Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human.

A variety of genes have been identified that specify the synthesis of the components of guanine nucleotide-binding proteins (G proteins). Eight different guanine nucleotide-binding alpha-subunit proteins, two different beta subunits, and one gamma subunit have been described. Hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids was used to assign many of these genes to human chromosomes. The retinal-specific transducin subunit genes GNAT1 and GNAT2 were on chromosomes 3 and 1; GNAI1, GNAI2, and GNAI3 were assigned to chromosomes 7, 3, and 1, respectively; GNAZ and GNAS were found on chromosomes 22 and 20. The beta subunits were also assigned--GNB1 to chromosome 1 and GNB2 to chromosome 7. Restriction fragment length polymorphisms were used to map the homologues of some of these genes in the mouse. GNAT1 and GNAI2 were found to map adjacent to each other on mouse chromosome 9 and GNAT2 was mapped on chromosome 17. The mouse GNB1 gene was assigned to chromosome 19. These mapping assignments will be useful in defining the extent of the G alpha gene family and may help in attempts to correlate specific genetic diseases with genes corresponding to G proteins.     

A Systematic Review of the Correlates of Violence Against Sex Workers

We conducted a systematic review in June 2012 (updated September 2013) to examine the prevalence and factors shaping sexual or physical violence against sex workers globally.We identified 1536 (update = 340) unique articles. We included 28 studies, with 14 more contributing to violence prevalence estimates. Lifetime prevalence of any or combined workplace violence ranged from 45% to 75% and over the past year, 32% to 55%. Growing research links contextual factors with violence against sex workers, alongside known interpersonal and individual risks.This high burden of violence against sex workers globally and large gaps in epidemiological data support the need for research and structural interventions to better document and respond to the contextual factors shaping this violence. Measurement and methodological innovation, in partnership with sex work communities, are critical.Frequent reports of incidents of widespread violence against sex workers continue to emerge globally,1–3 including media reports of abuse, human rights violations, and murder.4–7 Despite increasing recognition of violence in the general population as a public health and human rights priority by policymakers, researchers, and international bodies,8–10 violence against sex workers that occurs within and outside the context of sex work is frequently overlooked in international agendas to prevent violence. Although increasing research has explored the prevalence, determinants, and correlates of violence against women,8,11–14 comparable research specifically among sex workers is lacking. There remains limited review of the magnitude, severity, or type of violence experienced by sex workers globally. This paucity of data on prevalence and incidence of violence against sex workers has been highlighted in a review on the magnitude and scope of violence globally.15Negative health effects of intimate partner violence in the general population include poor health overall, physical and sexual injury, and mental health problems including depression, anxiety, and posttraumatic stress disorder.16–21 Intimate partner violence faced by women in the general population has also been linked to unwanted pregnancy, abortion, and increased risk for HIV and other sexually transmitted infections (STIs), through different direct and indirect mechanisms.22–26 Victims of violence in early childhood are also more likely to have increased risk for HIV and other STIs.27 However, the role of violence, both workplace violence and violence by intimate or other nonpaying partners, in influencing negative health outcomes among sex workers, who are highly stigmatized and often criminalized, has received comparably less attention.The legal status of sex work can be a critical factor in shaping patterns of violence against sex workers.1,28 In many settings, the criminalized or quasicriminalized nature of sex work means that violence that occurs in the context of sex work (i.e., as a workplace harm and abuse) is not monitored by any formal bodies, with few to no legal protections afforded to sex workers by police and judicial systems.1,28 Violence against sex workers is often not registered as an offense by the police and in some cases is perpetrated by police.29,30 Physical and sexual violence, and verbal abuse or threats of abuse from police, can prevent sex workers from reporting violence to the police or accessing other public agencies (e.g., health or social services), exacerbating their trauma and health risks.1,29,30 These risks include the risk for HIV and other STIs, and in some settings, threats of arrest for possession of condoms as evidence of engaging in sex work can deter sex workers from carrying condoms.30–32 This can create a climate of tolerance of violence and thereby perpetuate violence against sex workers.We conducted a systematic review to examine the documented magnitude of violence against sex workers and to review the factors that shape risk for violence against sex workers. In our review we were guided by theoretical frameworks that implicate structural factors in shaping vulnerabilities experienced by vulnerable populations.33–35 Within the interrelated physical, social, economic, and policy environments, factors operate to create different levels of susceptibility and risk.33–35 The current review provides an evidence base pertaining to violence against sex workers from which to better inform the development of public health and social interventions to reduce violence and ameliorate its impacts on sex workers.     

Femoral specializations to locomotor habits in early archosauriforms

The evolutionary history of archosaurs and their closest relatives is characterized by a wide diversity of locomotor modes, which has even been suggested as a pivotal aspect underlying the evolutionary success of dinosaurs vs. pseudosuchians across the Triassic–Jurassic transition. This locomotor diversity (e.g., more sprawling/erect; crouched/upright; quadrupedal/bipedal) led to several morphofunctional specializations of archosauriform limb bones that have been studied qualitatively as well as quantitatively through various linear morphometric studies. However, differences in locomotor habits have never been studied across the Triassic–Jurassic transition using 3D geometric morphometrics, which can relate how morphological features vary according to biological factors such as locomotor habit and body mass. Herein, we investigate morphological variation across a dataset of 72 femora from 36 different species of archosauriforms. First, we identify femoral head rotation, distal slope of the fourth trochanter, femoral curvature, and the angle between the lateral condyle and crista tibiofibularis as the main features varying between bipedal and quadrupedal taxa, all of these traits having a stronger locomotor signal than the lesser trochanter''s proximal extent. We show a significant association between locomotor mode and phylogeny, but with the locomotor signal being stronger than the phylogenetic signal. This enables us to predict locomotor modes of some of the more ambiguous early archosauriforms without relying on the relationships between hindlimb and forelimb linear bone dimensions as in prior studies. Second, we highlight that the most important morphological variation is linked to the increase of body size, which impacts the width of the epiphyses and the roundness and proximodistal position of the fourth trochanter. Furthermore, we show that bipedal and quadrupedal archosauriforms have different allometric trajectories along the morphological variation in relation to body size. Finally, we demonstrate a covariation between locomotor mode and body size, with variations in femoral bowing (anteroposterior curvature) being more distinct among robust femora than gracile ones. We also identify a decoupling in fourth trochanter variation between locomotor mode (symmetrical to semi‐pendant) and body size (sharp to rounded). Our results indicate a similar level of morphological disparity linked to a clear convergence in femoral robusticity between the two clades of archosauriforms (Pseudosuchia and Avemetatarsalia), emphasizing the importance of accounting for body size when studying their evolutionary history, as well as when studying the functional morphology of appendicular features. Determining how early archosauriform skeletal features were impacted by locomotor habits and body size also enables us to discuss the potential homoplasy of some phylogenetic characters used previously in cladistic analyses as well as when bipedalism evolved in the avemetatarsalian lineage. This study illuminates how the evolution of femoral morphology in early archosauriforms was functionally constrained by locomotor habit and body size, which should aid ongoing discussions about the early evolution of dinosaurs and the nature of their evolutionary “success” over pseudosuchians.     

The N-terminal end of the CH2 domain of chimeric human IgG1 anti-HLA-DR is necessary for C1q, Fc gamma RI and Fc gamma RIII binding.

We have found that amino acid residues necessary for C1q and Fc gamma R binding of human IgG1 are located in the N-terminal region of the CH2 domain, residues 231-238, using a matched set of engineered antibodies based on the anti-HLA-DR antibody L243. Changing the leucine 235 in the CH2 region of IgG3 and IgG4 to glutamic acid was already known to abolish Fc gamma RI binding. We have confirmed this for IgG1 and also found a concomitant abolition of human complement lysis with retention of Fc gamma RIII-mediated function. Changing the glycine at 237 to alanine of IgG1 also abolished Fc gamma RI binding and reduced human complement lysis and Fc gamma RIII-mediated function. Exchanging the whole region 233-236 with the sequence found in human IgG2, abolished Fc gamma RI binding and human complement lysis and reduced Fc gamma RIII-mediated function of IgG1. In contrast, a change in the previously described C1q-binding motif, from lysine at 320 to alanine, had no effect on IgG1-mediated complement lysis.     

Nanoparticle-mediated Gene Silencing Confers Radioprotection to Salivary Glands In Vivo

Radiation treatment of head and neck cancers causes irreversible damage of the salivary glands (SG). Here, we introduce a preclinical mouse model for small-interfering RNA (siRNA)-based gene silencing to provide protection of SG from radiation-induced apoptosis. Novel, pH-responsive nanoparticles complexed with siRNAs were introduced into mouse submandibular glands (SMG) by retroductal injection to modulate gene expression in vivo. To validate this approach, we first targeted Nkcc1, an ion transporter that is essential for saliva secretion. Nkcc1 siRNA delivery resulted in efficient knockdown, as quantified at the mRNA and the protein levels, and the functional result of Nkcc1 knockdown phenocopied the severe decrease in saliva secretion, characteristic of the systemic Nkcc1 gene knockout. To establish a strategy to prevent apoptotic cell loss due to radiation damage, siRNAs targeting the proapoptotic Pkcδ gene were administered into SMG before ionizing radiation. Knockdown of Pkcδ not only reduced the number of apoptotic cells during the acute phase of radiation damage, but also markedly improved saliva secretion at 3 months in irradiated animals, indicating that this treatment confers protection from hyposalivation. These results demonstrate that nanoparticle delivery of siRNAs targeting a proapoptotic gene is a localized, nonviral, and effective means of conferring radioprotection to the SGs.     

痛

黑暗!黑暗!!黑暗!!!这样的世界看不到半点光明。孤独的舞者终究还是孤独地倒下,然后又孤独地消失。黑暗呀,为什么老是缠绕着我?一声“妈妈”划破了天际,却也突不出黑暗的包围。谁来应我一声呀,妈妈,你在哪里呀?我的心在不停地挣扎,告诉自己:“不怕,不怕。”可这是在黑暗里呀,周