Influence of Tertiary paleoenvironmental changes on the diversification of South American mammals: a relaxed molecular clock study within xenarthrans

Background  

Comparative genomic data among organisms allow the reconstruction of their phylogenies and evolutionary time scales. Molecular timings have been recently used to suggest that environmental global change have shaped the evolutionary history of diverse terrestrial organisms. Living xenarthrans (armadillos, anteaters and sloths) constitute an ideal model for studying the influence of past environmental changes on species diversification. Indeed, extant xenarthran species are relicts from an evolutionary radiation enhanced by their isolation in South America during the Tertiary era, a period for which major climate variations and tectonic events are relatively well documented.     

Proliferative activity in the cerebellar external granular layer evaluated by bromodeoxyuridine labeling

We have optimised an indirect immunoperoxidase technique demonstrating bromodeoxyuridine (BrdU) incorporation into dividing cells for cerebellar tissue sections of four-day-old rats injected with this marker. This permits confident identification of granule-cell precursors engaged in DNA synthesis in the external granular layer of the developing cerebellum. Preservation of BrdU immunoreactivity is attained using methanol/acetic acid fixation and different pretreatments before immunostaining, while unlabeled nuclei can be recognized clearly after Feulgen or hematoxylin counterstaining. We established conditions to ensure satisfactory BrdU uptake without affecting cell-cycle progression during the postlabeling time period. The dose of BrdU employed provides saturation S-phase labeling from at least 1 h after BrdU delivery. Various kinetic parameters and phase durations have been determined in experiments involving a single injection or cumulative labeling sequences, and the cycle time was calculated based on two models of generative behavior: steady-state and exponential growth. The working hypothesis of steadystate kinetics can be adopted successfully if the existence of neuroblasts with different proliferation rates is taken into account.     

Changes in the associations of race and rurality with SARS-CoV-2 infection,mortality, and case fatality in the United States from February 2020 to March 2021: A population-based cohort study

BackgroundWe examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study.Methods and findingsIn a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value <0.001), mortality (AOR 3.85 [95% CI 3.30 to 4.50], p-value < 0.001), and case fatality (AOR 2.56, 95% CI 2.23 to 2.93, p-value < 0.001) in February to March 2020, but these associations were attenuated and not statistically significant by November 2020 for infection (AOR 1.03 [95% CI 1.00 to 1.07] p-value = 0.05) and mortality (AOR 1.08 [95% CI 0.96 to 1.20], p-value = 0.21) and were reversed for case fatality (AOR 0.86, 95% CI 0.78 to 0.95, p-value = 0.005). American Indian/Alaska Native (AI/AN versus White) race was associated with higher risk of SARS-CoV-2 infection in April and May 2020; this association declined over time and reversed by March 2021 (AOR 0.66 [95% CI 0.51 to 0.85] p-value = 0.004). Hispanic (versus non-Hispanic) ethnicity was associated with higher risk of SARS-CoV-2 infection and mortality during almost every time period, with no evidence of attenuation over time. Urban (versus rural) residence was associated with higher risk of infection (AOR 2.02, [95% CI 1.83 to 2.22], p-value < 0.001), mortality (AOR 2.48 [95% CI 2.08 to 2.96], p-value < 0.001), and case fatality (AOR 2.24, 95% CI 1.93 to 2.60, p-value < 0.001) in February to April 2020, but these associations attenuated over time and reversed by September 2020 (AOR 0.85, 95% CI 0.81 to 0.89, p-value < 0.001 for infection, AOR 0.72, 95% CI 0.62 to 0.83, p-value < 0.001 for mortality and AOR 0.81, 95% CI 0.71 to 0.93, p-value = 0.006 for case fatality). Throughout the observation period, high comorbidity burden, younger age, and obesity were consistently associated with infection, while high comorbidity burden, older age, and male sex were consistently associated with mortality. Limitations of the study include that changes over time in the associations of some risk factors may be affected by changes in the likelihood of testing for SARS-CoV-2 according to those risk factors; also, study results apply directly to VA enrollees who are predominantly male and have comprehensive healthcare and need to be confirmed in other populations.ConclusionsIn this study, we found that strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality observed early in the pandemic were ameliorated or reversed by March 2021.

George Ioannou and co-workers study the distribution of SARS-CoV-2 infections and outcomes among the United States population.     

Concomitant disorder and high‐affinity zinc binding in the human zinc‐ and iron‐regulated transport protein 4 intracellular loop

The human zinc‐ and iron‐regulated transport protein 4 (hZIP4) protein is the major plasma membrane protein responsible for the uptake of zinc in the body, and as such it plays a key role in cellular zinc homeostasis. hZIP4 plasma membrane levels are regulated through post‐translational modification of its large, disordered, histidine‐rich cytosolic loop (ICL2) in response to intracellular zinc concentrations. Here, structural characteristics of the isolated disordered loop region, both in the absence and presence of zinc, were investigated using nuclear magnetic resonance (NMR) spectroscopy. NMR chemical shifts, coupling constants and temperature coefficients of the apoprotein, are consistent with a random coil with minor propensities for transient polyproline Type II helices and β‐strand in regions implicated in post‐translational modifications. The ICL2 protein remains disordered upon zinc binding, which induces exchange broadening. Paramagnetic relaxation enhancement experiments reveal that the histidine‐rich region in the apoprotein makes transient tertiary contacts with predicted post‐translational modification sites. The residue‐specific data presented here strengthen the relationship between hZIP4 post‐translational modifications, which impact its role in cellular zinc homeostasis, and zinc sensing by the intracellular loop. Furthermore, the zinc sensing mechanism employed by the ICL2 protein demonstrates that high‐affinity interactions can occur in the presence of conformational disorder.     

A new AluI satellite DNA in the root-knot nematode Meloidogyne fallax: relationships with satellites from the sympatric species M. hapla and M. chitwoodi

A highly abundant satellite DNA comprising 20% of the Meloidogyne fallax (Nematoda, Tylenchida) genome was cloned and sequenced. The satellite monomer is 173 bp long and has a high A + T content of 72.3%, with frequent runs of A's and T's. The sequence variability of the monomers is 2.7%, mainly due to random distribution of single-point mutations. A search for evidence of internal repeated subunits in the monomer sequence revealed a 6-bp motif (AAATTT) for which five degenerated repeats, differing by just a single base pair, could be identified. Pairwise comparison of the M. fallax satellite with those from the sympatric species Meloidogyne chitwoodi and Meloidogyne hapla revealed a high sequence similarity (68.39%) with one satellite DNA subfamily in M. chitwoodi, which indicated an unexpected close relationship between them. Given the high copy number and the extreme sequence homogeneity among monomeric units, it may be assumed that the satellite DNA of M. fallax could have evolved through some recent and extensive amplification burst in the nematode genome. In this case, its relatively short life would not yet have allowed the accumulation of random mutations in independent amplified repeats. Considering the morphological resemblance between the two species and their ability to produce interspecific fertile hybrids under controlled conditions, these results indicate that M. fallax may share a common ancestor with M. chitwoodi, from which it could have diverged recently. All these data suggest that M. fallax could be the result of a recent speciation process and show that Meloidogyne satellite DNAs may be of interest to resolve phylogenetic relationships among closely related species from this genus.      

Can Zipf's law be adapted to normalize microarrays?

Background  

Normalization is the process of removing non-biological sources of variation between array experiments. Recent investigations of data in gene expression databases for varying organisms and tissues have shown that the majority of expressed genes exhibit a power-law distribution with an exponent close to -1 (i.e. obey Zipf's law). Based on the observation that our single channel and two channel microarray data sets also followed a power-law distribution, we were motivated to develop a normalization method based on this law, and examine how it compares with existing published techniques. A computationally simple and intuitively appealing technique based on this observation is presented.     

Stability of loops in the structure of lactose permease

Structural analysis of peptide fragments has provided useful information on the secondary structure of integral membrane proteins built from a helical bundle (up to seven transmembrane segments). Comparison of those results to recent X-ray crystallographic results showed agreement between the structures of the fragments and the structures of the intact proteins. Lactose permease of Escherichia coli (lac Y) offers an opportunity to test that hypothesis on a substantially larger integral membrane protein. Lac Y contains a bundle of 12 transmembrane segments connected by 11 loops. Eleven segments, each corresponding to one of the loops in this protein, were studied. Five of these segments form defined structures in solution as determined by multidimensional nuclear magnetic resonance. Four peptides form turns, and one peptide reveals the end of one of the transmembrane helices. These results suggest that some loops in helical bundles are stabilized by short-range interactions, particularly in smaller bundles, and such intrinsically stable loops may contribute to protein stability and influence the pathway of folding. Greater conformational flexibility may be found in large integral membrane proteins.