Reduced biceps femoris myoelectrical activity influences eccentric knee flexor weakness after repeat sprint running.

The aim of this study was to determine whether declines in knee flexor strength following overground repeat sprints were related to changes in hamstrings myoelectrical activity. Seventeen recreationally active men completed maximal isokinetic concentric and eccentric knee flexor strength assessments at 180°/s before and after repeat sprint running. Myoelectrical activity of the biceps femoris (BF) and medial hamstrings (MHs) was measured during all isokinetic contractions. Repeated measures mixed model [fixed factors = time (pre- and post-repeat sprint) and leg (dominant and nondominant), random factor = participants] design was fitted with the restricted maximal likelihood method. Repeat sprint running resulted in significant declines in eccentric, and concentric, knee flexor strength (eccentric = 26 ± 4 Nm, 15% P < 0.001; concentric 11 ± 2 Nm, 10% P < 0.001). Eccentric BF myoelectrical activity was significantly reduced (10%; P = 0.035). Concentric BF and all MH myoelectrical activity were not altered. The declines in maximal eccentric torque were associated with the change in eccentric BF myoelectrical activity (P = 0.013). Following repeat sprint running, there were preferential declines in the myoelectrical activity of the BF, which explained declines in eccentric knee flexor strength.

Identification of TB space-time clusters and hotspots in Ouest département, Haiti, 2011-2016.

BACKGROUND: Haiti has the highest incidence rate of TB in the Western Hemisphere, with an estimated 170 cases per 100,000 in 2019. Since 2010, control efforts have focused on targeted case-finding activities in urban areas, implementation of rapid molecular diagnostics at high-volume TB centers, and improved reporting. TB analyses are rarely focused on lower geographic units; thus, the major goal was to determine if there were focal areas of TB transmission from 2011 to 2016 at operational geographic levels useful for the National TB Control Program (PNLT). METHODS: We created a geocoder to locate TB cases at the smallest geographic level. Kulldorff's space-time permutation scan, Anselin Moran's I, and Getis-Ord Gi* statistics were used to determine the spatial distribution and clusters of TB. RESULTS: With 91% of cases linked using the geocoder, TB clusters were identified each year. Getis-Ord Gi* analysis revealed 14 distinct spatial clusters of high incidences in the Port-au-Prince metropolitan area. One hundred retrospective space-time clusters were detected. CONCLUSION: Our study confirms the presence of TB hotspots in the Ouest département, with most clusters in the Port-au-Prince metropolitan area. Results will help the PNLT and its partners better design case-finding strategies for these areas.

CONTEXTE: Haïti a le taux d'incidence le plus élevé de TB de l'hémisphère Ouest avec un nombre de cas estimé à 170 par 100 000 en 2019. Depuis 2010, les efforts de contrôle se sont focalisés sur des activités de recherche ciblée des cas dans les zones urbaines, la mise en œuvre de diagnostic moléculaire rapide dans des centres TB de grand volume et de meilleurs rapports. Les analyses TB sont rarement focalisées sur les unités géographiques; le but principal était de déterminer s'il existait des zones focales de transmission de la TB de 2011 à 2016 à des niveaux géographiques opérationnels utiles pour le Programme national de Lutte contre la TB (PNLT). MÉTHODES: Nous avons créé géocodeur pour localiser les cas de TB au plus petit niveau géographique. Le scan de permutation espace-temps de Kulldorff's, Anselin Moran's I et les statistiques de Getis-Ord Gi* ont été utilisés pour déterminer la distribution spatiale et les clusters de TB. RÉSULTATS: Avec 91% des cas liés avec le géocodeur, les clusters de TB ont été identifiés chaque année. L'analyse Getis-Ord Gi* a révélé 14 clusters spatiaux distincts d'incidence élevée dans la zone métropolitaine de Port-au-Prince. Cent clusters rétrospectifs espacetemps ont été détectés. CONCLUSION: Notre étude confirme la présence de hotspots TB dans la département Ouest, la majorité des clusters étant situés dans la zone métropolitaine de Port-au-Prince. Les résultats aideront le PNLT et ses partenaires à mieux affiner leurs stratégies de recherche des cas dans ces zones.

Analysis of breeding and pathology helps refine management practices of a large-scale N'-ethyl-N'-nitrosourea mouse mutagenesis programme.

N'-ethyl-N'-nitrosourea (ENU) is a powerful germline mutagen used in conjunction with phenotype-driven screens to generate novel mouse mutants. ENU also induces genetic lesions in somatic cells and dosage requires optimization between maximum germline mutation rate versus induced sterility and tumourigenesis that compromise the welfare and fecundity of the ENU-treated males. Here, we present our experience with BALB/cAnNCrl and C57BL/6J mice in terms of the pathology induced by ENU and its impact on breeding. In both mouse strains, morbidity and mortality rises with ENU dose. In more than 75% of C57BL/6J males, morbidity and mortality were attributable to the development of malignant T-lymphoblastic lymphoma. Approximately 50% of ENU-treated BALB/cAnNCrl males develop early malignant T-lymphoblastic lymphoma, but the cohort that survives develops late-onset lung carcinoma. Within strains, the latency of these clinically important tumour(s) was not dosage-dependent, but the proportion of mice developing tumours and consequently removed from the breeding programme increased with ENU dosage. The median number of offspring per ENU-treated C57BL/6J male in standard matings with C3H/HeH females decreased with increasing dosage. The two most important underlying causes for lower male fecundity were increased infertility in the highest dosage group and reduced numbers of litters born to the remaining fertile C57BL/6J males due to a higher incidence of morbidity. These findings have allowed us to refine breeding strategy. To maximize the number of offspring from each ENU-treated male, we now rotate productive males between two cages to expose them to more females. This optimizes the number of mutation carrying offspring while reducing the number of ENU-treated males that must be generated.

Genomic organization of mouse Capn5 and Capn6 genes confirms that they are a distinct calpain subfamily.

CAPN5 and CAPN6 are recently identified human and mouse genes lacking a calmodulin-like domain with homology to the calpain family of proteases. To clarify their relationship to the known calpains, we have compared their genomic organization and chromosome location with other human calpain gene family members. In the mouse, both genes have 11 introns of identical location, with 6 of these being similar in location to those of the known vertebrate members. Surprisingly, there were no splice junctions in common with the nematode gene tra-3, the calpain with highest homology to CAPN5 and CAPN6. CAPN5 is localized on human chromosome 11, closely linked to the mu-calpain gene CAPN1. CAPN6, which is expressed only in the placenta, is localized on the X chromosome, to which no other calpain has yet been mapped.

Expression of peptides encoded by exons in cloned mammalian DNA.

New synthetic approaches, such as combinatorial chemistry, provide a rich source of potential drug candidates. At the same time, the human genome initiative and other large-scale sequencing projects provide a large number of novel drug targets. However, the functional analysis of thousands of new genes remains a major challenge for the future. A systematic strategy for genome-wide functional analysis of genes could employ the fact that at least some modules in multi-domain proteins are encoded in individual exons. Exon amplification provides information about coding regions of most genes that is independent of their transcriptional status; exon amplification from entire mammalian genomes has been demonstrated. Here, we describe the development of an exon-trap system, lambdaGEE (for genomic exon expression), that couples exon amplification with the expression of exon-encoded peptides.

A new subfamily of vertebrate calpains lacking a calmodulin-like domain: implications for calpain regulation and evolution.

Calpains are calcium-dependent intracellular nonlysosomal proteases that are believed to participate in signal transduction. In vertebrates, five different calpains have so far been identified, of which three, mu-, m-, and mu/m-calpain, are ubiquitously expressed while the other two, nCL-1 (p94) and nCL-2, exhibit a restricted tissue distribution. We have identified two new vertebrate calpain genes, Capn5 and Capn6. The human and mouse amino acid sequences of these new calpains are the most divergent of the vertebrate calpains identified. They possess most of the residues conserved in calpain family members but the C-terminal region lacks any homology to the calmodulin-like domain of other vertebrate calpains. They both exhibit significant homology over the entire coding region to the protein encoded by the gene tra-3, involved in nematode sex determination, and Capn5 may represent its vertebrate orthologue. The predicted Capn6 protein lacks critical active site residues and may not be proteolytically active. Both genes are differentially expressed in human tissues with highest RNA levels for Capn5 occurring in the testis, liver, trachea, colon, and kidney, while Capn6 is highly expressed only in the placenta sample of the 50 tissues examined. Phylogenetic analysis suggests that the vertebrate calpains arose through a series of gene duplication events that began before the initial divergence of the vertebrate and invertebrate lineages. The discovery of these two new calpains highlights a hitherto unknown complexity of the calpain family with subclasses perhaps possessing different modes of regulation.

Molecular cloning of a zinc finger protein which binds to the heptamer of the signal sequence for V(D)J recombination.

The somatic V(D)J recombination for the assembly of the Ig and TCR genes is mediated by the recombination signal sequences (Rss) and the V(D)J recombinase. A cDNA clone was isolated from a lambda gt11 expression library made from mouse thymocyte poly(A)+ RNA, using the Rss as a ligand. The deduced amino acid sequence of the putative protein, designated Recognition component (Rc), reveals a pair of Cys2-His2 zinc fingers followed by a Glu- and Asp-rich acidic domain. In addition, there are five copies of the Ser/Thr-Pro-X-Arg/Lys sequence, which are putative DNA binding units. The zinc finger-acidic domain structures present in Rc are also found in several enhancer binding proteins, such as those for the kappa B motif of the Ig kappa light chain enhancer or related sequences. Bacterial fusion proteins for Rc bind preferentially to the Rss heptamer and to the kappa B motif. The dual affinities of Rc for the Rss heptamer and the kappa B motif suggest a possible link between Ig transcription and somatic recombination. The formation of multiple 'gel-shifted' DNA-protein complexes for Rc and its DNA ligand suggests that these complexes tend to multimerize.

HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.

A common chromosomal abnormality in childhood T-cell acute leukemia is a translocation, t(10;14) (q24;q11), that together with the variant t(7;10)(q35;q24) is present in up to 7% of this tumor type. The gene adjacent to the 10q24 region is transcriptionally activated after translocation to either TCRD (14q11) or TCRB (7q35). It encodes a homeobox gene closely related to the developmentally regulated homeotic genes of flies and mammals. The coding capacity of this activated gene, designated HOX11, is undisturbed in a T-cell line carrying the translocation t(7;10)(q35;q24). Therefore, the HOX11 homeobox gene seems to be involved in T-cell tumorigenesis.