Microglia are the resident immune cells of the CNS, and their response to infection, injury and disease is well documented. More recently, microglia have been shown to play a role in normal CNS ...development, with the fractalkine-Cx3cr1 signaling pathway of particular importance. This work describes the interaction between the light-sensitive photoreceptors and microglia during eye opening, a time of postnatal photoreceptor maturation. Genetic removal of Cx3cr1 (
) led to an early retinal dysfunction soon after eye opening postnatal day 17 (P17) and cone photoreceptor loss (P30 onward) in mice of either sex. This dysfunction occurred at a time when fractalkine expression was predominantly outer retinal, when there was an increased microglial presence near the photoreceptor layer and increased microglial-cone photoreceptor contacts. Photoreceptor maturation and outer segment elongation was coincident with increased opsin photopigment expression in wild-type retina, while this was aberrant in the
retina and outer segment length was reduced. A beadchip array highlighted Cx3cr1 regulation of genes involved in the photoreceptor cilium, a key structure that is important for outer segment elongation. This was confirmed with quantitative PCR with specific cilium-related genes,
and
, downregulated at eye opening (P14). While the overall cilium structure was unaffected, expression of Rpgr, Rpgrip1, and centrin were restricted to more proximal regions of the transitional zone. This study highlighted a novel role for microglia in postnatal neuronal development within the retina, with loss of fractalkine-Cx3cr1 signaling leading to an altered distribution of cilium proteins, failure of outer segment elongation and ultimately cone photoreceptor loss.
Microglia are involved in CNS development and disease. This work highlights the role of microglia in postnatal development of the light-detecting photoreceptor neurons within the mouse retina. Loss of the microglial Cx3cr1 signaling pathway resulted in specific alterations in the cilium, a key structure in photoreceptor outer segment elongation. The distribution of key components of the cilium transitional zone, Rpgr, Rpgrip1, and centrin, were altered in retinae lacking Cx3cr1 with reduced outer segment length and cone photoreceptor death observed at later postnatal ages. This work identifies a novel role for microglia in the postnatal maturation of retinal photoreceptors.
We present the noise performance of high electron mobility transistors (HEMT) developed by CNRS/C2N laboratory. Various HEMT’s gate geometries with 2 pF to 230 pF input capacitance have been studied ...at 4 K. A model for both voltage and current noises has been developed with frequency dependence up to 1 MHz. These HEMTs exhibit low dissipation, excellent noise performance and can advantageously replace traditional Si-JFETs for the readout of high impedance thermal sensor and semiconductor ionization cryogenic detectors. Our model predicts that cryogenic germanium detectors of 30 g with 10 eV heat and 20 eV
ee
baseline resolution are feasible if read out by HEMT-based amplifiers. Such resolution allows for high discrimination between nuclear and electron recoils at low threshold. This capability is of major interest for coherent elastic neutrino scattering and low-mass dark matter experiments such as Ricochet and EDELWEISS.
Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in ...the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.
Astrophysical observations indicate that dark matter constitutes most of the mass in our universe, but its nature remains unknown. Over the past decade, the Cryogenic Dark Matter Search (CDMS II) ...experiment has provided world-leading sensitivity for the direct detection of weakly interacting massive particle (WIMP) dark matter. The final exposure of our low-temperature germanium particle detectors at the Soudan Underground Laboratory yielded two candidate events, with an expected background of 0.9 ± 0.2 events. This is not statistically significant evidence for a WIMP signal. The combined CDMS II data place the strongest constraints on the WIMP-nucleon spin-independent scattering cross section for a wide range of WIMP masses and exclude new parameter space in inelastic dark matter models.
Abstract
The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize ...the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/min kg) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/min kg) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/min kg). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration–time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.
One of the major challenges for dairy producers is to produce, harvest, and store high-quality colostrum and feed it to their replacement heifer calves. Limited published data are available in ...Australia regarding the relationship between colostrum management, hygiene, and quality. The objectives of this study were to investigate (1) the colostrum storage and handling practices carried out on farm; (2) the immunoglobulin concentration and bacterial composition of colostrum being fed to replacement dairy heifer calves; (3) the percentage of colostrum being fed to replacement dairy heifer calves that meet industry recommendations; and (4) risk factors for bacterial contamination of colostrum. The study was carried out on 24 dairy farms located near Rochester, Victoria, Australia. Two hundred forty colostrum samples were collected (10 samples per farm). Each farm harvested and stored first-milking colostrum under normal farm conditions. A 10-mL sample of the colostrum was collected in a sterile container immediately before feeding, and a Brix refractometer reading was taken. The samples were then frozen at −4°C and submitted for bacterial concentration analysis. Fifty-eight percent of colostrum samples met the recommended industry standard of a total plate count (TPC) of <100,000cfu/mL, and 94% of colostrum samples met the recommended industry standard of total coliform count (TCC) of 10,000cfu/mL. However, when all the current industry recommendations for TPC, TCC, and Brix refractometer percentage for colostrum quality were considered, only 23% of the samples met all standards. These findings demonstrate that a large number of calves were at risk of receiving colostrum of poor quality, with high bacterial loads that may have interfered with the acquisition of transfer of passive immunity and affected calf health. Further investigation is required to identify the farm-specific factors that may influence the level of bacterial contamination of colostrum. Recommendations as a result of this study include refrigeration of excess colostrum shortly (within 1h) after collection and thorough disinfection of the calf feeding apparatus before use.
This study assessed mental and physical health correlates of dispositional forgiveness and religious coping responses in 213 help‐seeking veterans diagnosed with PTSD. Controlling for age, ...socioeconomic status, ethnicity, combat exposure, and hostility, the results indicated that difficulty forgiving oneself and negative religious coping were related to depression, anxiety, and PTSD symptom severity. Difficulty forgiving others was associated with depression and PTSD symptom severity, but not anxiety. Positive religious coping was associated with PTSD symptom severity in this sample. Further investigations that delineate the relevance of forgiveness and religious coping in PTSD may enhance current clinical assessment and treatment approaches.
Olfactory and gustatory changes may contribute to poor appetite and food aversion in chronic kidney disease (CKD), though the prevalence of olfactory and gustatory dysfunction is not known in the CKD ...population.
We conducted a cross-sectional study among 3527 US adults aged ≥40 years old in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. We measured the prevalence of olfactory and gustatory dysfunction among patients with CKD defined as eGFR < 60 ml/min/1.73m
using the "scratch and sniff" NHANES Pocket Smell Test and quinine whole-mouth test. We also examined the association between CKD and olfactory/gustatory dysfunction, and nutritional markers.
The prevalence of olfactory dysfunction was 30% among CKD and 15% among non-CKD (p < 0.001). The prevalence of gustatory dysfunction was 13% among CKD and 17% among non-CKD (p = 0.10). After adjusting for confounders, CKD was significantly associated with olfactory dysfunction (OR = 1.47, 95% CI 1.07, 2.01; p = 0.02) but not gustatory dysfunction (OR = 1.76, 95%CI 0.99, 3.11; p = 0.05). Among the CKD population, the odds of olfactory dysfunction was 72% higher for every 10 kg decrease in grip strength (OR = 1.72, 95% CI 1.39, 2.13; adjusted p = 0.005).
CKD was associated with higher odds of olfactory but not gustatory dysfunction. Olfactory dysfunction was associated with lower grip strength among those with CKD. Screening and early intervening on olfactory dysfunction among CKD may preserve muscle strength and improve nutritional status in this vulnerable population.
PDF
