The Role of the Primary Cilium in Sensing Extracellular pH

Biosensors on the membrane of the vascular endothelium are responsible for sensing mechanical and chemical signals in the blood. Transduction of these stimuli into intracellular signaling cascades regulate cellularprocesses including ion transport, gene expression, cellproliferation, and/or cell death. The primary cilium is a well-known biosensor of shear stress but its role in sensing extracellular pH change has never been examined. As a cellular extension into the immediate microenvironment, the ciliumcould be a prospective sensor for changes in pHand regulator of acid response in cells. We aim to test our hypothesis that the primary cilium plays the role of an acid sensor in cells using vascular endothelial and embryonic fibroblast cells as in vitro models. We measure changes in cellular pH using pH-sensitive 2\u27,7\u27-biscarboxyethy1-5,6-carboxyfluorescein acetoxy-methylester (BCECF) fluorescence and mitogen-activated protein kinase (MAPK) activity to quantify responses to both extracellular pH (pHo) and intracellular pH (pHi) changes. Our studies show that changes in pHo affect pHi in both wild-type and cilia-less Tg737 cells and that the kinetics of the pHi response are similar in both cells. Acidic pHo or pHi was observed to change the length of primary cilia in wild-type cells while the cilia in Tg737 remained absent. Vascular endothelial cells respond to acidic pH through activation of ERK1/2 and p38-mediated signaling pathways. The cilia-less Tg737 cells exhibit delayed responsiveness to pHo dependent and independent pHi acidification as depicted in the phosphorylation profile of ERK1/2 and p38. Otherwise, intracellular pH homeostatic response to acidic pHo is similar between wild-type and Tg737 cells, indicating that the primary cilia may not be the sole sensor for physiological pH changes. These endothelial cells respond to pH changes with a predominantly K+-dependent pHi recovery mechanism, regardless of ciliary presence or absence

Cord blood Vitamin D levels in newborns and its correlation with anthropometric indices of baby: A cross-sectional study

Objectives: The objectives were to study the cord blood Vitamin D levels in term neonates and the association of Vitamin D deficiency with birth weight and crown-heel length. Materials and Methods: This cross-sectional study was performed in the department of pediatrics at the tertiary care center. All term singleton infants were included in the study. A detailed history from the mothers was taken, and complete anthropometric assessment of babies was done. Cord blood was collected, transported, and analyzed for Vitamin D levels. Data were analyzed using SPSS software. Results: A total of 202 children were enrolled. The median cord Vitamin D level was 16.0 ng/dl (interquartile range 13–18.8 ng/dl). Deficiency of Vitamin D was noted in 162 babies (80.6%) and insufficiency in 26 (13%) neonates. A total of 92.6% (151) of Vitamin D-deficient babies were low birth weight (LBW) (p<0.001) and 96.5% (157) of babies of the Vitamin D-deficient babies had crown-heel length <50 cm (p<0.001). Conclusion: Majority of the studied newborns were deficient in Vitamin D, and a positive correlation was found between Vitamin D deficiency and LBW and decreased crown-heel length

Color vison deficieny among medical students: an unnoticed problem

ABSTRACT Color vision deficiency, most of the time remains an unnoticed problem; although it is not very rare. The faculty of appreciation of color is essential for our smooth daily activities. Unfortunately, even many doctors do not know the severity of their color vision deficiency and tend to assume it as slight, and a few, as in the general population, do not know about their disability. Some common difficulties reported by medical practitioners and medical students were in recognizing-widespread body color changes (pallor, cyanosis, jaundice, rashes, erythema of skin), colorful charts, slides, test-strips for blood and urine, body products: blood or bile in urine, faeces, sputum, vomit, microscopy, mouth and throat conditions, impressions presented in the Ishihara chart, titration end-points, tissue identification (surgery) etc. The present study was undertaken to evaluate the presence of congenital color vision deficiencies among the medical students. The study was carried out among the 1 st and 2 nd year medical students of Nepal Medical College and Teaching Hospital (n = 120) with the help of Ishihara chart, that was shown to all participants. They were asked to read the impressions in the color chart. The impression perceived by a person with normal color vision was different from the impression perceived by a person with color vision deficiency. It was noted that, among the study population (n = 120) 5.83% of the volunteers were color weak. Amongst the color-deficient volunteers, 57.0% were protanopic while 43.0% were deuteranopic. Medical students must be made aware of their congenital color vision deficiency and its effects on their work. Screening will enable the student and later the doctor to become aware of limitations in their powers of observation and devise ways of overcoming them; the patient will be protected from harm and litigation may be avoided when doctors have adapted their practice to their deficiency. Medical students and physicians must be screened for color vision deficiency and advised about it so they can take special care in clinical practice

Sensory Primary Cilium is a Responsive cAMP Microdomain in Renal Epithelia

Primary cilia are hair-like cellular extensions that sense microenvironmental signals surrounding cells. The role of adenylyl cyclases in ciliary function has been of interest because the product of adenylyl cyclase activity, cAMP, is relevant to cilia-related diseases. In the present study, we show that vasopressin receptor type-2 (V2R) is localized to cilia in kidney epithelial cells. Pharmacologic inhibition of V2R with tolvaptan increases ciliary length and mechanosensory function. Genetic knockdown of V2R, however, does not have any effect on ciliary length, although the effect of tolvaptan on ciliary length is dampened. Our study reveals that tolvaptan may have a cilia-specific effect independent of V2R or verapamil-sensitive calcium channels. Live-imaging of single cilia shows that V2R activation increases cilioplasmic and cytoplasmic cAMP levels, whereas tolvaptan mediates cAMP changes only in a cilia-specific manner. Furthermore, fluid-shear stress decreases cilioplasmic, but not cytoplasmic cAMP levels. Our data indicate that cilioplasmic and cytoplasmic cAMP levels are differentially modulated. We propose that the cilium is a critical sensor acting as a responsive cAMP microcompartment during physiologically relevant stimuli

Evidence of Polygenic Adaptation to High Altitude from Tibetan and Sherpa Genomes

Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude

Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently in Adult and Fetal Ovine Kidneys

Hypoxic environments at high altitude have significant effects on kidney injury. Following injury, renal primary cilia display length alterations. Primary cilia are mechanosensory organelles that regulate tubular architecture. The effect of hypoxia on cilia length is still controversial in cultured cells, and no corresponding in vivo study exists. Using fetal and adult sheep, we here study the effect of chronic hypobaric hypoxia on the renal injury, intracellular calcium signaling and the relationship between cilia length and cilia function. Our results show that although long-term hypoxia induces renal fibrosis in both fetal and adult kidneys, fetal kidneys are more susceptible to hypoxia-induced renal injury. Unlike hypoxic adult kidneys, hypoxic fetal kidneys are characterized by interstitial edema, tubular disparition and atrophy. We also noted that there is an increase in the cilia length as well as an increase in the cilia function in the hypoxic fetal proximal and distal collecting epithelia. Hypoxia, however, has no significant effect on primary cilia in the adult kidneys. Increased cilia length is also associated with greater flow-induced intracellular calcium signaling in renal epithelial cells from hypoxic fetuses. Our studies suggest that while hypoxia causes renal fibrosis in both adult and fetal kidneys, hypoxia-induced alteration in cilia length and function are specific to more severe renal injuries in fetal hypoxic kidneys

Vanishing wildlife corridors and options for restoration: a case study from Tanzania

Conserving wildlife corridors is increasingly important for maintaining ecological and genetic connectivity in times of unprecedented habitat fragmentation. Documenting connectivity loss, assessing root causes, and exploring restoration options are therefore priority conservation goals. A 2009 nationwide assessment in Tanzania documented 31 major remaining corridors, the majority of which were described as threatened. The corridor between the Udzungwa Mountains and the Selous Game Reserve in south-central Tanzania, a major link between western and southern wildlife communities, especially for the African elephant Loxodonta africana, provides an illuminating case study. A preliminary assessment in 2005 found that connectivity was barely persisting via two remaining routes. Here we present assessments of these two corridors conducted from 2007-2010, using a combination of dung surveys, habitat mapping and questionnaires. We found that both corridor routes have become closed over the last five years. Increased farming and livestock keeping, associated with both local immigration and population growth, were the main reasons for corridor blockage. However, continued attempts by elephants to cross by both routes suggest that connectivity can be restored. This entails a process of harmonizing differing land owners and uses towards a common goal. We provide recommendations for restoring lost connectivity and discuss the prospects for preventing further loss of corridors across the country