Improving tuberculosis diagnosis: Better tests or better healthcare?

In a Perspective accompanying Sylvia and colleagues, Carlton Evans and colleagues discuss the challenge of squaring policies around tuberculosis diagnosis with the realities of clinical practice in small villages and low-resource settings

Ecohydrology and ecosystem services of a natural and an artificial bofedal wetland in the central Andes

High-altitude wetlands of the Central Andes, locally known as bofedales, provide important ecosystem services, particularly carbon storage, forage provisioning, and water regulation. Local communities have artificially expanded bofedales by irrigating surrounding grasslands to maximise areas for alpaca grazing. Despite their importance, biophysical processes of both natural and artificial bofedales are still poorly studied, which hinders the development of adequate management and conservation strategies. We analyse and compare the vegetation composition, hydrological variables, groundwater chemistry, and soil characteristics of a natural and an artificial bofedal of at least 10 years old in southern Peru, to understand their interrelations and the consequences for ecosystem service provisioning. We do not find statistically significant differences in the soil, water, and vegetation characteristics. Soil organic carbon (SOC) content, which we use as a proxy for carbon storage, is negatively correlated to dissolved oxygen, pH, and soil water temperature. In addition, Non-Metric Multidimensional Scaling analysis shows a positive relation between plant community composition, SOC content, and water electric conductivity. Our results suggest a three-way interaction between hydrological, soil, and vegetation characteristics in the natural bofedal, which also holds for the artificial bofedal. Vegetation cover of two of the most highly nutritious species for alpaca, Lachemilla diplophylla and Lilaeopsis macloviana with 19-22% of crude protein, are weakly or not correlated to environmental variables, suggesting grazing might be obscuring these potential relationships. Given the high economic importance of alpaca breeding for local communities, expanding bofedales artificially appears an effective strategy to enhance their ecosystem services with minimal impact on the ecohydrological properties of bofedales

Mott physics and band topology in materials with strong spin-orbit interaction

Recent theory and experiment have revealed that strong spin-orbit coupling can have dramatic qualitative effects on the band structure of weakly interacting solids. Indeed, it leads to a distinct phase of matter, the topological band insulator. In this paper, we consider the combined effects of spin-orbit coupling and strong electron correlation, and show that the former has both quantitative and qualitative effects upon the correlation-driven Mott transition. As a specific example we take Ir-based pyrochlores, where the subsystem of Ir 5d electrons is known to undergo a Mott transition. At weak electron-electron interaction, we predict that Ir electrons are in a metallic phase at weak spin-orbit interaction, and in a topological band insulator phase at strong spin-orbit interaction. Very generally, we show that with increasing strength of the electron-electron interaction, the effective spin-orbit coupling is enhanced, increasing the domain of the topological band insulator. Furthermore, in our model, we argue that with increasing interactions, the topological band insulator is transformed into a "topological Mott insulator" phase, which is characterized by gapless surface spin-only excitations. The full phase diagram also includes a narrow region of gapless Mott insulator with a spinon Fermi surface, and a magnetically ordered state at still larger electron-electron interaction.Comment: 10+ pages including 3+ pages of Supplementary Informatio

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Conserved expression and functions of PDE4 in rodent and human heart

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation–contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, we explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. We find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. The major difference between the species is a fivefold higher amount of non-PDE4 activity in human hearts compared to rodents. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. Our findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has ‘global’ effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans. These differences may explain the distinct pharmacological effects of PDE4 inhibition in rodent and human hearts

Anatomy of Heinrich Layer 1 and its role in the last deglaciation

X-ray fluorescence (XRF) core scanning and X-ray computed tomography data were measured every 1 mm to study the structure of Heinrich Event 1 during the last deglaciation at International Ocean Discovery Program Site U1308. Heinrich Layer 1 comprises two distinct layers of ice-rafted detritus (IRD), which are rich in detrital carbonate (DC) and poor in foraminifera. Each DC layer consists of poorly sorted, coarse-grained clasts of IRD embedded in a dense, fine-grained matrix of glacial rock flour that is partially cemented. The radiocarbon ages of foraminifera at the base of the two layers indicate a difference of 1400 $^{14}$C years, suggesting that they are two distinct events, but the calendar ages depend upon assumptions made for surface reservoir ages. The double peak indicates at least two distinct stages of discharge of the ice streams that drained the Laurentide Ice Sheet through Hudson Strait during HE1 or, alternatively, the discharge of two independent ice streams containing detrital carbonate. Heinrich Event 1.1 was the larger of the two events and began at ~16.2 ka (15.5–17.1 ka) when the polar North Atlantic was already cold and Atlantic Meridional Overturning Circulation (AMOC) weakened. The younger peak (H1.2) at ~15.1 ka (14.3 to 15.9 ka) was a weaker event than H1.1 that was accompanied by minor cooling. Our results support a complex history for Heinrich Stadial 1 (HS1) with reduction in AMOC during the early part (~20–16.2 ka) possibly driven by melting of European ice sheets, whereas the Laurentide Ice Sheet assumed a greater role during the latter half (~16.2–14.7 ka).This research used data acquired at the XRF Core Scanner Lab at the MARUM–Center for Marine Environmental Sciences, University of Bremen, Germany. This research used samples provided by the International Ocean Discovery Program (IODP). Funding for this research was provided by the UK Natural Environmental Research Council (NERC) to Hodell. The NERC Radiocarbon Facility supported two radiocarbon dates, and Wally Broecker generously supported the remainder with funding from the Comer Family Foundation. Research by Rodríguez-Tovar and Dorador was financed by Project CGL2015-66835-P. B.M. acknowledges support from the CSIC-Ramón y Cajal postdoctoral programme RYC-2013-14073. J.F.E. would like to acknowledge funding under ERC Advanced grant 320750- Nanopaleomagnetism

PTHrP increases transcriptional activity of the integrin subunit α5

Increasing evidence is emerging highlighting the role of parathyroid hormone-related protein (PTHrP) during metastasis by regulating cell adhesion. The current study demonstrated that modulation of PTHrP expression by PTHrP overexpression and small interfering RNA-induced silencing resulted in changes in cell adhesion and integrin expression. RNA interference of endogenous PTHrP caused a significant reduction in cell adhesion of a breast cancer cell line to collagen type I, fibronectin and laminin (P<0.05) and of a colon cancer cell to collagen type I and fibronectin (P<0.05). Overexpression of PTHrP induced a significant increase in cell adhesion of colon (P<0.0001) and breast (P<0.05) cancer cells to the same extracellular matrix proteins. These PTHrP-mediated effects were attributed to changes in integrin expression as the differences in adhesion profile correlated with the integrin expression profile. In an attempt to elucidate the mechanism whereby PTHrP regulates integrin expression, promoter activity of the integrin α5 subunit was analysed and significant increases in transcriptional activity were observed in PTHrP overexpressing cells (P<0.0001), which was dependent on nuclear localisation. These results indicate that modulation of cell adhesion is a normal physiological action of PTHrP, mediated by increasing integrin gene transcription

CXCL12 inhibits expression of the NMDA receptor's NR2B subunit through a histone deacetylase-dependent pathway contributing to neuronal survival

Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repressor protein Rb, which is involved in the recruitment of chromatin modifiers (such as histone deacetylases (HDACs)) to gene promoters. In neurons, Rb controls activity-dependent genes essential to neuronal plasticity and survival, such as the N-methyl--aspartic acid (NMDA) receptor's subunit NR2B, the expression of which in the tetrameric ion channel largely affects calcium signaling by glutamate. In this study, we report that CXCL12 differentially modulates intracellular responses after stimulation of synaptic and extrasynaptic NMDA receptors, by a specific regulation of the NR2B gene that involves HDACs. Our results show that CXCL12 selectively inhibits NR2B expression in vitro and in vivo altering NMDA-induced calcium responses associated with neuronal death, while promoting prosurvival pathways that depend on stimulation of synaptic receptors. Along with previous studies, these findings underline the role of CXCL12/CXCR4 in the regulation of crucial components of glutamatergic transmission. These novel effects of CXCL12 may be involved in the physiological function of the chemokine in both developing and mature brains

Serum 25-hydroxyvitamin D, parathyroid hormone, calcium intake, and bone mineral density in Spanish adults

Summary Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion. Introduction This study aims to assess 25-hydroxyvitamin D?25(OH)D?status in Spanish adult subjects and to analyze its relationships with serum PTH levels, calcium intake, and bone mineral density (BMD). Methods A total of 1811 individuals (1154 postmenopausal women and 657 men) aged 44?93 years participated in the study. Serum 25(OH)D, intact parathyroid hormone (PTH), aminoterminal propeptide of type I collagen (P1NP), and Cterminal telopeptide of type I collagen (?-CTX) levels were measured by electrochemiluminescence. BMD was determined by dual x-ray absorptiometry (DXA) at lumbar spine, femoral neck, and total hip. Results Serum 25(OH)D levels were below 10, 20, and 30 ng/ml in 5, 40, and 83%of participants, respectively. There was a significant seasonal difference in mean serum 25(OH)D, with higher levels in summer?autumn. In multivariate analysis, 25(OH)D levels were negatively correlated with age, serum PTH and creatinine, body mass index, smoking, alcohol intake, and a number of chronic diseases, but positively with dairy calcium intake. The magnitude of the difference in serum PTH according to 25(OH)D quartiles was not influenced by calcium intake. A threshold of serum 25(OH)D around 30 ng/ml was observed for serum PTH and hip BMD. Conclusions Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion. Programs to improve vitamin D status may be required in our country

Rab11 and Actin Cytoskeleton Participate in Giardia lamblia Encystation, Guiding the Specific Vesicles to the Cyst Wall

The encystation process is crucial for survival and transmission of Giardia lamblia to new hosts. During this process, vesicular trafficking and the cytoskeleton play important roles. In eukaryotic cells, intracellular transport is regulated by proteins, including Rab-GTPases and SNAREs, which regulate vesicle formation along with recognition of and binding to the target membrane. Cytoskeletal structures are also involved in these processes. In this study, we demonstrate the participation of Rab11 in the transport of encystation-specific vesicles (ESVs). Additionally, we demonstrate that disruption of actin microfilaments affects ESVs transport. The modification of actin dynamics was also correlated with a reduction in rab11 and cwp1 expression. Furthermore, down-regulation of rab11 mRNA by a specific hammerhead ribozyme caused nonspecific localization of CWP1. We thus provide new information about the molecular machinery that regulates Giardia lamblia encystation. Given our findings, Rab11 and actin may be useful targets to block Giardia encystation