Absolute Proper Motions to B~22.5: V. Detection of Sagittarius Dwarf Spheroidal Debris in the Direction of the Galactic Anticenter

We have detected a population of predominantly blue (B-V <= 1.1) stars in the direction l = 167 deg., b = -35 deg. (Kapteyn Selected Area 71) that cannot be accounted for by standard starcount models. Down to V ~ 20, the colors and magnitudes of these stars are similar to those of the southern overdensity detected by the Sloan Digital Sky Survey, and identified as stripped material from the Sagittarius dwarf spheroidal galaxy. We present absolute proper motions for the stars in SA 71, and we find that the excess blue stars represent a distinct, kinematically cooler component than the Galactic field, and in reasonable agreement with predictions of Sgr disruption models. The density of the excess SA 71 stars at V ~ 18.8 and B-V <=1.1 is within a factor of two of the density of the SDSS-south Sgr stripped material, and of that predicted by the Helmi and White disruption model. Three additional anticenter fields (SA 29, 45 and 118) show very good agreement with standard starcount models.Comment: 13 pages, 3 figures, submitted to ApJL, accepted for Ap

Sex-Biased Evolutionary Forces Shape Genomic Patterns of Human Diversity

Comparisons of levels of variability on the autosomes and X chromosome can be used to test hypotheses about factors influencing patterns of genomic variation. While a tremendous amount of nucleotide sequence data from across the genome is now available for multiple human populations, there has been no systematic effort to examine relative levels of neutral polymorphism on the X chromosome versus autosomes. We analyzed ∼210 kb of DNA sequencing data representing 40 independent noncoding regions on the autosomes and X chromosome from each of 90 humans from six geographically diverse populations. We correct for differences in mutation rates between males and females by considering the ratio of within-human diversity to human-orangutan divergence. We find that relative levels of genetic variation are higher than expected on the X chromosome in all six human populations. We test a number of alternative hypotheses to explain the excess polymorphism on the X chromosome, including models of background selection, changes in population size, and sex-specific migration in a structured population. While each of these processes may have a small effect on the relative ratio of X-linked to autosomal diversity, our results point to a systematic difference between the sexes in the variance in reproductive success; namely, the widespread effects of polygyny in human populations. We conclude that factors leading to a lower male versus female effective population size must be considered as important demographic variables in efforts to construct models of human demographic history and for understanding the forces shaping patterns of human genomic variability

White matter plasticity in healthy older adults: The effects of aerobic exercise

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer\u27s disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60-79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter

Damage to the prefrontal cortex increases utilitarian moral judgements

The psychological and neurobiological processes underlying moral judgement have been the focus of many recent empirical studies1–11. Of central interest is whether emotions play a causal role in moral judgement, and, in parallel, how emotion-related areas of the brain contribute to moral judgement. Here we show that six patients with focal bilateral damage to the ventromedial prefrontal cortex (VMPC), a brain region necessary for the normal generation of emotions and, in particular, social emotions12–14, produce an abnor- mally ‘utilitarian’ pattern of judgements on moral dilemmas that pit compelling considerations of aggregate welfare against highly emotionally aversive behaviours (for example, having to sacrifice one person’s life to save a number of other lives)7,8. In contrast, the VMPC patients’ judgements were normal in other classes of moral dilemmas. These findings indicate that, for a selective set of moral dilemmas, the VMPC is critical for normal judgements of right and wrong. The findings support a necessary role for emotion in the generation of those judgements

Overexpression of sICAM-1 in the Alveolar Epithelial Space Results in an Exaggerated Inflammatory Response and Early Death in Gram Negative Pneumonia

Abstract Background A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM-1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection. Methods Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM-1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae. Results SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM-1 mice compared with wild-type mice but there were no difference in lung CFU between groups. Conclusions We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.http://deepblue.lib.umich.edu/bitstream/2027.42/112728/1/12931_2010_Article_1038.pd

Co-infection with Pansensitive and Multidrug-Resistant Strains of Mycobacterium tuberculosis

We report a case of a 23-year-old HIV-negative man with multidrug-resistant Mycobacterium tuberculosis that became evident while he was being treated for M. tuberculosis that was sensitive to all first-line drugs. This case should alert clinicians to consider co-infection as a possible cause of recrudescent disease

CPEB4–CLOCK crosstalk during temporal lobe epilepsy

Objective: Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood. Methods: Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high-performance liquid chromatography in plasma. Results: Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day. Significance: Our results reveal a new positive transcriptional–translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep–wake cycle during epilepsy.H2020 Marie Skłodowska-Curie Actions, Grant/Award Number:766124 and 796600; Irish Research Council, Grant/Award Number:GOIPD/2020/806; Programa de Atracción de Talento de la Comunidad de Madrid, Grant/Award Number: 2020-T2/BMD- 20180; Science Foundation Ireland, Grant/Award Number:16/RC/3948 and 17/CDA/4708;Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities, Grant/Award Number: PID2021- 123141OB- I0

A complex of BRCA2 and PP2A-B56 is required for DNA repair by homologous recombination

Mutations in the tumour suppressor gene BRCA2 are associated with predisposition to breast and ovarian cancers. BRCA2 has a central role in maintaining genome integrity by facilitating the repair of toxic DNA double-strand breaks (DSBs) by homologous recombination (HR). BRCA2 acts by controlling RAD51 nucleoprotein filament formation on resected single-stranded DNA, but how BRCA2 activity is regulated during HR is not fully understood. Here, we delineate a pathway where ATM and ATR kinases phosphorylate a highly conserved region in BRCA2 in response to DSBs. These phosphorylations stimulate the binding of the protein phosphatase PP2A-B56 to BRCA2 through a conserved binding motif. We show that the phosphorylation-dependent formation of the BRCA2-PP2A-B56 complex is required for efficient RAD51 filament formation at sites of DNA damage and HR-mediated DNA repair. Moreover, we find that several cancer-associated mutations in BRCA2 deregulate the BRCA2-PP2A-B56 interaction and sensitize cells to PARP inhibition. Collectively, our work uncovers PP2A-B56 as a positive regulator of BRCA2 function in HR with clinical implications for BRCA2 and PP2A-B56 mutated cancers

First circumglobal assessment of Southern Hemisphere humpback whale mitochondrial genetic variation and implications for management

The description of genetic population structure over a species\u27 geographic range can provide insights into its evolutionary history and also support effective management efforts. Assessments for globally distributed species are rare, however, requiring significant international coordination and collaboration. The global distribution of demographically discrete populations for the humpback whale Megaptera novaeangliae is not fully known, hampering the definition of appropriate management units. Here, we present the first circumglobal assessment of mito - chondrial genetic population structure across the species\u27 range in the Southern Hemisphere and Arabian Sea. We combine new and existing data from the mitochondrial (mt)DNA control region that resulted in a 311 bp consensus sequence of the mtDNA control region for 3009 individuals sampled across 14 breeding stocks and subpopulations currently recognized by the International Whaling Commission. We assess genetic diversity and test for genetic differentiation and also estimate the magnitude and directionality of historic matrilineal gene flow between putative populations. Our results indicate that maternally directed site fidelity drives significant genetic population structure between breeding stocks within ocean basins. However, patterns of connectivity differ across the circumpolar range, possibly as a result of differences in the extent of longitudinal movements on feeding areas. The number of population comparisons observed to be significantly differentiated were found to diminish at the subpopulation scale when nucleotide differences were examined, indicating that more complex processes underlie genetic structure at this scale. It is crucial that these complexities and uncertainties are afforded greater consideration in management and regulatory efforts