Ecology: a prerequisite for malaria elimination and eradication

* Existing front-line vector control measures, such as insecticide-treated nets and residual sprays, cannot break the transmission cycle of Plasmodium falciparum in the most intensely endemic parts of Africa and the Pacific * The goal of malaria eradication will require urgent strategic investment into understanding the ecology and evolution of the mosquito vectors that transmit malaria * Priority areas will include understanding aspects of the mosquito life cycle beyond the blood feeding processes which directly mediate malaria transmission * Global commitment to malaria eradication necessitates a corresponding long-term commitment to vector ecolog

Modeling the scaling properties of human mobility

While the fat tailed jump size and the waiting time distributions characterizing individual human trajectories strongly suggest the relevance of the continuous time random walk (CTRW) models of human mobility, no one seriously believes that human traces are truly random. Given the importance of human mobility, from epidemic modeling to traffic prediction and urban planning, we need quantitative models that can account for the statistical characteristics of individual human trajectories. Here we use empirical data on human mobility, captured by mobile phone traces, to show that the predictions of the CTRW models are in systematic conflict with the empirical results. We introduce two principles that govern human trajectories, allowing us to build a statistically self-consistent microscopic model for individual human mobility. The model not only accounts for the empirically observed scaling laws but also allows us to analytically predict most of the pertinent scaling exponents

Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

Scans for signatures of selection in Russian cattle breed genomes reveal new candidate genes for environmental adaptation and acclimation

Domestication and selective breeding has resulted in over 1000 extant cattle breeds. Many of these breeds do not excel in important traits but are adapted to local environments. These adaptations are a valuable source of genetic material for efforts to improve commercial breeds. As a step toward this goal we identified candidate regions to be under selection in genomes of nine Russian native cattle breeds adapted to survive in harsh climates. After comparing our data to other breeds of European and Asian origins we found known and novel candidate genes that could potentially be related to domestication, economically important traits and environmental adaptations in cattle. The Russian cattle breed genomes contained regions under putative selection with genes that may be related to adaptations to harsh environments (e.g., AQP5, RAD50, and RETREG1). We found genomic signatures of selective sweeps near key genes related to economically important traits, such as the milk production (e.g., DGAT1, ABCG2), growth (e.g., XKR4), and reproduction (e.g., CSF2). Our data point to candidate genes which should be included in future studies attempting to identify genes to improve the extant breeds and facilitate generation of commercial breeds that fit better into the environments of Russia and other countries with similar climates

Efficacy and Safety of Upadacitinib Treatment in Adolescents With Moderate-to-Severe Atopic Dermatitis

Importance: Atopic dermatitis onset usually occurs in childhood. Persistence of disease into adolescence and adulthood is common. It is important to evaluate new treatment options in adolescents because of the high unmet need in this population. Objective: To assess the efficacy and safety of upadacitinib to treat moderate-to-severe atopic dermatitis in adolescents. Design, setting, and participants: Prespecified analysis of adolescents enrolled in 3 randomized, double-blind, placebo-controlled phase 3 clinical trials in more than 20 countries across Europe, North and South America, Oceania, the Middle East, and the Asia-Pacific region from July 2018 through December 2020. Participants were adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis. Data analysis was performed from April to August 2021. Interventions: Patients were randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up). Main outcomes and measures: Safety and efficacy, including at least a 75% improvement in the Eczema Area and Severity Index from baseline and validated Investigator Global Assessment for Atopic Dermatitis score of 0 (clear) or 1 (almost clear) at week 16 (coprimary end points). Results: A total of 552 adolescents (290 female; 262 male) were randomized. Mean (SD) age was 15.4 (1.8), 15.5 (1.7), and 15.3 (1.8) years for adolescents in Measure Up 1, Measure Up 2, and AD Up, respectively. In Measure Up 1, Measure Up 2, and AD Up, respectively, a greater proportion of adolescents (% [95% CI]) achieved at least 75% improvement in the Eczema Area and Severity Index at week 16 with upadacitinib 15 mg (73% [63%-84%], 69% [57%-81%], 63% [51%-76%]), and upadacitinib 30 mg (78% [68%-88%], 73% [62%-85%], 84% [75%-94%]), than with placebo (12% [4%-20%], 13% [5%-22%], 30% [19%-42%]; nominal P < .001 for all comparisons vs placebo). Similarly, a greater proportion of adolescents treated with upadacitinib achieved a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 at week 16 and improvements in quality of life with upadacitinib than with placebo. Upadacitinib was generally well tolerated in adolescents. Acne was the most common adverse event, and all acne events were mild or moderate. Conclusions and relevance: In this analysis of 3 randomized clinical trials, upadacitinib was an effective treatment for adolescents with moderate-to-severe atopic dermatitis, with an acceptable safety profile.info:eu-repo/semantics/publishedVersio

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

Eliminating Malaria Vectors.

Malaria vectors which predominantly feed indoors upon humans have been locally eliminated from several settings with insecticide treated nets (ITNs), indoor residual spraying or larval source management. Recent dramatic declines of An. gambiae in east Africa with imperfect ITN coverage suggest mosquito populations can rapidly collapse when forced below realistically achievable, non-zero thresholds of density and supporting resource availability. Here we explain why insecticide-based mosquito elimination strategies are feasible, desirable and can be extended to a wider variety of species by expanding the vector control arsenal to cover a broader spectrum of the resources they need to survive. The greatest advantage of eliminating mosquitoes, rather than merely controlling them, is that this precludes local selection for behavioural or physiological resistance traits. The greatest challenges are therefore to achieve high biological coverage of targeted resources rapidly enough to prevent local emergence of resistance and to then continually exclude, monitor for and respond to re-invasion from external populations

Classical risk factors of cardiovascular disease among Chinese male steel workers: a prospective cohort study for 20 years

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) constitutes a major public health problem in China and worldwide. We aimed to examine classical risk factors and their magnitudes for CVD in a Chinese cohort with over 20 years follow-up.</p> <p>Methods</p> <p>A cohort of 5092 male steelworkers recruited from 1974 to 1980 in Beijing of China was followed up for an average of 20.84 years. Cox proportional-hazards regression model were used to evaluate the risk of developing a first CVD event in the study participants who were free of CVD at the baseline.</p> <p>Results</p> <p>The multivariable-adjusted hazard ratio (HR) associated with every 20 mmHg rise in systolic blood pressure (SBP) was 1.63 in this Chinese male population, which was higher than in Caucasians. Compared to non-smokers, men who smoked not less than one-pack-a-day had a HR of 2.43 (95% confidence interval [CI], 1.75-3.38). The HR (95% CI) for every 20 mg/dl increase in total serum cholesterol (TC) and for every point rise in body mass index (BMI) was 1.13 (1.04-1.23) and 1.06 (1.02-1.09), respectively.</p> <p>Conclusions</p> <p>Our study documents that hypertension, smoking, overweight and hypercholesterolemia are major conventional risk factors of CVD in Chinese male adults. Continued strengthening programs for prevention and intervention on these risk factors are needed to reduce the incidence of CVD in China.</p

RhoH Regulates Subcellular Localization of ZAP-70 and Lck in T Cell Receptor Signaling

RhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse. RhoH with Lck and ZAP-70 localizes in the detergent-soluble membrane fraction where the complex is associated with CD3ζ phosphorylation. To determine if impaired translocation of ZAP-70 was a major determinant of defective T cell development, Rhoh-/- bone marrow cells were transduced with a chimeric myristoylation-tagged ZAP-70. Myr-ZAP-70 transduced cells partially reversed the in vivo defects of RhoH-associated thymic development and TCR signaling. Together, our results suggest that RhoH regulates TCR signaling via recruitment of ZAP-70 and Lck to CD3ζ in the immunological synapse. Thus, we define a new function for a RhoH GTPase as an adaptor molecule in TCR signaling pathway

Genome-Wide Functional Divergence after the Symbiosis of Proteobacteria with Insects Unraveled through a Novel Computational Approach

Symbiosis has been among the most important evolutionary steps to generate biological complexity. The establishment of symbiosis required an intimate metabolic link between biological systems with different complexity levels. The strict endo-cellular symbiotic bacteria of insects are beautiful examples of the metabolic coupling between organisms belonging to different kingdoms, a eukaryote and a prokaryote. The host (eukaryote) provides the endosymbiont (prokaryote) with a stable cellular environment while the endosymbiont supplements the host's diet with essential metabolites. For such communication to take place, endosymbionts' genomes have suffered dramatic modifications and reconfigurations of proteins' functions. Two of the main modifications, loss of genes redundant for endosymbiotic bacteria or the host and bacterial genome streamlining, have been extensively studied. However, no studies have accounted for possible functional shifts in the endosymbiotic proteomes. Here, we develop a simple method to screen genomes for evidence of functional divergence between two species clusters, and we apply it to identify functional shifts in the endosymbiotic proteomes. Despite the strong effects of genetic drift in the endosymbiotic systems, we unexpectedly identified genes to be under stronger selective constraints in endosymbionts of aphids and ants than in their free-living bacterial relatives. These genes are directly involved in supplementing the host's diet with essential metabolites. A test of functional divergence supports a strong relationship between the endosymbiosis and the functional shifts of proteins involved in the metabolic communication with the insect host. The correlation between functional divergence in the endosymbiotic bacterium and the ecological requirements of the host uncovers their intimate biochemical and metabolic communication and provides insights on the role of symbiosis in generating species diversity