Early anthropogenic impact on Western Central African rainforests 2,600 y ago

A potential human footprint on Western Central African rainforests before the Common Era has become the focus of an ongoing controversy. Between 3,000 y ago and 2,000 y ago, regional pollen sequences indicate a replacement of mature rainforests by a forest–savannah mosaic including pioneer trees. Although some studies suggested an anthropogenic influence on this forest fragmentation, current interpretations based on pollen data attribute the ‘‘rainforest crisis’’ to climate change toward a drier, more seasonal climate. A rigorous test of this hypothesis, however, requires climate proxies independent of vegetation changes. Here we resolve this controversy through a continuous 10,500-y record of both vegetation and hydrological changes from Lake Barombi in Southwest Cameroon based on changes in carbon and hydrogen isotope compositions of plant waxes. δ¹³C-inferred vegetation changes confirm a prominent and abrupt appearance of C4 plants in the Lake Barombi catchment, at 2,600 calendar years before AD 1950 (cal y BP), followed by an equally sudden return to rainforest vegetation at 2,020 cal y BP. δD values from the same plant wax compounds, however, show no simultaneous hydrological change. Based on the combination of these data with a comprehensive regional archaeological database we provide evidence that humans triggered the rainforest fragmentation 2,600 y ago. Our findings suggest that technological developments, including agricultural practices and iron metallurgy, possibly related to the large-scale Bantu expansion, significantly impacted the ecosystems before the Common Era

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy

Dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and stage 4 or 5 chronic kidney disease

OBJECTIVE: To determine whether dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and renal impairment. RESEARCH DESIGN AND METHODS: We performed a cross-sectional study of consecutive patients with diabetes and stage 4 or 5 chronic kidney disease (CKD) attending clinics in Manchester (U.K.). Patients were classified as either receiving dialysis therapy (dialysis) or not (no dialysis). Foot assessment included diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), prior foot ulceration and amputation, and foot self-care. Risk factors for prevalent foot ulceration were assessed by logistic regression. RESULTS: We studied 326 patients with diabetes and CKD (mean age 64 years; 61% male; 78% type 2 diabetes; 11% prevalent foot ulceration). Compared with no dialysis patients, dialysis patients had a higher prevalence of DPN (79 vs. 65%), PAD (64 vs. 43%), prior amputations (15 vs. 6.4%), prior foot ulceration (32 vs. 20%), and prevalent foot ulceration (21 vs. 5%, all P < 0.05). In univariate analyses, foot ulceration was related to wearing bespoke footwear (odds ratio 5.6 [95% CI 2.5–13]) dialysis treatment (5.1 [2.3–11]), prior foot ulceration (4.8 [2.3–9.8], PAD (2.8 [1.3–6.0], and years of diabetes (1.0 [1.0–1.1], all P < 0.01). In multivariate logistic regression, only dialysis treatment (4.2 [1.7–10], P = 0.002) and prior foot ulceration (3.1 [1.3–7.1], P = 0.008) were associated with prevalent foot ulceration. CONCLUSIONS: Dialysis treatment was independently associated with foot ulceration. Guidelines should highlight dialysis as an important risk factor for foot ulceration requiring intensive foot care

Plant-waxes hydrogen and carbon isotopic composition and pollen data of sediment core B14 (Lake Barombi)

A potential human footprint on Western Central African rainforests before the Common Era has become the focus of an ongoing controversy. Between 3,000 y ago and 2,000 y ago, regional pollen sequences indicate a replacement of mature rainforests by a forest-savannah mosaic including pioneer trees. Although some studies suggested an anthropogenic influence on this forest fragmentation, current interpretations based on pollen data attribute the ''rainforest crisis'' to climate change toward a drier, more seasonal climate. A rigorous test of this hypothesis, however, requires climate proxies independent of vegetation changes. Here we resolve this controversy through a continuous 10,500-y record of both vegetation and hydrological changes from Lake Barombi in Southwest Cameroon based on changes in carbon and hydrogen isotope compositions of plant waxes. d13C-inferred vegetation changes confirm a prominent and abrupt appearance of C4 plants in the Lake Barombi catchment, at 2,600 calendar years before AD 1950 (cal y BP), followed by an equally sudden return to rainforest vegetation at 2,020 cal y BP. dD values from the same plant wax compounds, however, show no simultaneous hydrological change. Based on the combination of these data with a comprehensive regional archaeological database we provide evidence that humans triggered the rainforest fragmentation 2,600 y ago. Our findings suggest that technological developments, including agricultural practices and iron metallurgy, possibly related to the large-scale Bantu expansion, significantly impacted the ecosystems before the Common Era

Negative feedback control of neuronal activity by microglia

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease