Functional stability of HIV-1 envelope trimer affects accessibility to broadly neutralizing antibodies at its apex

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex. </jats:p

The impacts of climate change on UK energy demand

The impacts of climate change on the energy system are diverse; this article focuses on the potential effects on UK energy demand and the ramifications for national infrastructure building on the findings of the UK’s 2012 Climate Change Risk Assessment. It reviews the available literature, where it exists, on the relationships among current energy demand, weather and climate change, and the implications for these relationships due to mitigation plans and potential adaptation responses. The review highlights the mechanisms by which future climate change, in particular changes in mean and extreme temperature, could affect the annual amount of UK energy demand and the seasonal, daily and spatial variation of the impacts. Published literature quantifying the effects of climate change on UK energy demand is limited; thus, where evidence is not available, information on the current relationship between weather and demand is combined with expert judgement to highlight potential demand responses to a changing climate without quantification. The impacts identified could have significant implications for the long-term planning of energy infrastructure and system operation and building design, depending on their magnitude, highlighting the need for further research in this area

Cascading Globalization and Local Response: Indian Fishers’ Response to Export Market Liberalization

Scholars have long debated whether trade liberalization has positive or negative effects on resource use and ecosystems. This study examines the conditions under which resource use increases or decreases in response to reduced trade barriers, specifically after the 2008 World Trade Organization decision that led the United States to reduce anti-dumping duties on Indian shrimp. At the district level in South India, fishing fleet expansion was correlated with access to global market information via mobile phones. Model simulations indicate that increased mobile phone saturation could expand fish- ing effort sufficiently to deplete multiple marine species groups, while other species benefit from the loss of predators. However, scenario analysis suggests that regulatory interventions could mitigate these ecosystem pressures while still permitting fishers to benefit from increased access to global market information

Low-cost and biodegradable thermoelectric devices based on van der Waals semiconductors on paper substrates

We present a method to fabricate handcrafted thermoelectric devices on standard office paper substrates. The devices are based on thin films of WS2, Te, and BP (P-type semiconductors) and TiS3 and TiS2 (N-type semiconductors), deposited by simply rubbing powder of these materials against paper. The thermoelectric properties of these semiconducting films revealed maximum Seebeck coefficients of (+1.32 ± 0.27) mV/K and (-0.82 ± 0.15) mV/K for WS2 and TiS3, respectively. Additionally, Peltier elements were fabricated by interconnecting the P-type and N-type films with graphite electrodes. A thermopower value up to 6.11 mV/K was obtained when the Peltier element is constructed with three junctions. The findings of this work show proof-of-concept devices to illustrate the potential application of semiconducting van der Waals materials in future thermoelectric power generation as well as temperature sensing for low-cost disposable electronic device

From Poverty to Disaster and Back: a Review of the Literature

Poor people are disproportionally affected by natural hazards and disasters. This paper provides a review of the multiple factors that explain why this is the case. It explores the role of exposure (often, but not always, poor people are more likely to be affected by hazards), vulnerability (when they are affected, poor people tend to lose a larger fraction of their wealth), and socio-economic resilience (poor people have a lower ability to cope with and recover from disaster impacts). Finally, the paper highlights the vicious circle between poverty and disaster losses: poverty is a major driver of people’s vulnerability to natural disasters, which in turn increase poverty in a measurable and significant way. The main policy implication is that poverty reduction can be considered as disaster risk management, and disaster risk management can be considered as poverty reduction

Searching for molecular markers in head and neck squamous cell carcinomas (HNSCC) by statistical and bioinformatic analysis of larynx-derived SAGE libraries

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies in humans. The average 5-year survival rate is one of the lowest among aggressive cancers, showing no significant improvement in recent years. When detected early, HNSCC has a good prognosis, but most patients present metastatic disease at the time of diagnosis, which significantly reduces survival rate. Despite extensive research, no molecular markers are currently available for diagnostic or prognostic purposes. Methods: Aiming to identify differentially-expressed genes involved in laryngeal squamous cell carcinoma (LSCC) development and progression, we generated individual Serial Analysis of Gene Expression (SAGE) libraries from a metastatic and non-metastatic larynx carcinoma, as well as from a normal larynx mucosa sample. Approximately 54,000 unique tags were sequenced in three libraries. Results: Statistical data analysis identified a subset of 1,216 differentially expressed tags between tumor and normal libraries, and 894 differentially expressed tags between metastatic and non-metastatic carcinomas. Three genes displaying differential regulation, one down-regulated (KRT31) and two up-regulated (BST2, MFAP2), as well as one with a non-significant differential expression pattern (GNA15) in our SAGE data were selected for real-time polymerase chain reaction (PCR) in a set of HNSCC samples. Consistent with our statistical analysis, quantitative PCR confirmed the upregulation of BST2 and MFAP2 and the downregulation of KRT31 when samples of HNSCC were compared to tumor-free surgical margins. As expected, GNA15 presented a non-significant differential expression pattern when tumor samples were compared to normal tissues. Conclusion: To the best of our knowledge, this is the first study reporting SAGE data in head and neck squamous cell tumors. Statistical analysis was effective in identifying differentially expressed genes reportedly involved in cancer development. The differential expression of a subset of genes was confirmed in additional larynx carcinoma samples and in carcinomas from a distinct head and neck subsite. This result suggests the existence of potential common biomarkers for prognosis and targeted-therapy development in this heterogeneous type of tumor.Fundação de Amparo a Pesquisa do Estado de São Paulo/FAPESP [05/51467-0]; [04/12054-9]; [07/50894-7]Ludwig Institute for Cancer ResearchConselho Nacional de Pesquisas/CNPqCoordenacao de Aperfeicoamento do Pessoal do Ensino Superior/CAPE

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Unexplained pancytopenia in acute myeloid leukemia treatment

Certain histopathological findings have been described in acute myeloid leukemia (AML) patients during treatment that define the hematologic outcomes. Such entities as bone marrow necrosis and hemophagocytic lymphohistiocytosis have been reported. These often result in severe pancytopenia