β-Catenin is a pH sensor with decreased stability at higher intracellular pH.

β-Catenin functions as an adherens junction protein for cell-cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein-protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R-β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013

Carbon payment strategies in coffee agroforests shape climate and biodiversity outcomes

Agricultural supply chains increasingly mitigate climate change and biodiversity loss through initiatives that either plant trees or protect threatened carbon stocks on farmlands. We conducted a global meta-analysis to evaluate how these programs may impact carbon and biodiversity outcomes across coffee agriculture, which spans a vegetation complexity gradient from monoculture to biodiverse agroforestry. For aboveground carbon, we estimated coffee farms currently hold 481.59 TgC globally and could sequester an additional 81.53-86.50 TgC under different agroforestry adoption scenarios. However, more than twice as much aboveground carbon could be lost under intensification scenarios (174.23-221.45 TgC). While tree diversity supports overall biodiversity in agroforestry, we found it does not independently increase carbon, indicating carbon and biodiversity outcomes may be decoupled. Ultimately, tree planting programs in coffee can sequester meaningful carbon volumes but may fail to achieve global carbon and biodiversity goals if they do not also protect existing agroforestry and diversify planting efforts

The access and rehabilitation working process in Primary Health Care

For adequate rehabilitation service offer in Brazil, it is necessary to understand the availability of access to Rede Assistencial de Saúde (RAS) [Brazilian Health Care Network (HCN)] and develop practices to meet health needs. The objective was to estimate the distribution trend of rehabilitation human resources in HCN between 2007 and 2015, especially in Primary Health Care (PHC) and get to know the practice of Clínica Ampliada (CA) [Extended Clinical Care (ECC)], Projeto Terapêutico Singular (PTS) [Singular Therapeutic Project (STP)], and Apoio Matricial (AM) [Matrix Support (MS)] of speech therapists, physical therapist, and occupational therapists. We searched for professionals from the Health Care Network using Cadastro Nacional de Estabelecimentos de Saúde (CNES) [Brazilian National Register of Health Establishments (NRHE)], and the monthly trend was elaborated through Prais-Winsten linear regression models. Aiming at knowing the practices of ECC, STP, and MS, “Discourses of the Collective Subject” were made from interviews held with 12 professionals. Medium complexity services had higher concentration of professionals, except for the hospitals in São Paulo city, and PHC had the lower possibility of access. Though shy, healthcare increased for all three professionals, with emphasis on physical therapists in hospitals in São Paulo city, in a comparison between the state (0.73%) and city (0.95%). In PHC, the highest raises were for occupational therapists of São Paulo city and physical therapists in Brazil. For MS, ECC and STP, besides the difficulty of the working process itself, ideas such as “plurality of concepts,” “biopsychosocial perspective,” and “possibility of adaptation” of care were predominant. Despite the growing numbers, the availability of professionals is still low and uneven, concentrated in specialty, and emphasising the expansion of physical therapy in hospitals and occupational therapy in PHC.Para que se tenga una adecuada oferta de servicios de rehabilitación en Brasil es necesario conocer el acceso disponible en la Red Asistencial de Salud (RAS) y desarrollar prácticas que abarcan las necesidades de la atención de salud. Se intentó estimar la distribución de los recursos humanos de rehabilitación en la RAS 2007-2015, en especial en la Atención Primaria de Salud (APS) y conocer la práctica de la Clínica Ampliada (CA), del Proyecto Terapéutico Singular (PTS) y de la Ayuda Matricial (AM) de fonoaudiólogos, fisioterapeutas y terapeutas ocupacionales. La búsqueda por estos profesionales de la Red Asistencial se dio a través del Registro Nacional de Establecimientos de Salud (RNES). Se estableció la tendencia mensual mediante modelos de regresión lineal Prais-Winsten. A fin de conocer las prácticas de los CA, PTS y AM se constituyeron discursos de sujeto colectivo desde entrevistas con 12 profesionales. La media complejidad concentró la mayoría de los profesionales, excepto en los hospitales de la ciudad de São Paulo. Pero la accesibilidad a la APS fue menor. Aunque no fue muy alta, se observó evolución de estos tres profesionales en la atención sanitaria, con énfasis en los fisioterapeutas del hospital de São Paulo, referente al estado (0,73%) y ciudad (0,95%). En la APS, el mayor incremento fue del terapeuta ocupacional en la ciudad de São Paulo y del fisioterapeuta por todo el país. En la AM, CA y PTS, además de la dificultad en la práctica, se encontraron respectivamente ideas de “pluralidad de conceptos”, “perspectiva biopsicosocial” y “posibilidad de adaptarse” al cuidado. Aunque esté aumentando, la disponibilidad de estos profesionales todavía es pequeña y desigual, concentrada en la especialidad, lo que señala la necesidad de ampliar el número de fisioterapeutas en hospitales y de terapeutas ocupacionales en la APS.Para a adequada oferta de serviços de reabilitação no Brasil é preciso conhecer a disponibilidade de acesso existente na Rede Assistencial de Saúde (RAS) e desenvolver práticas que atendam às necessidades de saúde. Buscou-se estimar a tendência da distribuição de recursos humanos de reabilitação na RAS 2007-2015, especificamente na Atenção Primária à Saúde (APS) e conhecer a prática de Clínica Ampliada (CA), Projeto Terapêutico Singular (PTS) e Apoio Matricial (AM) para fonoaudiólogos, fisioterapeutas e terapeutas ocupacionais. Buscou-se profissionais na Rede Assistencial pelo Cadastro Nacional de Estabelecimentos de Saúde (CNES). A tendência mensal foi construída por modelos de regressão linear Prais-Winsten. Para conhecer as práticas de CA, PTS e AM, construiu-se discursos do sujeito coletivo a partir de entrevistas de 12 profissionais. Média complexidade teve a maior concentração de profissionais, exceto em hospitais na cidade de São Paulo. A APS, por sua vez, teve a menor possibilidade de acesso. Mesmo tímido, houve crescimento dos três profissionais na assistência, com ênfase para os fisioterapeutas em hospital de São Paulo, em relação ao estado (0,73%) e cidade (0,95%). Na APS, o crescimento maior foi do terapeuta ocupacional em São Paulo-cidade e do fisioterapeuta no Brasil. Para AM, CA e PTS, além da dificuldade do fazer, destacaram-se, respectivamente, ideias de “pluralidade de concepções”, “visão biopsicossocial” e “possibilidade de adaptação” do cuidado. Embora crescente, a disponibilidade de profissionais é baixa e desigual, concentrada na especialidade e enfatizando ampliação de fisioterapeutas no hospital e terapeutas ocupacionais na APS

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

KDM2B recruitment of the polycomb group complex, PRC1.1, requires cooperation between PCGF1 and BCORL1

Accepted author manuscriptKDM2B recruits H2A-ubiquitinating activity of a non-canonical Polycomb Repression Complex 1 (PRC1.1) to CpG islands, facilitating gene repres sion. We investigated the molecular basis of recruit ment using in vitro assembly assays to identify minimal components, subcomplexes, and domains required for recruitment. A minimal four-component PRC1.1 complex can be assembled by combining two separately isolated subcomplexes: the DNA binding KDM2B/SKP1 heterodimer and the hetero dimer of BCORL1 and PCGF1, a core component of PRC1.1. The crystal structure of the KDM2B/ SKP1/BCORL1/PCGF1 complex illustrates the crucial role played by the PCGF1/BCORL1 hetero dimer. The BCORL1 PUFD domain positions resi dues preceding the RAWUL domain of PCGF1 to create an extended interface for interaction with KDM2B, which is unique to the PCGF1-containing PRC1.1 complex. The structure also suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex and the possible molecular consequences of BCOR PUFD internal tandem duplications found in pediatric kidney and brain tumors.Ye

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 x 10(-5)) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 x 10(-8)). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 x 10(-9)). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression