Body Mass Index and All-Cause Mortality in a Large Prospective Cohort of White and Black U.S. Adults

Remaining controversies on the association between body mass index (BMI) and mortality include the effects of smoking and prevalent disease on the association, whether overweight is associated with higher mortality rates, differences in associations by race and the optimal age at which BMI predicts mortality. To assess the relative risk (RR) of mortality by BMI in Whites and Blacks among subgroups defined by smoking, prevalent disease, and age, 891,572 White and 38,119 Black men and women provided height, weight and other information when enrolled in the Cancer Prevention Study II in 1982. Over 28 years of follow-up, there were 434,400 deaths in Whites and 18,702 deaths in Blacks. Cox proportional-hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI). Smoking and prevalent disease status significantly modified the BMI-mortality relationship in Whites and Blacks; higher BMI was most strongly associated with higher risk of mortality among never smokers without prevalent disease. All levels of overweight and obesity were associated with a statistically significantly higher risk of mortality compared to the reference category (BMI 22.5–24.9 kg/m²), except among Black women where risk was elevated but not statistically significant in the lower end of overweight. Although absolute mortality rates were higher in Blacks than Whites within each BMI category, relative risks (RRs) were similar between race groups for both men and women (p-heterogeneity by race  = 0.20 for men and 0.23 for women). BMI was most strongly associated with mortality when reported before age 70 years. Results from this study demonstrate for the first time that the BMI-mortality relationship differs for men and women who smoke or have prevalent disease compared to healthy never-smokers. These findings further support recommendations for maintaining a BMI between 20–25 kg/m² for optimal health and longevity.     

NuMA interaction with chromatin is vital for proper chromosome decondensation at the mitotic exit

NuMA is an abundant long coiled-coil protein that plays a prominent role in spindle organization during mitosis. In interphase, NuMA is localized to the nucleus and hypothesized to control gene expression and chromatin organization. However, because of the prominent mitotic phenotype upon NuMA loss, its precise function in the interphase nucleus remains elusive. Here, we report that NuMA is associated with chromatin in interphase and prophase but released upon nuclear envelope breakdown (NEBD) by the action of Cdk1. We uncover that NuMA directly interacts with DNA via evolutionarily conserved sequences in its C-terminus. Notably, the expression of the DNA-binding–deficient mutant of NuMA affects chromatin decondensation at the mitotic exit, and nuclear shape in interphase. We show that the nuclear shape defects observed upon mutant NuMA expression are due to its potential to polymerize into higher-order fibrillar structures. Overall, this work establishes the spindle-independent function of NuMA in choreographing proper chromatin decompaction and nuclear shape by directly associating with the DNA.     

MD simulations reveal alternate conformations of the oxyanion hole in the Zika virus NS2B/NS3 protease

Recent crystallography studies have shown that the binding site oxyanion hole plays an important role in inhibitor binding, but can exist in two conformations (active/inactive). We have undertaken molecular dynamics (MD) calculations to better understand oxyanion hole dynamics and thermodynamics. We find that the Zika virus (ZIKV) NS2B/NS3 protease maintains a stable closed conformation over multiple 100-ns conventional MD simulations in both the presence and absence of inhibitors. The S1, S2, and S3 pockets are stable as well. However, in two of eight simulations, the A132-G133 peptide bond in the binding pocket of S1' spontaneously flips to form a 3₁₀-helix that corresponds to the inactive conformation of the oxyanion hole, and then maintains this conformation until the end of the 100-ns conventional MD simulations without inversion of the flip. This conformational change affects the S1' pocket in ZIKV NS2B/NS3 protease active site, which is important for small molecule binding. The simulation results provide evidence at the atomic level that the inactive conformation of the oxyanion hole is more favored energetically when no specific interactions are formed between substrate/inhibitor and oxyanion hole residues. Interestingly, however, transition between the active and inactive conformation of the oxyanion hole can be observed by boosting the valley potential in accelerated MD simulations. This supports a proposed induced-fit mechanism of ZIKV NS2B/NS3 protease from computational methods and provides useful direction to enhance inhibitor binding predictions in structure-based drug design.     

Design and Characterization of Metformin-Loaded Solid Lipid Nanoparticles for Colon Cancer

Colorectal cancer is a global concern, and its treatment is fraught with non-selective effects including adverse side effects requiring hospital visits and palliative care. A relatively safe drug formulated in a bioavailability enhancing and targeting delivery platform will be of significance. Metformin-loaded solid lipid nanoparticles (SLN) were designed, optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release. Optimized SLN were 195.01?±?6.03 nm in size, ?17.08?±?0.95 mV with regard to surface charge, fibrous in shape, largely amorphous, and release of metformin was controlled. The optimized size, charge, and shape suggest the solid lipid nanoparticles will migrate and accumulate in the colon tumor preventing its proliferation and subsequently leading to tumor shrinkage and cell death.     

Gain adjustment of inhibitory synapses in the auditory system

A group of central auditory neurons residing in the lateral superior olivary nucleus (LSO) responds selectively to interaural level differences and may contribute to sound localization. In this simple circuit, ipsilateral sound increases firing of LSO neurons, whereas contralateral sound inhibits the firing rate via activation of the medial nucleus of the trapezoid body (MNTB). During development, individual MNTB fibers arborize within the LSO, but they undergo a restriction of their boutons that ultimately leads to mature topography. A critical issue is whether a distinct form of inhibitory synaptic plasticity contributes to MNTB synapse elimination within LSO. Whole-cell recording from LSO neurons in brain slices from developing gerbils show robust long-term depression (LTD) of the MNTB-evoked IPSP/Cs when the MNTB was activated at a low frequency (1 Hz). These inhibitory synapses also display mixed GABA/glycinergic transmission during development, as assessed physiologically and immunohistochemically (Kotak et al. 1998). While either glycine or GABA_A receptors could independently display inhibitory LTD, focal delivery of GABA, but not glycine, at the postsynaptic-locus induces depression. Furthermore, the GABA_B receptor antagonist, SCH-50911, prevents GABA or synaptically induced depression. Preliminary evidence also indicated strengthening of inhibitory transmission (LTP) by a distinct pattern of inhibitory activity. These data support the idea that GABA is crucial for the expression inhibitory LTD and that this plasticity may underlie the early refinement of inhibitory synaptic connections in the LSO.     

Tactile stimulation of the swimmeret alters motor programs for abdominal posture in the lobsterHomarus americanus

The influence of mechanosensory stimulation of a second segment swimmeret upon the abdominal postural program was examined in an isolated abdominal nerve cord-swimmeret preparation. The swimmeret was stimulated in several different ways to assess the extent of influence exerted on abdominal positioning. Localized tactile stimulation of the swimmeret surface with a mechanical probe usually generated flexion inhibition where the flexor inhibitor (f5) was activated while the small and medium flexor excitors were inhibited. Flexion inhibition was much stronger in females than males. In 50% of the animals a weak flexion excitation was seen. After 3-6 hours the response of one-third of these preparations changed to flexion inhibition. Strong manual stimulation of the swimmeret surface inhibited all of the flexor excitors (f1, f2, f3, f4, and f6) while exciting the inhibitor f5 and increasing extensor activity. Similar extension responses were observed in both sexes. Repeated tactile stimulation of the swimmeret surface elicited a response similar to that evoked during manual stimulation. The strongest extension response was produced at 2 Hz which falls within the normal range of swimmeret beating in intact lobsters. Similar extension responses were also obtained during spontaneous swimmeret beating and rhythmic manual movement of the swimmeret.(ABSTRACT TRUNCATED AT 250 WORDS)     

Construction of a 1.5-Mb Bacterial Artificial Chromosome Contig in Xp11.23, a Region of High Gene Content

To generate sequence-ready templates for the gene-rich Xp11.23 region, we have constructed a 1.5-Mb bacterial artificial chromosome (BAC) contig spanning the interval between the DNA markers OATL1 and DXS255. The contig includes 28 BACs, ranging in size from 58 to 285 kb with an average size of 135 kb, which provide 2.5-fold coverage of the region. The BAC contig was constructed based entirely on the content of 40 DNA markers from a previously established YAC contig and 11 new markers developed from BAC-end DNA sequences, 4 of which were required to close gaps in the map. There was no evidence of rearrangement, instability, or chimerism in any of the BAC clones. The BAC cloning system appears to provide robust and total physical coverage of this gene-rich region with clones that are suitable for DNA sequencing.     

Sedentary behavior, recreational physical activity, and 7-year weight gain among postmenopausal U.S. women

Objective: To assess the relationship among recreational physical activity (PA), non‐occupational sedentary behavior, and 7‐year weight gain among postmenopausal U.S. women 40 to 69 years old. Research Methods and Procedures: In 1992 and 1999, 18,583 healthy female participants from the Cancer Prevention Study II Nutrition Cohort completed questionnaires on anthropometric characteristics and lifestyle factors. The associations between recreational PA [in metabolic equivalent (MET) hours per week] and non‐occupational sedentary behavior (in hours per day) at baseline and risk for 7‐year weight gain (5 to 9 or ≥10 vs. ±4 pounds) were assessed using multivariate logistic regression analysis. Results: Neither PA nor sedentary behavior was associated with a 5‐ to 9‐pound weight gain. Among women who were not overweight at baseline (BMI <25.0), the odds of ≥10‐pound weight gain were 12% lower (odds ratio, 0.88; 95% confidence interval, 0.77 to 0.99) for those in the highest category of recreational PA (≥18 MET h/wk) compared with >0 to <4 MET h/wk; odds were 47% higher (odds ratio, 1.47; 95% confidence interval, 1.21 to 1.79) for non‐overweight women who reported ≥6 h/d of non‐occupational sedentary behavior compared with <3 h/d. Neither PA nor sedentary behavior were associated with risk of ≥10‐pound weight gain weight among women who were overweight at baseline (BMI ≥25.0). Discussion: Both recreational PA and non‐occupational sedentary behavior independently predicted risk of ≥10‐pound weight gain among postmenopausal women who were not overweight at baseline. Public health messages to prevent weight gain among normal‐weight postmenopausal women may need to focus on decreasing time spent in sedentary behaviors and increasing the amount of time spent on PA.