Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function

Mutations in the human LIS1 gene cause type I lissencephaly, a severe brain developmental disease involving gross disorganization of cortical neurons. In lower eukaryotes, LIS1 participates in cytoplasmic dynein-mediated nuclear migration. We previously reported that mammalian LIS1 functions in cell division and coimmunoprecipitates with cytoplasmic dynein and dynactin. We also localized LIS1 to the cell cortex and kinetochores of mitotic cells, known sites of dynein action. We now find that the COOH-terminal WD repeat region of LIS1 is sufficient for kinetochore targeting. Overexpression of this domain or full-length LIS1 displaces CLIP-170 from this site without affecting dynein and other kinetochore markers. The NH2-terminal self-association domain of LIS1 displaces endogenous LIS1 from the kinetochore, with no effect on CLIP-170, dynein, and dynactin. Displacement of the latter proteins by dynamitin overexpression, however, removes LIS1, suggesting that LIS1 binds to the kinetochore through the motor protein complexes and may interact with them directly. We find that of 12 distinct dynein and dynactin subunits, the dynein heavy and intermediate chains, as well as dynamitin, interact with the WD repeat region of LIS1 in coexpression/coimmunoprecipitation and two-hybrid assays. Within the heavy chain, interactions are with the first AAA repeat, a site strongly implicated in motor function, and the NH2-terminal cargo-binding region. Together, our data suggest a novel role for LIS1 in mediating CLIP-170–dynein interactions and in coordinating dynein cargo-binding and motor activities

Coastal Subsistence, Maritime Trade, and the Colonization of Small Offshore Islands in Eastern African Prehistory

Recent archaeological research has firmly established eastern Africa's offshore islands as important localities for understanding the region's pre-Swahili maritime adaptations and early Indian Ocean trade connections. While the importance of the sea and small offshore islands to the development of urbanized and mercantile Swahili societies has long been recognized, the formative stages of island colonization—and in particular the processes by which migrating Iron Age groups essentially became “maritime”—are still relatively poorly understood. Here we present the results of recent archaeological fieldwork in the Mafia Archipelago, which aims to understand these early adaptations and situate them within a longer-term trajectory of island settlement and pre-Swahili cultural developments. We focus on the results of zooarchaeological, archaeobotanical, and material culture studies relating to early subsistence and trade on this island to explore the changing significance of marine resources to the local economy. We also discuss the implications of these maritime adaptations for the development of local and long-distance Indian Ocean trade networks

Coastal subsistence, maritime trade, and the colonization of small offshore islands in eastern African prehistory

Recent archaeological research has firmly established eastern Africa’s offshore islands as important localities for understanding the region’s pre-Swahili maritime adaptations and early Indian Ocean trade connections. While the importance of the sea and small offshore islands to the development of urbanized and mercantile Swahili societies has long been recognized, the formative stages of island colonization—and in particular the processes by which migrating Iron Age groups essentially became “maritime”—are still relatively poorly understood. Here we present the results of recent archaeological fieldwork in the Mafia Archipelago, which aims to understand these early adaptations and situate them within a longer-term trajectory of island settlement and pre-Swahili cultural developments. We focus on the results of zooarchaeological, archaeobotanical, and material culture studies relating to early subsistence and trade on this island to explore the changing significance of marine resources to the local economy. We also discuss the implications of these maritime adaptations for the development of local and long-distance Indian Ocean trade networks.The Sealinks Project is funded through a grant toNicole Boivin from the European Research Council (StarterGrant 206148) under the “Ideas” specific Programme of the 7th Framework Programme (FP7). Additional funding includes: postdoctoral fellowships from the British Academy (2010–2013) and the University of Queensland (2015–2017) to Alison Crowther; a Fondation Fyssen Postdoctoral Grant toEr´endira Quintana Morales; and a postdoctoral fellowship from the Government of the Balearic Islands (Conselleria d’Educaci´o) and the European Social Fund to Llorenc¸ Picornell-Gelabert. Fieldwork was carried out under COSTECH Research Permit no. 2012-303-ER-2011-85 and the Division of Antiquities (Ministry of Natural Resources and Tourism, Tanzania) excavation license no. EA.402/605/01 issued to Alison Crowther, and with the support and permission of theRegionalAdministrative Secretary (Dar es Salaam andCoast/Pwani), the District Administrative Secretary (Mafia), and the Village Executive Officer (Mtendaji wa Kijiji, Juani).http://www.tandfonline.com/loi/uica20hb2016Anthropology and Archaeolog

Coastal subsistence, maritime trade, and the colonization of small offshore islands in eastern African prehistory

Recent archaeological research has firmly established eastern Africa’s offshore islands as important localities for understanding the region’s pre-Swahili maritime adaptations and early Indian Ocean trade connections. While the importance of the sea and small offshore islands to the development of urbanized and mercantile Swahili societies has long been recognized, the formative stages of island colonization—and in particular the processes by which migrating Iron Age groups essentially became “maritime”—are still relatively poorly understood. Here we present the results of recent archaeological fieldwork in the Mafia Archipelago, which aims to understand these early adaptations and situate them within a longer-term trajectory of island settlement and pre-Swahili cultural developments. We focus on the results of zooarchaeological, archaeobotanical, and material culture studies relating to early subsistence and trade on this island to explore the changing significance of marine resources to the local economy. We also discuss the implications of these maritime adaptations for the development of local and long-distance Indian Ocean trade networks.The Sealinks Project is funded through a grant toNicole Boivin from the European Research Council (StarterGrant 206148) under the “Ideas” specific Programme of the 7th Framework Programme (FP7). Additional funding includes: postdoctoral fellowships from the British Academy (2010–2013) and the University of Queensland (2015–2017) to Alison Crowther; a Fondation Fyssen Postdoctoral Grant toEr´endira Quintana Morales; and a postdoctoral fellowship from the Government of the Balearic Islands (Conselleria d’Educaci´o) and the European Social Fund to Llorenc¸ Picornell-Gelabert. Fieldwork was carried out under COSTECH Research Permit no. 2012-303-ER-2011-85 and the Division of Antiquities (Ministry of Natural Resources and Tourism, Tanzania) excavation license no. EA.402/605/01 issued to Alison Crowther, and with the support and permission of theRegionalAdministrative Secretary (Dar es Salaam andCoast/Pwani), the District Administrative Secretary (Mafia), and the Village Executive Officer (Mtendaji wa Kijiji, Juani).http://www.tandfonline.com/loi/uica20hb2016Anthropology and Archaeolog

Compositional analysis of bacterial communities in seawater, sediment, and sponges in the Misool coral reef system, Indonesia

Sponge species have been deemed high microbial abundance (HMA) or low microbial abundance (LMA) based on the composition and abundance of their microbial symbionts. In the present study, we evaluated the richness and composition of bacterial communities associated with one HMA sponge (Xestospongia testudinaria; Demospongiae: Haplosclerida: Petrosiidae), one LMA sponge (Stylissa carteri; Demospongiae: Scopalinida - Scopalinidae), and one sponge with a hitherto unknown microbial community (Aaptos suberitoides; Demospongiae: Suberitida: Suberitidae) inhabiting the Misool coral reef system in the West Papua province of Indonesia. The bacterial communities of these sponge species were also compared with seawater and sediment bacterial communities from the same coastal coral reef habitat. Using a 16S rRNA gene barcoded pyrosequencing approach, we showed that the most abundant phylum overall was Proteobacteria. The biotope (sponge species, sediment or seawater) explained almost 84% of the variation in bacterial composition with highly significant differences in composition among biotopes and a clear separation between bacterial communities from seawater and S. carteri; X. testudinaria and A. suberitoides and sediment. The Chloroflexi classes SAR202 and Anaerolineae were most abundant in A. suberitoides and X. testudinaria and both of these species shared several OTUs that were largely absent in the remaining biotopes. This suggests that A. suberitoides is a HMA sponge. Although similar, the bacterial communities of S. carteri and seawater were compositionally distinct. These results confirm compositional differences between sponge and non-sponge biotopes and between HMA and LMA sponges.publishe

An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis