The Acquired Immunodeficiency Syndrome in New England: An Epidemiological Review of the First Six Years

Between 1981 and 1987 — the six-year period following initial recognition of the acquired immunodeficiency syndrome (AIDS) — 1,475 cases were reported among residents of the six New England states. Of nearly 40,000 cases nationwide, 3.8 percent occurred among New England residents, though the region \u27s population represents 5.5 percent ofthe total United States population. The groups most affected include homosexual or bisexual men (65 percent) and intravenous drug users (20 percent). However, in the two southernmost states — Rhode Island and Connecticut — 32 to 40 percent of all cases have used intravenous drugs. In these states, the male:female ratio of adult cases is 6:1, compared to 12:1 in the remainder of the region. In Massachusetts, the disease incidence rate is equivalent to that of Connecticut (144 cases per 1 million population); however, a greater proportion of cases (69 percent versus 45 percent) are homosexual and bisexual men, and the incidence rate for adult females is lower (49 versus 100 cases/million). Maine, New Hampshire, and Vermont have low cumulative incidence rates (\u3c50 cases/million), and no cases among adult females or associated with blood transfusion. In northern New England, 2 percent of adults with AIDS became infected through heterosexual contact, compared to 10 percent in the southern half of the region. Sources of other data, resulting from serologic testing for human immunodeficiency virus (HIV), confirm the predominance of infection in southern New England. Rates of HIV seropositivity in military recruits, blood donors, and specific high-risk populations are uniformly lower in New England than in high-incidence regions. This review is based on statistics provided by AIDS surveillance programs operated by the Departments of Public Health in the six New England states

Event review: Center for American Archeology Flintknapping Workshop with Tim Dillard, Kampsville, Illinois, U.S.A.

Center for American Archeology Flintknapping Workshop with Tim Dillard, Kampsville, Illinois, USA. May 2014

Ubiquitin-driven protein condensation stabilizes clathrin-mediated endocytosis.

Clathrin-mediated endocytosis is an essential cellular pathway that enables signaling and recycling of transmembrane proteins and lipids. During endocytosis, dozens of cytosolic proteins come together at the plasma membrane, assembling into a highly interconnected network that drives endocytic vesicle biogenesis. Recently, multiple groups have reported that early endocytic proteins form flexible condensates, which provide a platform for efficient assembly of endocytic vesicles. Given the importance of this network in the dynamics of endocytosis, how might cells regulate its stability? Many receptors and endocytic proteins are ubiquitylated, while early endocytic proteins such as Eps15 contain ubiquitin-interacting motifs. Therefore, we examined the influence of ubiquitin on the stability of the early endocytic protein network. In vitro, we found that recruitment of small amounts of polyubiquitin dramatically increased the stability of Eps15 condensates, suggesting that ubiquitylation could nucleate endocytic assemblies. In live-cell imaging experiments, a version of Eps15 that lacked the ubiquitin-interacting motif failed to rescue defects in endocytic initiation created by Eps15 knockout. Furthermore, fusion of Eps15 to a deubiquitylase enzyme destabilized nascent endocytic sites within minutes. In both in vitro and live-cell settings, dynamic exchange of Eps15 proteins, a measure of protein network stability, was decreased by Eps15-ubiquitin interactions and increased by loss of ubiquitin. These results collectively suggest that ubiquitylation drives assembly of the flexible protein network responsible for catalyzing endocytic events. More broadly, this work illustrates a biophysical mechanism by which ubiquitylated transmembrane proteins at the plasma membrane could regulate the efficiency of endocytic internalization

Semisynthetic Neoclerodanes as Kappa Opioid Receptor Probes

Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors

Length of stay and determinants of early discharge after facility-based childbirth in Cameroon: analysis of the 2018 Demographic and Health Survey.

BACKGROUND: A minimum length of stay following facility birth is a prerequisite for women and newborns to receive the recommended monitoring and package of postnatal care. The first postnatal care guidelines in Cameroon were issued in 1998 but adherence to minimum length of stay has not been assessed thus far. The objective of this study was to estimate the average length of stay and identify determinants of early discharge after facility birth. METHODS: We analyzed the Cameroon 2018 Demographic and Health Survey. We included 4,567 women who had a live birth in a heath facility between 2013 and 2018. We calculated their median length of stay in hours by mode of birth and the proportion discharged early (length of stay < 24 h after vaginal birth or < 5 days after caesarean section). We assessed the association between sociodemographic, context-related, facility-related, obstetric and need-related factors and early discharge using bivariate and multivariable logistic regression. RESULTS: The median length of stay (inter quartile range) was 36 (9-84) hours after vaginal birth (n = 4,290) and 252 (132-300) hours after caesarean section (n = 277). We found that 28.8% of all women who gave birth in health facilities were discharged too early (29.7% of women with vaginal birth and 15.1% after a caesarean section). Factors which significantly predicted early discharge in multivariable regression were: maternal age < 20 years (compared to 20-29 years, aOR: 1.44; 95%CI 1.13-1.82), unemployment (aOR: 0.78; 95%CI: 0.63-0.96), non-Christian religions (aOR: 1.65; 95CI: 1.21-2.24), and region of residence-Northern zone aOR:9.95 (95%CI:6.53-15.17) and Forest zone aOR:2.51 (95%CI:1.79-3.53) compared to the country's capital cities (Douala or Yaounde). None of the obstetric characteristics was associated with early discharge. CONCLUSIONS: More than 1 in 4 women who gave birth in facilities in Cameroon were discharged too early; this mostly affected women following vaginal birth. The reasons leading to lack of adherence to postnatal care guidelines should be better understood and addressed to reduce preventable complications and provide better support to women and newborns during this critical period

Entrapment of Viral Capsids in Nuclear PML Cages Is an Intrinsic Antiviral Host Defense against Varicella-Zoster Virus

The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML-NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins