Geospatial analysis of salmonellosis and its association with socioeconomic status in Texas

ObjectiveThe study’s objective was to find the association between salmonellosis and socioeconomic status (SES) in hot spot areas and statewide counties.DesignA retrospective cohort study.SettingThe data were recorded regarding salmonellosis in 2017 from the Texas surveillance database. It included assessment of hot spot analysis and SES association with salmonellosis at the county level.ParticipantsPatients with salmonellosis of all age groups in Texas.ResultsThere were a total of 5113 salmonellosis from 254 counties with an unadjusted crude rate of 18 per 100 000 person-years. Seven SES risk factors in the hot spot counties were as follows: low values of the severe housing problem, unemployment, African American and high values of social association rate, fast food/full-service restaurant use, Hispanic and Hispanic senior low access-to-store (p<0.05). A 12% difference existed between local health departments in hot (25%) and cold spot (37%) counties (χ2 (1, n=108)=0.5, p=0.81).Statewide independent risk factors were severe housing problem (incidence rate ratio (IRR)=1.1; 95% CI: 1.05 to 1.14), social association rate (IRR=0.89; 95% CI: 0.87 to 0.92), college education (IRR=1.05; 95% CI: 1.04 to 1.07) and non-Hispanic senior local access-to-store (IRR=1.98; 95% CI: 1.26 to 3.11). The severe housing problem predicted zero occurrences of infection in a county (OR=0.51; 95% CI: 0.28 to 0.95).ConclusionsDisparity exists in salmonellosis and SES. Attention to unmet needs will decrease salmonellosis. Severe housing problem is a notable risk.

Crowding within synaptic junctions influence the degradation of adenoside nucleotides by CD39 and CD73 ectonucleotidases

Synapsed cells can communicate using exocytosed nucleotides like adenosine triphosphate (ATP). Ectonucleotidases localized to a synaptic junction degradesuch nucleotides into metabolites like adenosine monophosphate (AMP) or adenosine, oftentimes in a sequential manner. CD39 and CD73 are a representativeset of coupled ectonucleotidases, where CD39 first converts ATP and adenosine diphosphate (ADP) into AMP, after which the AMP product is dephosphorylated into adenosine by CD73. Hence, CD39/CD73 help shape cellular responses to extracellular ATP. In a previous study [1] we demonstrated that the rates of coupled CD39/CD73 activity within synapse-like junctions are strongly controlled by the enzymes' co-localization, their surface charge densities, and the electrostatic potential of the surrounding cell membranes. In this study, we demonstrate that crowders within a synaptic junction, which can include globular proteins like cytokines and membrane-bound proteins, impact coupled CD39/CD73 electronucleotidase activity and in turn, the availability of intrasynapse ATP. Specifically, we simulated a spatially-explicit, reaction-diffusion model for the coupled conversion of ATP -> AMP and AMP -> adenosine in a model synaptic junction with crowders via the finite element method. Our modeling results suggest that the association rate for ATP to CD39 is strongly influenced by the density of intrasynaptic protein crowders, as increasing crowder density suppressed ATP association kinetics. Much of this suppression can be rationalized based on a loss of configurational entropy. The surface charges of crowders can further influence the association rate, with the surprising result that favorable crowder/nucleotide electrostatic interactions can yield CD39 association rates that are faster than crowder-free configurations. However, attractive crowder/nucleotide interactions decrease the rate and efficiency of adenosine production, which in turn increases the availability of ATP and AMP within the synapse relative to crowder-free configurations. These findings highlight how CD39/CD73 ectonucleotidase activity, electrostatics and crowding within synapses influence the availability of nucleotides for intercellular communication.

Exploring the kinetic selectivity of drugs targeting the β1-adrenoceptor

In this study, we report the β1-adrenoceptor binding kinetics of several clinically relevant β1/2-adrenoceptor (β1/2AR) agonists and antagonists. We demonstrate that the physicochemical properties of a molecule directly affect its kinetic association rate (kon) and affinity for the target. In contrast to our findings at the β2-adrenoceptor, a drug’s immobilized artificial membrane partition coefficient (KIAM), reflecting both hydrophobic and electrostatic interactions of the drug with the charged surface of biological membranes, was no better predictor than simple hydrophobicity measurements such as log P or logD7.4, characterized by a distribution between water and a non-aqueous organic phase (e.g. n-octanol) at predicting association rate. Overall, this suggests that hydrophobic interactions rather than a combination of polar and hydrophobic interactions play a more prominent role in dictating the binding of these ligands to the β1-adrenoceptor.Using a combination of kinetic data, detailed structural and physicochemical information we rationalize the above findings and speculate that the association of positively charged ligands at the β1AR is curtailed somewhat by its predominantly neutral/positive charged extracellular surface. Consequently, hydrophobic interactions in the ligand binding pocket dominate the kinetics of ligand binding. In comparison at the β2AR, a combination of hydrophobicity and negative charge attracts basic, positively charged ligands to the receptor’s surface promoting the kinetics of ligand binding. Additionally, we reveal the potential role kinetics plays in the on-target and off-target pharmacology of clinically used β-blockers.

A Geospatial Analysis of salmonellosis and its with socioeconomic status in Texas

Background: Social, behavioral, and environmental factors affect salmonellosis. The study's objective was to find the association between salmonellosis and socioeconomic status (SES) in hot spot areas and statewide counties. Methods: Retrospective county-level data on salmonellosis in 2017 were obtained from the Texas surveillance database. A statistically significant hot spot analysis identified high infection rates. We compared the socioeconomic status factors between hot and cold spot counties. We modeled zero-inflation negative binomial regression, and the final model's residual was tested for spatial clustering. Results: There were a total of 5113 salmonelloses from 254 counties with an unadjusted crude rate of 18 per 100,000 Person-year. Nine SES risk factors in the hot spot counties were as follows: low values of the severe housing problem, unemployment, African American, and high values of college education, social association rate, fast food/full-service restaurant use, Hispanic, and senior low access-to-store (P < 0.05). A 12% difference existed between local health departments in hot (25%) and cold spot (37%) counties (P = 0.81). Statewide independent risk factors were severe housing problem (IRR = 1.1; CI:1.05-1.14), social association rate (IRR = 0.89; CI:0.87-0.92), college education (IRR = 1.05; CI: 1.04-1.07), and non-Hispanic senior local access-to-store (IRR = 1.98; CI: 1.26-3.11). The severe housing problem predicted zero occurrences of infection in a county (OR = 0.51; CI: 0.28-0.95). Conclusions: Disparity exists in salmonellosis and socioeconomic status. Attention to unmet needs will decrease salmonellosis. A severe housing problem is a notable risk.

Determinants of COVID-19 Case Fatality Rate in the US: Spatial Analysis Over One Year of the Pandemic

Background: The United States continues to account for the highest proportion of the global Coronavirus Disease-2019 (COVID-19) cases and deaths. Currently, it is important to contextualize COVID-19 fatality to guide mitigation efforts. Objectives: The objective of this study was to assess the ecological factors (policy, health behaviors, socio-economic, physical environment, and clinical care) associated with COVID-19 case fatality rate (CFR) in the United States. Methods: Data from the New York Times’ COVID-19 repository and the Centers for Disease Control and Prevention Data (01/21/2020 - 02/27/2021) were used. County-level CFR was modeled using the Spatial Durbin model (SDM). The SDM estimates were decomposed into direct and indirect impacts. Results: The study found percent positive for COVID-19 (0.057% point), stringency index (0.014% point), percent diabetic (0.011% point), long-term care beds (log) (0.010% point), premature age-adjusted mortality (log) (0.702 % point), income inequality ratio (0.078% point), social association rate (log) (0.014% point), percent 65 years old and over (0.055% point), and percent African Americans (0.016% point) in a given county were positively associated with its COVID-19 CFR. The study also found food insecurity, long-term beds (log), mental health-care provider (log), workforce in construction, social association rate (log), and percent diabetic of a given county as well as neighboring county were associated with given county’s COVID-19 CFR, indicating significant externalities. Conclusion: The spatial models identified percent positive for COVID-19, stringency index, elderly, college education, race/ethnicity, residential segregation, premature mortality, income inequality, workforce composition, and rurality as important ecological determinants of the geographic disparities in COVID-19 CFR.

Assessing the Role of Calmodulin’s Linker Flexibility in Target Binding

Calmodulin (CaM) is a highly-expressed Ca2+ binding protein known to bind hundreds of protein targets. Its binding selectivity to many of these targets is partially attributed to the protein’s flexible alpha helical linker that connects its N- and C-domains. It is not well established how its linker mediates CaM’s binding to regulatory targets yet. Insights into this would be invaluable to understanding its regulation of diverse cellular signaling pathways. Therefore, we utilized Martini coarse-grained (CG) molecular dynamics simulations to probe CaM/target assembly for a model system: CaM binding to the calcineurin (CaN) regulatory domain. The simulations were conducted assuming a ‘wild-type’ calmodulin with normal flexibility of its linker, as well as a labile, highly-flexible linker variant to emulate structural changes that could be induced, for instance, by post-translational modifications. For the wild-type model, 98% of the 600 simulations across three ionic strengths adopted a bound complex within 2 μs of simulation time; of these, 1.7% sampled the fully-bound state observed in the experimentally-determined crystallographic structure. By calculating the mean-first-passage-time for these simulations, we estimated the association rate to be ka= 8.7 × 108 M−1 s−1, which is similar to the diffusion-limited, experimentally-determined rate of 2.2 × 108 M−1 s−1. Furthermore, our simulations recapitulated its well-known inverse relationship between the association rate and the solution ionic strength. In contrast, although over 97% of the labile linker simulations formed tightly-bound complexes, only 0.3% achieved the fully-bound configuration. This effect appears to stem from a difference in the ensembles of extended and collapsed states which are controlled by the linker flexibility. Therefore, our simulations suggest that variations in the CaM linker’s propensity for alpha helical secondary structure can modulate the kinetics of target binding.

A highly conserved 310 helix within the kinesin motor domain is critical for kinesin function and human health

KIF1A is a critical cargo transport motor within neurons. More than 100 known mutations result in KIF1A-associated neurological disorder (KAND), a degenerative condition for which there is no cure. A missense mutation, P305L, was identified in children diagnosed with KAND, but the molecular basis for the disease is unknown. We find that this conserved residue is part of an unusual 310 helix immediately adjacent to the family-specific K-loop, which facilitates a high microtubule-association rate. We find that the mutation negatively affects several biophysical parameters of the motor. However, the microtubule-association rate of the motor is most markedly affected, revealing that the presence of an intact K-loop is not sufficient for its function. We hypothesize that the 310 helix facilitates a specific K-loop conformation that is critical for its function. We find that the function of this proline is conserved in kinesin-1, revealing a fundamental principle of the kinesin motor mechanism.

Assessing the Role of CaM's Linker Flexibility in Target Binding

Calmodulin (CaM) is a universal calcium binding protein known to bind at least 300 targets. The selectivity and specificity towards these targets are partially attributed to the protein's flexible alpha-helical linker that connects its N- and C- domains. However, how this flexible linker mediates the driving forces guiding CaM's binding to regulatory targets is not well-established. Therefore, we utilized coarse-grained (CG) Martini molecular dynamics simulations to probe interrelationships between CaM/target assembly and the role of its linker region. As a model system, we simulated the binding of CaM to the CaM binding region (CaMBR) of calcineurin (CaN). The simulations were conducted assuming a 'wild-type' calmodulin with normal flexibility of its linker between the N- and C-terminal domains, as well as a labile, highly flexible linker variant. For the wild-type model, 98% of the 600 simulations across three ionic strengths adopted a tightly-bound complex within 2 μs of simulation time; of these, 1.7% sampled the fully-bound state observed in experimentally-determined crystallographic structure. By calculating the mean-first-passage-time for these simulations, we estimated the association rate to be ka =6.3×108 M −1 s−1, which is similar to the experimentally-determined rate of 2.2×108 M −1 s−1 (Cook et al 2020). Further, our simulations recapitulated the inverse relationship between the association rate and solution ionic strength reported in the literature. In contrast, although over 97% of the labile linker simulations formed tightly-bound complexes, only 0.3% achieved the fully-bound configuration and its ionic strength dependence is attenuated. These effects appear to stem from a difference in the ensembles of extended and collapsed states controlled by the linker properties. Specifically, the labile linker variant samples fewer extended states compatible with target peptide binding. Therefore, our simulations suggest that variations in the CaM linker's propensity for alpha-helical secondary structure can modulate the kinetics of target binding. This finding is important, given that some CaM variants found in the human population and post-translational modifications sites fall within this linker region, which may alter the protein's normal regulatory functions.

Long-term associations among male sperm whales (Physeter macrocephalus)

Little is known about the social structure of male sperm whales (Physeter macrocephalus) after they leave their natal units. While previous studies found no evidence for preferred associations among males, the observation of mass-strandings consisting exclusively of males, suggest that they have strong social bonds. To investigate the social associations among male sperm whales, we used half weight index of association, permutation tests and standardized lagged association rate models on a large photo-identification database collected between 2006 and 2017 in Nemuro Strait, Japan. Our results suggest that while male sperm whales are not as social as females, they do form long term associations, have preferred companionship, and forage in social proximity to each other. The best-fitting model to the standardized lagged association rate showed that associations among males last for at least 2.7 years and as most males leave the area after 2 years, associations may last for longer. Twenty dyads were observed associating over more than 2 years, for a maximum 5 years. One dyad was observed associating on 19 different days and clustered on 7 different days. Male associations may function to enhance foraging or to fend off predators. Such relationships seem to be adapted to a pelagic habitat with uncertain resource availability and predation pressure.