The rockefeller university

Hybridization in ants can have consequences different from those observed in most other species, with many of the potential deleterious effects being mitigated due to haplodiploidy and eusociality. In some species where colonies are either headed by multiple queens or single queens that mate with many males, hybridization is associated with genetic caste determination, where hybrids develop into workers and purebred individuals develop into queens. A previous study suggested that hybridization occurs between two Dorylus army ant species with multiply mated queens. However, the extent and exact pattern of hybridization have remained unclear, and its possible effect on caste determination has not been investigated. In this study, we aimed to determine the extent and direction of hybridization by measuring how frequently hybrids occur in colonies of both species, and to investigate the possibility of genetic caste determination. We show that hybridization is bidirectional and occurs at equal rates in both species. Hybrid workers make up only 1-2% of the population, and successful interspecific matings represent approximately 2% of all matings in both species. This shows that, although interspecific matings that give rise to worker offspring occur regularly, they are much rarer than intraspecific mating. Finally, we find no evidence of an association between hybridization and genetic caste determination in this population. This means that genetic caste determination is not a necessary outcome of hybridization in ants, even in species where queens mate with multiple males.

Immunodeficient mice transplanted with human cell populations or tissues, also known as human immune system (HIS) mice, have emerged as an important and versatile tool for the in vivo study of human immunodeficiency virus-type 1 (HIV-1) pathogenesis, treatment, and persistence in various biological compartments. Recent work in HIS mice has demonstrated their ability to recapitulate critical aspects of human immune responses to HIV-1 infection, and such studies have informed our knowledge of HIV-1 persistence and latency in the context of combination antiretroviral therapy. The central nervous system (CNS) is a unique, immunologically privileged compartment susceptible to HIV-1 infection, replication, and immune-mediated damage. The unique, neural, and glia-rich cellular composition of this compartment, as well as the important role of infiltrating cells of the myeloid lineage in HIV-1 seeding and replication makes its study of paramount importance, particularly in the context of HIV-1 cure research. Current work on the replication and persistence of HIV-1 in the CNS, as well as cells of the myeloid lineage thought to be important in HIV-1 infection of this compartment, has been aided by the expanded use of these HIS mouse models. In this review, we describe the major HIS mouse models currently in use for the study of HIV-1 neuropathogenesis, recent insights from the field, limitations of the available models, and promising advances in HIS mouse model development.

Phagocytosis of dying cells is critical in development and immunity(1-3). Although proteins for recognition and engulfment of cellular debris following cell death are known(4,5), proteins that directly mediate phagosome sealing are uncharacterized. Furthermore, whether all phagocytic targets are cleared using the same machinery is unclear. Degeneration of morphologically complex cells, such as neurons, glia and melanocytes, produces phagocytic targets of various shapes and sizes located in different microenvironments(6,7). Thus, such cells offer unique settings to explore engulfment programme mechanisms and specificity. Here, we report that dismantling and clearance of a morphologically complex Caenorhabditis elegans epithelial cell requires separate cell soma, proximal and distal process programmes. Similar compartment-specific events govern the elimination of a C. elegans neuron. Although canonical engulfment proteins drive cell soma clearance, these are not required for process removal. We find that EFF-1, a protein previously implicated in cell-cell fusion(8), specifically promotes distal process phagocytosis. EFF-1 localizes to phagocyte pseudopod tips and acts exoplasmically to drive phagosome sealing. eff-1 mutations result in phagocytosis arrest with unsealed phagosomes. Our studies suggest universal mechanisms for dismantling morphologically complex cells and uncover a phagosome-sealing component that promotes cell process clearance.

Charge-dependent azimuthal correlations of same-and opposite-sign pairs with respect to the second-and third-order event planes have been measured in pPb collisions at root s(NN) = 8.16 TeV and PbPb collisions at 5.02 TeV with the CMS experiment at the LHC. The measurement is motivated by the search for the charge separation phenomenon predicted by the chiral magnetic effect (CME) in heavy ion collisions. Three-and two-particle azimuthal correlators are extracted as functions of the pseudorapidity difference, the transverse momentum (p(T)) difference, and the p(T) average of same-and opposite-charge pairs in various event multiplicity ranges. The data suggest that the charge-dependent three-particle correlators with respect to the second-and third-order event planes share a common origin, predominantly arising from charge-dependent two-particle azimuthal correlations coupled with an anisotropic flow. The CME is expected to lead to a v(2)-independent three-particle correlation when the magnetic field is fixed. Using an event shape engineering technique, upper limits on the v(2)-independent fraction of the three-particle correlator are estimated to be 13% for pPb and 7% for PbPb collisions at 95% confidence level. The results of this analysis, both the dominance of two-particle correlations as a source of the three-particle results and the similarities seen between PbPb and pPb, provide stringent constraints on the origin of charge-dependent three-particle azimuthal correlations and challenge their interpretation as arising from a chiral magnetic effect in heavy ion collisions.

Atopic dermatitis (AD) and psoriasis are inflammatory skin diseases that negatively affect patients' quality of life. Although distinctions exist between these diseases, both are characterized by erythematous, thickened epidermal lesions that vary in intensity and affected body surface area. Early models of aetiology attributed symptoms of both diseases to cutaneous inflammation at lesion sites, but recent studies have established that activated immune mediators in the circulation drive disease severity. Activation of T helper 2 (Th2) and Th22 cells in the circulation appears to be the principal initiator of acute AD pathology, with the emergence of Th1 and Th17/interleukin (IL)-23 pathway activation marking the transition to a chronic state. The Th17/IL-23 pathway also has an important role in psoriasis. The role of systemic inflammation in AD and psoriasis is supported by the occurrence of non-cutaneous comorbidities that affect patients, most of which intensify morbidity and disability associated with lesional skin. Atopic dermatitis is associated with allergic disorders consisting of the atopic march, whereas psoriasis is frequently accompanied by psoriatic arthritis. Patients with both disorders are at significantly higher risk of obesity, metabolic disorders, and cardiovascular diseases, all of which feature inflammatory components in their pathology models. These insights have led to novel therapeutics aimed at addressing psoriasis by targeting tumor necrosis factor- and Th17-related cytokine pathways. The success of these agents in psoriasis management is driving new therapeutic approaches for moderate-to-severe AD, including agents targeting the Th2 and Th17/Th22 cytokine pathways.

Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Depistage et de Traitement de la Lepre et de l'Ulcere de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.

The NMDA (N-methyl-d-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel(1). Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.

Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide(1). In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates(2,3). As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Gu,rin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-gamma immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30). Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect. This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.