Distinct RGK GTPases Differentially Use α1- and Auxiliary β-Binding-Dependent Mechanisms to Inhibit CaV1.2/CaV2.2 Channels

CaV1/CaV2 channels, comprised of pore-forming α1 and auxiliary (β,α2δ) subunits, control diverse biological responses in excitable cells. Molecules blocking CaV1/CaV2 channel currents (ICa) profoundly regulate physiology and have many therapeutic applications. Rad/Rem/Rem2/Gem GTPases (RGKs) strongly inhibit CaV1/CaV2 channels. Understanding how RGKs block ICa is critical for insights into their physiological function, and may provide design principles for developing novel CaV1/CaV2 channel inhibitors. The RGK binding sites within CaV1/CaV2 channel complexes responsible for ICa inhibition are ambiguous, and it is unclear whether there are mechanistic differences among distinct RGKs. All RGKs bind β subunits, but it is unknown if and how this interaction contributes to ICa inhibition. We investigated the role of RGK/β interaction in Rem inhibition of recombinant CaV1.2 channels, using a mutated β (β2aTM) selectively lacking RGK binding. Rem blocked β2aTM-reconstituted channels (74% inhibition) less potently than channels containing wild-type β2a (96% inhibition), suggesting the prevalence of both β-binding-dependent and independent modes of inhibition. Two mechanistic signatures of Rem inhibition of CaV1.2 channels (decreased channel surface density and open probability), but not a third (reduced maximal gating charge), depended on Rem binding to β. We identified a novel Rem binding site in CaV1.2 α1C N-terminus that mediated β-binding-independent inhibition. The CaV2.2 α1B subunit lacks the Rem binding site in the N-terminus and displays a solely β-binding-dependent form of channel inhibition. Finally, we discovered an unexpected functional dichotomy amongst distinct RGKs— while Rem and Rad use both β-binding-dependent and independent mechanisms, Gem and Rem2 use only a β-binding-dependent method to inhibit CaV1.2 channels. The results provide new mechanistic perspectives, and reveal unexpected variations in determinants, underlying inhibition of CaV1.2/CaV2.2 channels by distinct RGK GTPases

A Case Study for the Leadership Initiative for Supporting (Bilingual) Teacher Acquisition (LISTA)

This paper presents a qualitative pilot study program evaluation of the Leadership Initiative for Strategic (Bilingual) Teacher Acquisition (LISTA) program in a rural region of Texas. The LISTA program aimed to empower bilingual leaders in education by addressing the limited availability of leadership coaching, particularly tailored to recognize and affirm the cultural capital of Hispanic/Latino leaders. The sessions were organized and developed by an experienced leadership coach with a strong focus on equity and social justice in the education and nonprofit sectors. Through a methodology encompassing open-ended survey questions, focus groups, and reflective journals, this evaluation assesses the program\u27s impact on the participants and explores their experiences and perspectives within the LISTA program. The findings shed light on the effectiveness and potential improvements of the program, providing valuable insights for future iterations

Synteny analysis in Rosids with a walnut physical map reveals slow genome evolution in long-lived woody perennials.

BackgroundMutations often accompany DNA replication. Since there may be fewer cell cycles per year in the germlines of long-lived than short-lived angiosperms, the genomes of long-lived angiosperms may be diverging more slowly than those of short-lived angiosperms. Here we test this hypothesis.ResultsWe first constructed a genetic map for walnut, a woody perennial. All linkage groups were short, and recombination rates were greatly reduced in the centromeric regions. We then used the genetic map to construct a walnut bacterial artificial chromosome (BAC) clone-based physical map, which contained 15,203 exonic BAC-end sequences, and quantified with it synteny between the walnut genome and genomes of three long-lived woody perennials, Vitis vinifera, Populus trichocarpa, and Malus domestica, and three short-lived herbs, Cucumis sativus, Medicago truncatula, and Fragaria vesca. Each measure of synteny we used showed that the genomes of woody perennials were less diverged from the walnut genome than those of herbs. We also estimated the nucleotide substitution rate at silent codon positions in the walnut lineage. It was one-fifth and one-sixth of published nucleotide substitution rates in the Medicago and Arabidopsis lineages, respectively. We uncovered a whole-genome duplication in the walnut lineage, dated it to the neighborhood of the Cretaceous-Tertiary boundary, and allocated the 16 walnut chromosomes into eight homoeologous pairs. We pointed out that during polyploidy-dysploidy cycles, the dominant tendency is to reduce the chromosome number.ConclusionSlow rates of nucleotide substitution are accompanied by slow rates of synteny erosion during genome divergence in woody perennials

The zinc finger transcription factor PLAGL2 enhances stem cell fate and activates expression of ASCL2 in intestinal epithelial cells

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Age specificity in explicit and implicit endorsement of prescriptive age stereotypes

In this study, we investigated explicit and implicit endorsement of prescriptive age stereotypes . To achieve that, we captured endorsement of a wide range of prescriptive expectations targeting both younger (younger adults are expected to be ambitious, eager to learn, unconventional, respectful) and older (older adults are expected to stay active, to be generous, dignified, and wise) people. Younger ( n = 58, 50% female, M age = 26.07 years, SD = 3.01) and older adults ( n = 75, 44% female, M age = 66.69 years, SD = 4.63) participated in the study. We assessed implicit endorsement of prescriptive age stereotypes with the Propositional Evaluation Paradigm (PEP) and used a direct measure to assess explicit endorsement. In general, we found strong support for age-specificity in both explicit and implicit endorsement of prescriptive age stereotypes: Sentences ascribing expectations for young/old to the respective age group (e.g., “young should be ambitious”; “old should be wise”) were endorsed much more strongly than sentences in which expectations for young/old were ascribed to the other age group (e.g., “old should be ambitious”; “young should be wise”). Age group differences in the endorsement of prescriptive age stereotypes were found. Compared to younger participants, older participants showed stronger endorsement for prescriptive beliefs targeting both younger and older targets. Explicit and implicit endorsement of prescriptive age stereotypes did not correlate with one another, thus revealing they might assess independent belief systems with different predictive potential

OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.

BackgroundMitochondrial fusion protein mutations are a cause of inherited neuropathies such as Charcot-Marie-Tooth disease and dominant optic atrophy. Previously we reported that the fusion protein optic atrophy 1 (OPA1) is decreased in heart failure.Methods and resultsWe investigated cardiac function, mitochondrial function, and mtDNA stability in a mouse model of the disease with OPA1 mutation. The homozygous mutation is embryonic lethal. Heterozygous OPA(+/-) mice exhibit reduced mtDNA copy number and decreased expression of nuclear antioxidant genes at 3 to 4 months. Although initial cardiac function was normal, at 12 months the OPA1(+/-) mouse hearts had decreased fractional shortening, cardiac output, and myocyte contraction. This coincided with the onset of blindness. In addition to small fragmented mitochondria, aged OPA1(+/-) mice had impaired cardiac mitochondrial function compared with wild-type littermates.ConclusionsOPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late-onset cardiomyopathy

U-Scores for Multivariate Data In Sports

In many sport competitions athletes, teams, or countries are evaluated based on several variables. The strong assumptions underlying traditional ‘linear weight’ scoring systems (that the relative importance, interactions and linearizing transformations of the variables are known) can often not be justified on theoretical grounds, and empirical ‘validation’ of weights, interactions and transformations, is problematic when a ‘gold standard’ is lacking. With μ-scores (u-scores for multivariate data) one can integrate information even if the variables have different scales and unknown interactions or if the events counted are not directly comparable, as long as the variables have an ‘orientation’. Using baseball as an example, we discuss how measures based on μ-scores can complement the existing measures for ‘performance’ (which may depend on the situation) by providing the first multivariate measures for ‘ability’ (which should be independent of the situation). Recently, μ-scores have been extended to situations where count variables are graded by importance or relevance, such as medals in the Olympics (Wittkowski 2003) or Tour-de-France jerseys (Cherchye and Vermeulen 2006, 2007). Here, we present extensions to ‘censored’ variables (life-time achievements of active athletes), penalties (counting a win more than two ties) and hierarchically structured variables (Nordic, alpine, outdoor, and indoor Olympic events). The methods presented are not restricted to sports. Other applications of the method include medicine (adverse events), finance (risk analysis), social choice theory (voting), and economy (long-term profit)

Reassessment of the evolution of wheat chromosomes 4A, 5A, and 7B.

Key messageComparison of genome sequences of wild emmer wheat and Aegilops tauschii suggests a novel scenario of the evolution of rearranged wheat chromosomes 4A, 5A, and 7B. Past research suggested that wheat chromosome 4A was subjected to a reciprocal translocation T(4AL;5AL)1 that occurred in the diploid progenitor of the wheat A subgenome and to three major rearrangements that occurred in polyploid wheat: pericentric inversion Inv(4AS;4AL)1, paracentric inversion Inv(4AL;4AL)1, and reciprocal translocation T(4AL;7BS)1. Gene collinearity along the pseudomolecules of tetraploid wild emmer wheat (Triticum turgidum ssp. dicoccoides, subgenomes AABB) and diploid Aegilops tauschii (genomes DD) was employed to confirm these rearrangements and to analyze the breakpoints. The exchange of distal regions of chromosome arms 4AS and 4AL due to pericentric inversion Inv(4AS;4AL)1 was detected, and breakpoints were validated with an optical Bionano genome map. Both breakpoints contained satellite DNA. The breakpoints of reciprocal translocation T(4AL;7BS)1 were also found. However, the breakpoints that generated paracentric inversion Inv(4AL;4AL)1 appeared to be collocated with the 4AL breakpoints that had produced Inv(4AS;4AL)1 and T(4AL;7BS)1. Inv(4AS;4AL)1, Inv(4AL;4AL)1, and T(4AL;7BS)1 either originated sequentially, and Inv(4AL;4AL)1 was produced by recurrent chromosome breaks at the same breakpoints that generated Inv(4AS;4AL)1 and T(4AL;7BS)1, or Inv(4AS;4AL)1, Inv(4AL;4AL)1, and T(4AL;7BS)1 originated simultaneously. We prefer the latter hypothesis since it makes fewer assumptions about the sequence of events that produced these chromosome rearrangements

Mutation signature analysis identifies increased mutation caused by tobacco smoke associated DNA adducts in larynx squamous cell carcinoma compared with oral cavity and oropharynx.

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts