTO, whereas the two forms coexist in HMX/FOX-7. For HMX/TATB, HMX/NTO, and α-HMX/FOX-7, increasing the proportion of the cocrystal component with the highest detonation heat (HMX in the first two cases, FOX-7 in the latter) increases the detonation heat, velocity, and pressure of the cocrystal. However, increasing the proportion of the component with the highest detonation heat in β-HMX/FOX-7 and γ-CL-20/FOX-7 increases the detonation heat of the cocrystal but decreases its detonation velocity. An investigation of the surface electrostatic potential revealed how the sensitivity changes upon cocrystal formation.

Open image in new window

Graphical Abstract Surface electrostatic potential of HMX/TATB

     

Auditing sex- and gender-based medicine (SGBM) content in medical school curriculum: a student scholar model

Background

Sex- and gender-based medicine (SGBM) aims to (1) delineate and investigate sex- and gender-based differences in health, disease, and response to treatment and (2) apply that knowledge to clinical care to improve the health of both women and men. However, the integration of SGBM into medical school curricula is often haphazard and poorly defined; schools often do not know the current status of SGBM content in their curricula, even if they are committed to addressing gaps and improving SGBM delivery. Therefore, complete auditing and accounting of SGBM content in the existing medical school curriculum is necessary to determine the baseline status and prepare for successful integration of SGBM content into that curriculum.

Methods

A review of course syllabi and lecture objectives as well as a targeted data analysis of the Curriculum Management and Information Tool (CurrMIT) were completed prior to a real-time curriculum audit. Subsequently, six “student scholars,” three first-year and three second-year medical students, were recruited and trained to audit the first 2 years of the medical school curriculum for SGBM content, thus completing an audit for both of the pre-clinical years simultaneously. A qualitative analysis and a post-audit comparative analysis were completed to assess the level of SGBM instruction at our institution.

Results

The review of syllabi and the CurrMIT data analysis did not generate a meaningful catalogue of SGBM content in the curriculum; most of the content identified specifically targeted women’s or men’s health topics and not sex- or gender-based differences. The real-time student audit of the existing curriculum at Texas Tech revealed that most of the SGBM material was focused on the physiological/anatomical sex differences or gender differences in disease prevalence, with minimal coverage of sex- or gender-based differences in diagnosis, prognosis, treatment, and outcomes.

Conclusions

The real-time student scholar audit was effective in identifying SGBM content in the existing medical school curriculum that was not possible with a retrospective review of course syllabi and lecture objectives or curriculum databases such as the CurrMIT. The audit results revealed the need for improved efforts to teach SGBM topics in our school’s pre-clinical curriculum.

     

A Multi-Atlas Labeling Approach for Identifying Subject-Specific Functional Regions of Interest

The functional region of interest (fROI) approach has increasingly become a favored methodology in functional magnetic resonance imaging (fMRI) because it can circumvent inter-subject anatomical and functional variability, and thus increase the sensitivity and functional resolution of fMRI analyses. The standard fROI method requires human experts to meticulously examine and identify subject-specific fROIs within activation clusters. This process is time-consuming and heavily dependent on experts’ knowledge. Several algorithmic approaches have been proposed for identifying subject-specific fROIs; however, these approaches cannot easily incorporate prior knowledge of inter-subject variability. In the present study, we improved the multi-atlas labeling approach for defining subject-specific fROIs. In particular, we used a classifier-based atlas-encoding scheme and an atlas selection procedure to account for the large spatial variability across subjects. Using a functional atlas database for face recognition, we showed that with these two features, our approach efficiently circumvented inter-subject anatomical and functional variability and thus improved labeling accuracy. Moreover, in comparison with a single-atlas approach, our multi-atlas labeling approach showed better performance in identifying subject-specific fROIs.     

A New Equation to Estimate Muscle Mass from Creatinine and Cystatin C

Background

With evaluation for physical performance, measuring muscle mass is an important step in detecting sarcopenia. However, there are no methods to estimate muscle mass from blood sampling.

Methods

To develop a new equation to estimate total-body muscle mass with serum creatinine and cystatin C level, we designed a cross-sectional study with separate derivation and validation cohorts. Total body muscle mass and fat mass were measured using dual-energy x-ray absorptiometry (DXA) in 214 adults aged 25 to 84 years who underwent physical checkups from 2010 to 2013 in a single tertiary hospital. Serum creatinine and cystatin C levels were also examined.

Results

Serum creatinine was correlated with muscle mass (P < .001), and serum cystatin C was correlated with body fat mass (P < .001) after adjusting glomerular filtration rate (GFR). After eliminating GFR, an equation to estimate total-body muscle mass was generated and coefficients were calculated in the derivation cohort. There was an agreement between muscle mass calculated by the novel equation and measured by DXA in both the derivation and validation cohort (P < .001, adjusted R² = 0.829, β = 0.95, P < .001, adjusted R² = 0.856, β = 1.03, respectively).

Conclusion

The new equation based on serum creatinine and cystatin C levels can be used to estimate total-body muscle mass.     

Genetic Variants of TPCN2 Associated with Type 2 Diabetes Risk in the Chinese Population

Objective

The aim of this study was to determine whether TPCN2 genetic variants are associated with type 2 diabetes and to elucidate which variants in TPCN2 confer diabetes susceptibility in the Chinese population.

Research Design and Methods

The sample population included 384 patients with type 2 diabetes and 1468 controls. Anthropometric parameters, glycemic and lipid profiles and insulin resistance were measured. We selected 6 TPCN2 tag single nucleotide polymorphisms (rs35264875, rs267603153, rs267603154, rs3829241, rs1551305, and rs3750965). Genotypes were determined using a Sequenom MassARRAY SNP genotyping system.

Results

Ultimately, we genotyped 3 single nucleotide polymorphisms (rs3750965, rs3829241, and rs1551305) in all individuals. There was a 5.1% higher prevalence of the rs1551305 variant allele in type 2 diabetes individuals (A) compared with wild-type homozygous individuals (G). The AA genotype of rs1551305 was associated with a higher diabetes risk (p<0.05). The distributions of rs3829241 and rs3750965 polymorphisms were not significantly different between the two groups. HOMA-%B of subjects harboring the AA genotype of rs1551305 decreased by 14.87% relative to the GG genotype.

Conclusions

TPCN2 plays a role in metabolic regulation, and the rs1551305 single nucleotide polymorphism is associated with type 2 diabetes risk. Future work will begin to unravel the underlying mechanisms.     

Association of PON1, P2Y12 and COX1 with Recurrent Ischemic Events in Patients with Extracranial or Intracranial Stenting

Background and Purpose

Short-term combined use of clopidogrel and aspirin improves cerebrovascular outcomes in patients with symptomatic extracranial or intracranial stenosis. Antiplatelet non-responsiveness is related to recurrent ischemic events, but the culprit genetic variants responsible for the non-responsiveness have not been well studied. We aimed to identify the genetic variants associated with poor clinical outcomes.

Methods

Patients with symptomatic extracranial or intracranial stenosis scheduled for stenting and receiving dual antiplatelets (clopidogrel 75 mg and aspirin 100 mg daily) for at least 5 days before intervention were enrolled. Ischemic events including recurrent transient ischemic attack, stroke, myocardial infarction, and vascular-related mortality within 12 months follow-up were recorded. We examined the influence of genetic polymorphisms on treatment outcome in our patients.

Results

A total of 268 patients were enrolled into our study and ischemic events were observed in 39 patients. For rs662 of paraoxonase 1 (PON1), allele C was associated with an increased risk of ischemic events (OR = 1.64, 95%CI = 1.03–2.62, P = 0.029). The A-allele carriers of rs2046934 of P2Y12 had a significant association with adverse events (OR = 2.01, 95%CI = 1.10–3.67, P = 0.041). The variant T-allele of cyclooxygenase-1 (COX1) rs1330344 significantly increased the risk of recurrent clinical events (OR = 1.85, 95%CI = 1.12–3.03, P = 0.017). The other single nucleotide polymorphism (SNP) had no association with ischemic events.

Conclusions

PON1, P2Y12 and COX1 polymorphisms were associated with poorer vascular outcomes. Testing for these polymorphisms may be valuable in the identification of patients at risk for recurrent ischemic events.     

An Active Type I-E CRISPR-Cas System Identified in Streptomyces avermitilis

CRISPR-Cas systems, the small RNA-dependent immune systems, are widely distributed in prokaryotes. However, only a small proportion of CRISPR-Cas systems have been identified to be active in bacteria. In this work, a naturally active type I-E CRISPR-Cas system was found in Streptomyces avermitilis. The system shares many common genetic features with the type I-E system of Escherichia coli, and meanwhile shows unique characteristics. It not only degrades plasmid DNA with target protospacers, but also acquires new spacers from the target plasmid DNA. The naive features of spacer acquisition in the type I-E system of S. avermitilis were investigated and a completely conserved PAM 5’-AAG-3’ was identified. Spacer acquisition displayed differential strand bias upstream and downstream of the priming spacer, and irregular integrations of new spacers were observed. In addition, introduction of this system into host conferred phage resistance to some extent. This study will give new insights into adaptation mechanism of the type I-E systems in vivo, and meanwhile provide theoretical foundation for applying this system on the genetic modification of S. avermitilis.