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SAMHD1 is a key regulator of dNTP metabolism, being activated by dGTP and converting dNTPs into their respective nucleosides. As a result, it plays a significant role in several distinct diseases. Not only is SAMHD1 a restriction factor for HIV-1 replication, which requires dNTPs for replication, but it is also required for genome stability, is mutated in multiple cancers, and loss of function mutations cause Acardi-Goutières Syndrome, an early-onset inherited encephalopathy. In this paper we knock out the SAMHD1 gene in pluripotent stem cells, and show that it also affects nucleoside analogue sensitivity of dividing cells and deoxyguanosine toxicity in a cell cycle-independent manner. Comparing wild type and gene-edited macrophages, we also show that deoxyguanosine toxicity is associated with pro-inflammatory cell death, modifications in uric acid production and the formation of monosodium urate crystals within the macrophages. These novel features of the SAMHD1−/− phenotype provide unique insights into the aetiology of Acardi-Goutières Syndrome, and have implications for certain chemotherapeutic agents.

Two new species, Abantiades concordia sp. nov. and Abantiades malleus sp. nov., are described from Australia. Both species were collected in the Eastern Goldfields subregion of the Coolgardie bioregion in Western Australia. Abantiades concordia sp. nov. is shown to be closely related to A. paradoxa (Tindale, 1932) by sequence similarity of the mtDNA (COI) gene. The female of A. paradoxa is also described here for the first time. Abantiades paradoxa and the new species A. concordia sp. nov. are morphologically similar with respect to the structure of their genitalia, sternite VIII, wing patterning and their antennae with bi-forked rami. Abantiades malleus sp. nov. is quite distinct by sequence similarity of the mtDNA (COI) gene, but related in a clade with A. marcidus Tindale,1932, A. albofasciatus (Swinhoe, 1892), and A. furva (Tindale,1932), the latter species once placed in the synonymised Bordaia Tindale, 1932. Discussion of similar species once grouped under the genus Bordaia and under the genus Trictena Meyrick, 1890 (both junior synonyms of Abantiades Herrich-Schäffer, 1855) is also included.

The diversity and abundance of native invertebrates is declining globally, which could have significant consequences for ecosystem functioning. Declines are likely to be at least as severe as those observed for vertebrates, although often are difficult to quantify due to a lack of historic baseline data and limited monitoring effort. The Lepidoptera are well studied in Australia compared with other invertebrates, so we know that some species are imperilled or declining. Despite this, few butterfly taxa are explicitly listed for protection by legislation. Here we aim to identify the butterfly taxa that would most benefit from listing by determining the Australian butterflies at most immediate risk of extinction. We also identify the research and management actions needed to retain them. For 26 taxa identified by experts and various conservation schedules, we used structured expert elicitation to estimate the probability of extinction within 20 years (i.e. by 2040) and to identify key threatening processes, priority research and management needs. Collation and analysis of expert opinion indicated that one taxon, the laced fritillary (Argynnis hyperbius inconstans), is particularly imperilled, and that four taxa (Jalmenus eubulus, Jalmenus aridus, Hypochrysops piceatus and Oreisplanus munionga larana) have a moderate–high (>30%) risk of extinction by 2040. Mapped distributions of the 26 butterflies revealed that most are endemic to a single state or territory, and that many occupy narrow ranges. Inappropriate fire regimes, habitat loss and fragmentation (through agricultural practices), invasive species (mostly through habitat degradation caused by weeds and rabbits) and climate change were the most prevalent threats affecting the taxa considered. Increased resourcing and management intervention will be required to prevent these extinctions. We provide specific recommendations for averting such losses.

Abantiades penneshawensis Moore & Beaver sp. nov. and Abantiades rubrus Moore & Beaver sp. nov. are described as new. Both species are endemic to Kangaroo Island, and although both are related to species that occur on the Australian mainland and other islands, they are distinguished from those sister and phenotypically similar species by morphology and mtDNA (COI) barcodes. These two new species raise the number of Abantiades species on Kangaroo Island to six, three being endemic, and 45 species in the genus for the whole of Australia. There are now 13 species of Hepialidae (one undescribed) known from Kangaroo Island and we discuss the potential effects of recent catastrophic fire on some distributions.

The brown pansy, Junonia stygia (Aurivillius, 1894) (Lepidoptera: Nymphalidae), is a widespread West African forest butterfly. Genome skimming by Illumina sequencing allowed assembly of a complete 15,233 bp circular mitogenome from J. stygia consisting of 79.5% AT nucleotides. Mitochondrial gene order and composition is identical to other butterfly mitogenomes. Junonia stygia COX1 features an atypical CGA start codon, while ATP6, COX1, COX2, ND4, and ND4L exhibit incomplete stop codons. Phylogenetic reconstruction supports a monophyletic Subfamily Nymphalinae, Tribe Junoniini, and genus Junonia. The phylogenetic tree places Junonia iphita and J. stygia as basal mitogenome lineages sister to the remaining Junonia sequences.

Author(s): Moore, Michael; Dilcher, Brian; Minardi, Joseph; Quedado, Kimberly; Shaver, Erica | Abstract: Introduction: Dyspnea is commonly evaluated in the emergency department (ED).The differential diagnosis is broad. Due to the large volume of dyspneic patients evaluated, emergency physicians (EP) will encounter uncommon diagnoses. Early, liberal application of point-of-care ultrasound (POCUS) may decrease diagnostic error and improve care for these patients.Case Report: We report a 48-year-old male presenting to the ED with cough and progressively worsening dyspnea for 11 months after multiple healthcare visits. Using POCUS, the EP was immediately able to diagnose a severe dilated cardiomyopathy (DCM) with left ventricular thrombus.Conclusion: Given that non-ischemic DCM is one of the most common etiologies of heart failure, often presenting with respiratory symptoms, POCUS is key to rapid diagnosis and, along with modalities such as electrocardiography and chest radiograph, should be standard practice in the workup of dyspnea, regardless of age or comorbidities.

A distinct group of Abantiades Herrich-Schäffer species is here confirmed as a valid clade that we refer to as the “dark obscura clade” supported by morphological and mtDNA evidence. The clade is the sister group of A. obscura Simonsen of north-western Australia and comprises four new species: Abantiades centralia sp. nov., A. kayi sp. nov., A. zonatriticum sp. nov., and A. hutchinsoni sp. nov. These species together with A. obscura, are reciprocally allopatric and have a combined distribution spanning much of the western half of Australia and this distribution is consistent with their each differentiating locally from a widespread ancestor. The four new species raise the diversity of Abantiades to 42 species. [Zoobank urn:lsid:zoobank.org:pub:C05458D1-0D34-4432-8EC4-D031ED6B7BEF]

Refereed/Peer-reviewed Abantiades cephalocorvus sp. nov. and Abantiades tembyi sp. nov. are described, along with the previously undescribed females of A. macropusinsulariae Simonsen, 2018 and A. pallida Simonsen, 2018. All of these species belong to a triforked Abantiades Herrich-Schäffer clade that is loosely centred around the Nullarbor and other arid regions of Australia. We explore DNA barcodes (mtDNA COI gene) from these and other Abantiades and discuss their significance for species recognition. The species distributions are entirely or largely allopatric and we discuss their origins from a widespread common ancestor that was likely distributed over inland and coastal regions in the mid- to late-Mesozoic before the onset of desertification. Notes on new distributional data for all of the known species in this clade are included.

Four new Aenetus Herrich-Schäffer species are described from northern Australasia; Aenetus simonseni sp. nov. from the top-end of the Northern Territory, Australia, A. maiasinus sp. nov. from the Kimberley region of Western Australia, A. trigonogrammus sp. nov. from south-eastern Queensland, Australia, and A. albadamanteum sp. nov. from eastern Papua New Guinea. Aenetus simonseni sp. nov. and A. maiasinus sp. nov. appear to belong to the tegulatus-group of species (sensu Grehan et al. 2018), A. trigonogrammus sp. nov. is part of the splendens-group of species (sensu Simonsen 2018), while A. albadamanteum sp. nov. shares morphological similarities with A. hampsoni (Joicey & Noakes, 1914), A. crameri Viette, 1956, and A. toxopeusi Viette, 1956, from New Guinea, and A. cohici Viette, 1961 from New Caledonia. The four new species are illustrated and compared with superficially similar species in morphology and, for two species, molecular (mtDNA COI gene) sequences.

Seasonal surface freshening of the Makassar Strait, the main conduit of the Indonesian Throughflow (ITF), is a key factor controlling the ITF. Here we present a 262 year reconstruction of seasonal sea-surface-salinity variability from 1742 to 2004 Common Era by using coral δ18O records from the central Makassar Strait. Our record reveals persistent seasonal freshening and also years with significant truncations of seasonal freshening that correlate exactly with South Pacific Convergence Zone (SPCZ) zonal events >4000 km to the east. During these events, the SPCZ dramatically rotates ~15° north to near the equator and stronger westward flowing South Pacific boundary currents force higher-salinity water through the Makassar Strait in February–May halting the normal seasonal freshening in the strait. By these teleconnections, our Makassar coral δ18O series provides the first record of the recurrence interval of these zonal SPCZ events and demonstrates that they have occurred on a semiregular basis since the mid-1700s.

We analyse COI sequence data from 140 specimens of the Australian ‘tripectinate-Abantiades’ to explore the group's molecular diversity and identify potential taxonomic challenges for future studies. A recent taxonomic revision raised the number of species in the group from three to 10. Our results generally agree with that study, but we identify further potential new species. However, our results also highlight the limitations of single gene taxonomic studies as some otherwise well-defined species are non-monophyletic in our analyses – in particular Abantiades argentata Tindale appears paraphyletic with respect to several other lineages, and may comprise more than one species. Overall, the mitochondrial COI diversity of the ‘tripectinate-Abantiades’ can be divided into three major groups, with a majority of the species found in the semi-arid regions of South Australia and Western Australia Refereed/Peer-reviewed

In this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFα-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MΦ) and progressive loss of iPS-MΦ production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases.

Recent studies of post-war chronic disease epidemiology have generally focused on the histories of research in the USA and UK. Using the archival records of a major British funding body, the Colonial Medical Research Committee and its successor the Tropical Medical Research Board, this article demonstrates the advantages of bringing a post-colonial analytic to this historiography. It highlights how the administrative and medical interests in population difference at the centre of the new epidemiology came to map onto political apparatus initially created to know, reform and govern colonial subjects. Although detached from imperial aims, British medical scientists nonetheless attached value to colonial populations on the basis of British benefit and turned various sites into laboratories to extract it. This relationship did not die with the end of imperial rule. British scientists continued to pursue chronic disease epidemiology in former colonies well into the post-war period, informing debates about Britain's own public health concerns.

Protease activity within nascently released human immunodeficiency virus type 1 (HIV-1) particles is responsible for the cleavage of the viral polyproteins Gag and Gag–Pol into their constituent parts, which results in the subsequent condensation of the mature conical core surrounding the viral genomic RNA. Concomitant with viral maturation is a conformational change in the packaged viral RNA from a loosely associated dimer into a more thermodynamically stable form. In this study we used suboptimal concentrations of two protease inhibitors, lopinavir and atazanavir, to study their effects on Gag polyprotein processing and on the properties of the RNA in treated virions. Analysis of the treated virions demonstrated that even with high levels of inhibition of viral infectivity (IC 90 ), most of the Gag and Gag–Pol polyproteins were processed, although slight but significant increases in processing intermediates of Gag were detected. Drug treatments also caused a significant increase in the proportion of viruses displaying either immature or aberrant mature morphologies. The aberrant mature particles were characterized by an electron-dense region at the viral periphery and an electron-lucent core structure in the viral center, possibly indicating exclusion of the genomic RNA from these viral cores. Intriguingly, drug treatments caused only a slight decrease in overall thermodynamic stability of the viral RNA dimer, suggesting that the dimeric viral RNA was able to mature in the absence of correct core condensation.

Recombination is a major force for generating human immunodeficiency virus type 1 (HIV-1) diversity and produces numerous recombinants circulating in the human population. We previously established a cell-based system using green fluorescent protein gene (gfp) as a reporter to study the mechanisms of HIV-1 recombination. We now report an improved system capable of detecting recombination using authentic viral sequences. Frameshift mutations were introduced into the gag gene so that parental viruses do not express full-length Gag; however, recombination can generate a progeny virus that expresses a functional Gag. We demonstrate that this Gag reconstitution assay can be used to detect recombination between two group M HIV-1 variants of the same or of different subtypes. Using both gfp and gag assays, we found that, similar to group M viruses, group O viruses also recombine frequently. When recombination between a group M virus and a group O virus was examined, we found three distinct barriers for intergroup recombination. First, similar to recombination within group M viruses, intergroup recombination is affected by the identity of the dimerization initiation signal (DIS); variants with the same DIS recombined at a higher rate than those with different DIS. Second, using the gfp recombination assay, we showed that intergroup recombination occurs much less frequently than intragroup recombination, even though the gfp target sequence is identical in all viruses. Finally, Gag reconstitution between variants from different groups is further reduced compared with green fluorescent protein, indicating that sequence divergence interferes with recombination efficiency in the gag gene. Compared with identical sequences, we estimate that recombination rates are reduced by 3-fold and by 10- to 13-fold when the target regions in gag contain 91% and 72-73% sequence identities, respectively. These results show that there are at least three distinct mechanisms preventing exchange of genetic information between divergent HIV-1 variants from different groups.

RNA-based drugs are an emerging class of therapeutics. They have the potential to regulate proteins, chromatin, as well as bind to specific proteins of interest in the form of aptamers. These aptamers are protected from nuclease attack by chemical modifications that enhance their stability for in vivo usage. However, nucleases are ubiquitous, and as we have yet to characterize the entire human microbiome it is likely that many nucleases are yet to be identified. Any novel, unusual enzymes present in vivo might reduce the efficacy of RNA-based therapeutics, even when they are chemically modified. We have previously identified an RNA-based aptamer capable of neutralizing a broad spectrum of clinical HIV-1 isolates and are developing it as a vaginal and rectal microbicide candidate. As a first step we addressed aptamer stability in the milieu of proteins present in these environments. Here we uncover a number of different nucleases that are able to rapidly degrade 2′-F-modified RNA. We demonstrate that the aptamer can be protected from the nuclease(s) present in the vaginal setting, without affecting its antiviral activity, by replacement of key positions with 2′-O-Me-modified nucleotides. Finally, we show that the aptamer can be protected from all nucleases present in both vaginal and rectal compartments using Zn2+ cations. In conclusion we have derived a stable, antiviral RNA-based aptamer that could form the basis of a pre-exposure microbicide or be a valuable addition to the current tenofovir-based microbicide candidate undergoing clinical trials.

To use advanced powder X-ray diffraction (PXRD) to characterize the structure of anhydrous theophylline following compaction, alone, and as part of a binary mixture with either alpha-lactose monohydrate or microcrystalline cellulose.Compacts formed from (1) pure theophylline and (2) each type of binary mixture were analyzed intact using PXRD. A novel mathematical technique was used to accurately separate multi-component diffraction patterns. The pair distribution function (PDF) of isolated theophylline diffraction data was employed to assess structural differences induced by consolidation and evaluated by principal components analysis (PCA).Changes induced in PXRD patterns by increasing compaction pressure were amplified by the PDF. Simulated data suggest PDF dampening is attributable to molecular deviations from average crystalline position. Samples compacted at different pressures were identified and differentiated using PCA. Samples compacted at common pressures exhibited similar inter-atomic correlations, where excipient concentration factored in the analyses involving lactose.Practical real-space structural analysis of PXRD data by PDF was accomplished for intact, compacted crystalline drug with and without excipient. PCA was used to compare multiple PDFs and successfully differentiated pattern changes consistent with compaction-induced disordering of theophylline as a single component and in the presence of another material.

Limits to the aqueous solubility of emerging new chemical entities, as well as older drug molecules, represent a barrier to solid oral dosage form development. Numerous techniques are conventionally employed in aqueous solubility enhancement, although a universal strategy has proven elusive. Formation of binary solid composites, such as eutectics or amorphous solid dispersions, offers an alternative to traditional solubility enhancement techniques. The reality of these systems, however, is that very few examples have been made commercially available, ultimately stemming from a lack of understanding regarding structural and thermodynamic stability-indicating phenomena associated with higher-energy solid materials. In the present work, a comprehensive structurally based review of the fundamental solid-state properties of binary composite materials is presented. Specific emphasis is placed on current topics of research in the area of binary composite formation and the relationship to the underutilization of this technology with the pharmaceutical industry.

Chronic granulomatous disease (CGD) is a rare genetic disease characterized by severe and persistent childhood infections. It is caused by the lack of an antipathogen oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses with concomitant issues of insertional mutagenesis, inaccurate gene dosage, and gene silencing. Here, we explore the potential of the recently described clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of homologous recombination. Using induced pluripotent stem cells derived from a CGD patient containing a single intronic mutation in the CYBB gene, we show that footprintless gene editing is a viable option to correct disease mutations. Gene correction results in restoration of oxidative burst function in iPS-derived phagocytes by reintroduction of a previously skipped exon in the cytochrome b-245 heavy chain (CYBB) protein. This study provides proof-of-principle for a gene therapy approach to CGD treatment using CRISPR-Cas9., Highlights • Chronic granulomatous disease–causing mutation was corrected in patient-derived iPS cells using CRISPR-Cas9 • A key to efficiency is prevention of CRISPR activity on corrected gene • Potentially clinically relevant efficiencies are attainable with CRISPR-Cas9 • The defect in ROS production from macrophages was overcome in patient-derived cells

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.

An analytical, non-destructive method using parallel-beam transmission powder X-ray diffractometry (PXRD) is presented for in situ whole compact detection and quantification of solid-state phase transformations in powder compacts. Accurate quantification of analyte in intact compacts using PXRD requires a mathematical correction prior to interpolation of calibration data to account for sample differences that result as a function of pressure; namely, compact thickness and solid fraction. Chlorpropamide is examined as a model system, selected because of its susceptibility to polymorphic transformations when consolidated using moderately low pressures. The results indicate that quantification of the transformed phase of chlorpropamide without corrections for solid fraction and thickness, underestimates the extent of transformation by 2.4%. Although the magnitude of the correction for this particular system of polymorphs is small, more significant values are expected for other compounds, particularly those with sufficient compactibility to allow the formation of low solid fraction calibration samples.

The 20th century evolution of basin-wide gradients in surface ocean properties provides one essential test for recent models of the interaction between the Asian monsoon and the tropical ocean, because various feedback mechanisms should result in characteristic regional patterns of variability. Although the instrumental record of climate variability in the tropics is essentially limited to the last few decades, the stable isotopic composition of living corals provides an effective means for extending the instrumental observations. Here we present two coral isotopic records from the Indonesian Maritime Continent, and we use these records with other previously published records to describe: (i) the relationship between western Pacific and central Pacific climate variability over the past century, with special emphasis on the biennial band; and (ii) the strength of the west–east ‘Indian Ocean Dipole’. We find that the amplitude of the biennial cycle in the Pacific did not vary inversely with the strength of ENSO (El Nino Southern Oscillation), as might be expected from some models of monsoonal feedback on the central Pacific. Instead, the biennial variability was modulated on decadal timescales throughout much of the Pacific. We also show that the zonal oxygen isotopic gradient in the Indian Ocean coral records was significantly correlated with central Pacific sea surface temperature on a variety of timescales. Thus, it is likely that this ‘coral dipole’ was a product of strong ENSO-like teleconnections over the Indian Ocean, as opposed to being the result of unique Indian Ocean or monsoonal dynamics.

Objective To assess the unmet need for comprehensive behavioural intervention for tics (CBIT) and habit reversal therapy (HRT) in adults and children with Tourette Syndrome. Method Patients with Tourette Syndrome who attended the St George’s clinic between 2004 and 2015 were selected for the study (Total 388). Basic clinical characteristics and the status of CBIT/HRT was assessed for each case. It was classified as being: (1) recommended by the clinician, (2) directly referred for therapy, (3) actually received therapy, (4) stated not suitable as not indicated for reasons such as significant learning difficulty or implied lack of availability of therapists or (5) explicitly stated to be inaccessible for the patient or (6) not mentioned at all in the notes. Results Of the 388 patients 24% were female and 76% male. 41% were adults and 56% were children of 17 years and under. In total only 111 (29%) had behavioural therapy mentioned in their clinical notes. This has increased over the years with an increase from 6% in adults in 2005 to 43% in 2015 and from 11% in children in 2005 to 78% in 2015. 23 patients (6%) were categorised as not suitable. Behavioural therapy was recommended but not eventually provided to 31 of these patients (8%). In a further 35 patients (9%), behavioural therapy was deemed inaccessible by the clinician to begin with, before any attempt was even made for a referral. Only 18 (5%) patients were actually referred for behavioural therapy and 4 (1%) patients out the total 388 received behavioural therapy (2 children and 2 adults) although missing notes may have reduced this number. Conclusion Behavioural therapies are an evidence-based treatment for Tourette syndrome. The data presented here were extracted from clinical notes and were not collected prospectively for this purpose so it was often difficult to know if clinicians omitted explicit mention of CBIT/HRT because of lack of availability or on the basis of patient selection. Increasing interest over the years is however demonstrated here by an increasing focus in the patient notes, but there is still very little access to this form of treatment, a national problem. Anecdotally, many more referrals have been made for children from this clinic to another centre in the last 12 months. Under provision in the NHS of specialised psychological services for Tourette syndrome needs to be urgently addressed.

Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir and mediating neurological disorders. Cell-free HIV-1 infection of macrophages is inefficient, in part due to low plasma membrane expression of viral entry receptors. We find that macrophages selectively capture and engulf HIV-1-infected CD4+ T cells leading to efficient macrophage infection. Infected T cells, both healthy and dead or dying, were taken up through viral envelope glycoprotein-receptor-independent interactions, implying a mechanism distinct from conventional virological synapse formation. Macrophages infected by this cell-to-cell route were highly permissive for both CCR5-using macrophage-tropic and otherwise weakly macrophage-tropic transmitted/founder viruses but restrictive for nonmacrophage-tropic CXCR4-using virus. These results have implications for establishment of the macrophage reservoir and HIV-1 dissemination in vivo.

Stable isotope records from sclerosponges collected at 10–20 m depth in the Indonesian Seaway and Solomon Islands are particularly well suited for reconstructing century-scale trends in ambient temperature variability and the oceanic uptake of fossil fuel carbon. Basal U/Th dates demonstrate that the sclerosponges analyzed are 85–100 years old. Isotopic records from the Indonesian specimens suggest a strong subsurface cooling over the past 20 years that is not manifested in either surface instrumental or shallower coral proxy records. However, analysis of observed subsurface temperatures in Indonesia, observed winds in the west Pacific, and simulated subsurface temperatures from a steady state general circulation model hindcast forced by observed winds combine to suggest that thermocline adjustments could account for at least part of the recent cooling inferred from the Indonesian sclerosponges. If so, the sclerosponge data suggests that, on average, the west Pacific thermocline has shoaled significantly over at least the past 2 decades.

Standard ocean/climate indices such as the Nino-3 sea surface temperature (SST) index, based on sparse instrumental data, and atmospheric indices such as the Southern Oscillation Index (SOI), may now be substituted and/or extended by coral-based indices. Several elements or their isotopes are incorporated in coral aragonitic skeletons at predictable concentrations, some of which are temperature or salinity dependent. The availability of century-old corals, at key oceanographic sites, permits the establishment of a network of proxy climate indices.

The prophylactic use of topical antiviral agents has recently been validated by the reduction in human immunodeficiency virus (HIV) type 1 infection incidence seen using tonofovir-containing microbicides. In order to develop a wide-spectrum microbicide to prevent infection with a wide range of sexually transmitted viruses, we have previously reported the development of HIV-neutralizing aptamers and here report the isolation and characterization of aptamers that neutralize herpes simplex virus type 2 (HSV-2). These aptamers bind the envelope glycoprotein (gD), are potent (IC50 of 20–50 nM) and are able to block infection pathways dependent on both major entry receptors, Nectin1 and HVEM. Structural analysis and mutagenesis of these aptamers reveal a core specificity element that could provide the basis for pharmaceutical development. As HSV-2 is a major risk factor for the acquisition of HIV-1, a microbicide capable of preventing HSV-2 infection would not only reduce the morbidity associated with HSV-2, but also that derived from HIV-1.

The use of a novel, in silico method for making an intelligent polymer selection to physically stabilize small molecule organic (SMO) solid compounds formulated as amorphous molecular solid dispersions is reported. 12 compounds (75%, w/w) were individually co-solidified with polyvinyl pyrrolidone:vinyl acetate (PVPva) copolymer by melt-quenching. Co-solidified products were analyzed intact using differential scanning calorimetry (DSC) and the pair distribution function (PDF) transform of powder X-ray diffraction (PXRD) data to assess miscibility. Molecular descriptor indices were calculated for all twelve compounds using their reported crystallographic structures. Logistic regression was used to assess correlation between molecular descriptors and amorphous molecular solid dispersion potential. The final model was challenged with three compounds. Of the 12 compounds, 6 were miscible with PVPva ( i.e. successful formation) and 6 were phase separated ( i.e. unsuccessful formation). 2 of the 6 unsuccessful compounds exhibited detectable phase-separation using the PDF method, where DSC indicated miscibility. Logistic regression identified 7 molecular descriptors correlated to solid dispersion potential ( α = 0.001). The atomic mass-weighted third-order R autocorrelation index (R3m) was the only significant descriptor to provide completely accurate predictions of dispersion potential. The three compounds used to challenge the R3m model were also successfully predicted.