Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing.

Glia interact with multiple neurons, but it is unclear whether their interactions with each neuron are different. Our interrogation at single-cell resolution reveals that a single glial cell exhibits specificity in its interactions with different contacting neurons. Briefly, C. elegans amphid sheath (AMsh) glia apical-like domains contact 12 neuron-endings. At these ad-neuronal membranes, AMsh glia localize the K/Cl transporter KCC-3 to a microdomain exclusively around the thermosensory AFD neuron to regulate its properties. Glial KCC-3 is transported to ad-neuronal regions, where distal cilia of non-AFD glia-associated chemosensory neurons constrain it to a microdomain at AFD-contacting glial membranes. Aberrant KCC-3 localization impacts both thermosensory (AFD) and chemosensory (non-AFD) neuron properties. Thus, neurons can interact non-synaptically through a shared glial cell by regulating microdomain localization of its cues. As AMsh and glia across species compartmentalize multiple cues like KCC-3, we posit that this may be a broadly conserved glial mechanism that modulates information processing across multimodal circuits.

Molecular heterogeneity of C. elegans glia across sexes.

A comprehensive description of nervous system function, and sex dimorphism within, is incomplete without clear assessment of the diversity of its component cell types, neurons and glia. C. elegans has an invariant nervous system with the first mapped connectome of a multicellular organism and single-cell atlas of component neurons. Here we present single nuclear RNA-seq evaluation of glia across the entire adult C. elegans nervous system, including both sexes. Machine learning models enabled us to identify both sex-shared and sex-specific glia and glial subclasses. We have identified and validated molecular markers in silico and in vivo for these molecular subcategories. Comparative analytics also reveals previously unappreciated molecular heterogeneity in anatomically identical glia between and within sexes, indicating consequent functional heterogeneity. Furthermore, our datasets reveal that while adult C. elegans glia express neuropeptide genes, they lack the canonical unc-31/CAPS-dependent dense core vesicle release machinery. Thus, glia employ alternate neuromodulator processing mechanisms. Overall, this molecular atlas, available at www.wormglia.org, reveals rich insights into heterogeneity and sex dimorphism in glia across the entire nervous system of an adult animal.

Neuron cilia constrain glial regulators to microdomains around distal neurons.

Each glia interacts with multiple neurons, but the fundamental logic of whether it interacts with all equally remains unclear. We find that a single sense-organ glia modulates different contacting neurons distinctly. To do so, it partitions regulatory cues into molecular microdomains at specific neuron contact-sites, at its delimited apical membrane. For one glial cue, K/Cl transporter KCC-3, microdomain-localization occurs through a two-step, neuron-dependent process. First, KCC-3 shuttles to glial apical membranes. Second, some contacting neuron cilia repel it, rendering it microdomain-localized around one distal neuron-ending. KCC-3 localization tracks animal aging, and while apical localization is sufficient for contacting neuron function, microdomain-restriction is required for distal neuron properties. Finally, we find the glia regulates its microdomains largely independently. Together, this uncovers that glia modulate cross-modal sensor processing by compartmentalizing regulatory cues into microdomains. Glia across species contact multiple neurons and localize disease-relevant cues like KCC-3. Thus, analogous compartmentalization may broadly drive how glia regulate information processing across neural circuits.

A Systematic Review of Inequalities in the Mental Health Experiences of Black African, Black Caribbean and Black-mixed UK Populations: Implications for Action.

BACKGROUND: Measurable differences in the experience and treatment of mental health conditions have been found to exist between different racial categories of community groups. The objective of this research was to review the reported mental health of Black African-Caribbean communities in the UK, determinants of mental health, and interventions to enhance their experiences of mental health services. METHOD: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement was applied. To be included, papers must be published in a peer reviewed journal; report on adult populations (over 18) from any of Black African, Black Caribbean or Black mixed people in the UK; and assess (quantitative), or discuss (qualitative) mental health experiences, determinants of mental health, or interventions intended to enhance experiences of mental health services among the target population. The aims, inclusion criteria, data extraction, and data quality evaluation were specified in advance. Searches were conducted using EBSCO (PsychInfo; MEDLINE; CINAHL Plus; psychology and behavioural sciences collection). The search strategy included search terms relating to the aim. Risk of bias was assessed using a standard tool, records were organised using Endnote, and data were extracted and synthesised using Microsoft Excel. RESULTS: Thirty-six studies were included, of which 26 were quantitative and six reported exclusively on Black participants. Black populations were less likely to access mental health support via traditional pathways due to stigma and mistrust of mental health services. Black Africans especially, sought alternative help from community leaders, which increased the likelihood of accessing treatment at the point of crisis or breakdown, which in turn increased risk of being detained under the Mental Health Act and via the criminal justice system. DISCUSSION: Findings suggest a cycle of poor mental health, coercive treatment, stigma, and mistrust of services as experienced by Black communities. Evidence was limited by poorly defined ethnic categories, especially where Black populations were subsumed into one category. It is recommended that mental health services work collaboratively with cultural and faith communities in supporting Black people to cope with mental illness, navigate mental health pathways, and provide culturally appropriate advice. Protocol Registration Number PROSPERO CRD42021261510.

Social touch during development: Long-term effects on brain and behavior.

In this paper, our goal is to explore what is known about the role of social touch during development. We first address the neural substrates of social touch and the role of tactile experience in neural development. We discuss natural variation in early exposure to social touch, followed by a discussion on experimental manipulations of social touch during development and "natural experiments", such as early institutionalization. We then consider the role of other developmental and experiential variables that predict social touch in adults. Throughout, we propose and consider new theoretical models of the role of social touch during development on later behavior and neurobiology.

International collaborative study for the calibration of proposed International Standards for thromboplastin, rabbit, plain, and for thromboplastin, recombinant, human, plain.

Essentials Two candidate International Standards for thromboplastin (coded RBT/16 and rTF/16) are proposed. International Sensitivity Index (ISI) of proposed standards was assessed in a 20-centre study. The mean ISI for RBT/16 was 1.21 with a between-centre coefficient of variation of 4.6%. The mean ISI for rTF/16 was 1.11 with a between-centre coefficient of variation of 5.7%. SUMMARY: Background The availability of International Standards for thromboplastin is essential for the calibration of routine reagents and hence the calculation of the International Normalized Ratio (INR). Stocks of the current Fourth International Standards are running low. Candidate replacement materials have been prepared. This article describes the calibration of the proposed Fifth International Standards for thromboplastin, rabbit, plain (coded RBT/16) and for thromboplastin, recombinant, human, plain (coded rTF/16). Methods An international collaborative study was carried out for the assignment of International Sensitivity Indexes (ISIs) to the candidate materials, according to the World Health Organization (WHO) guidelines for thromboplastins and plasma used to control oral anticoagulant therapy with vitamin K antagonists. Results Results were obtained from 20 laboratories. In several cases, deviations from the ISI calibration model were observed, but the average INR deviation attributabled to the model was not greater than 10%. Only valid ISI assessments were used to calculate the mean ISI for each candidate. The mean ISI for RBT/16 was 1.21 (between-laboratory coefficient of variation [CV]: 4.6%), and the mean ISI for rTF/16 was 1.11 (between-laboratory CV: 5.7%). Conclusions The between-laboratory variation of the ISI for candidate material RBT/16 was similar to that of the Fourth International Standard (RBT/05), and the between-laboratory variation of the ISI for candidate material rTF/16 was slightly higher than that of the Fourth International Standard (rTF/09). The candidate materials have been accepted by WHO as the Fifth International Standards for thromboplastin, rabbit plain, and thromboplastin, recombinant, human, plain.

Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services.

These guidelines, informed by the best available evidence and consensus expert opinion, provide a framework to guide the timely initiation of chemotherapy for treating cancer. They sit at the intersection of patient experience, state-of-the-art disease management and rational efficient service provision for these patients at a system level. Internationally, cancer waiting times are routinely measured and publicly reported. In Australia, there are existing policies and guidelines relating to the timeliness of cancer care for surgery and radiation therapy; however, until now, equivalent guidance for chemotherapy was lacking. Timeliness of care should be informed, where available, by evidence for improved patient outcomes. Independent of this, it should be recognised that shorter waiting periods are likely to reduce patient anxiety. While these guidelines were developed as part of a proposed framework for consideration by the Victorian Department of Health, they are clinically relevant to national and international cancer services. They are intended to be used by clinical and administrative staff within cancer services. Adoption of these guidelines, which are for the timely triage, review and treatment of cancer patients receiving systemic chemotherapy, aims to ensure that patients receive care within a timeframe that will maximise health outcomes, and that access to care is consistent and equitable across cancer services. Local monitoring of performance against this guideline will enable cancer service providers to manage proactively future service demand.

Reproductive health indicators of fishes from Pennsylvania watersheds: association with chemicals of emerging concern.

Fishes were collected at 16 sites within the three major river drainages (Delaware, Susquehanna, and Ohio) of Pennsylvania. Three species were evaluated for biomarkers of estrogenic/antiandrogenic exposure, including plasma vitellogenin and testicular oocytes in male fishes. Smallmouth bass Micropterus dolomieu, white sucker Catostomus commersonii, and redhorse sucker Moxostoma species were collected in the summer, a period of low flow and low reproductive activity. Smallmouth bass were the only species in which testicular oocytes were observed; however, measurable concentrations of plasma vitellogenin were found in male bass and white sucker. The percentage of male bass with testicular oocytes ranged from 10 to 100%, with the highest prevalence and severity in bass collected in the Susquehanna drainage. The percentage of males with plasma vitellogenin ranged from 0 to 100% in both bass and sucker. Biological findings were compared with chemical analyses of discrete water samples collected at the time of fish collections. Estrone concentrations correlated with testicular oocytes prevalence and severity and with the percentage of male bass with vitellogenin. No correlations were noted with the percentage of male sucker with vitellogenin and water chemical concentrations. The prevalence and severity of testicular oocytes in bass also correlated with the percent of agricultural land use in the watershed above a site. Two sites within the Susquehanna drainage and one in the Delaware were immediately downstream of wastewater treatment plants to compare results with upstream fish. The percentage of male bass with testicular oocytes was not consistently higher downstream; however, severity did tend to increase downstream.

Detection of MYD88 L265P in peripheral blood of patients with Waldenström's Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance.

MYD88 L265P is highly prevalent in Waldenstrom's Macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (MGUS). We investigated whether MYD88 L265P could be identified by peripheral blood (PB) allele-specific PCR. MYD88 L265P was detected in untreated WM (114/118; 96.6%); previously treated WM (63/102; 61.8%); and IgM MGUS (5/12; 41.7%) but in none of 3 hyper-IgM or 40 healthy individuals. Median PB MYD88 L265P ΔCt was 3.77, 7.24, 10.89, 12.33 and 14.07 for untreated WM, previously treated WM, IgM MGUS, hyper-IgM and healthy individuals, respectively (P<0.0001). For the 232 IgM MGUS and WM patients, PB MYD88 L265P ΔCt moderately correlated to bone marrow (BM) disease (r=-0.3553; P<0.0001), serum IgM (r=-0.3262; P<0.0001) and hemoglobin (r=0.3005; P<0.0001) levels. PB MYD88 L265P ΔCt and serum IgM correlated similarly with BM disease burden. For positive patients, PB MYD88 L265P ΔCt was <6.5 in 100/114 (88%) untreated WM, and >6.5 in 4/5 (80%) IgM MGUS patients (P=0.0034). Attainment of a negative PB MYD88 L265P mutation status was associated with lower BM disease (P=0.001), serum IgM (P=0.019) and higher hemoglobin (P=0.004) levels in treated patients. These studies show the feasibility for detecting MYD88 L265P by PB examination, and the potential for PB MYD88 L265P ΔCt use in the diagnosis and management of WM patients.

Phase-sensitive frequency conversion of quadrature modulated signals.

Two mechanisms that can make frequency conversion based on nonlinear mixing dependent on the phase of the input signal are identified. A novel phase-to-polarization converter that converts the orthogonal phase components of an input signal to two orthogonally polarized outputs is proposed. The operation of this scheme and a previously reported scheme at an increased symbol rate are simulated with semiconductor optical amplifiers (SOAs) as the nonlinear devices. Experimental results demonstrate the effectiveness of SOAs for nonlinear mixing over a wide range of wavelengths and difference frequencies and confirm the accuracy of the numerical model.

Interaction between nitric oxide and superoxide in the macula densa in aldosterone-induced alterations of tubuloglomerular feedback.

Tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole is modulated by a balance between release of superoxide (O(2)(-)) and nitric oxide (NO) in macula densa (MD) cells. Aldosterone activates mineralocorticoid receptors that are expressed in the MD and induces both NO and O(2)(-) generation. We hypothesize that aldosterone enhances O(2)(-) production in the MD mediated by protein kinase C (PKC), which buffers the effect of NO in control of TGF response. Studies were performed in microdissected and perfused MD and in a MD cell line, MMDD1 cells. Aldosterone significantly enhanced O(2)(-) generation both in perfused MD and in MMDD1 cells. When aldosterone (10(-7) mol/l) was added in the tubular perfusate, TGF response was reduced from 2.4 ± 0.3 µm to 1.4 ± 0.2 µm in isolated perfused MD. In the presence of tempol, a O(2)(-) scavenger, TGF response was 1.5 ± 0.2 µm. In the presence of both tempol and aldosterone in the tubular perfusate, TGF response was further reduced to 0.4 ± 0.2 µm. To determine if PKC is involved in aldosterone-induced O(2)(-) production, we exposed the O(2)(-) cells to a nonselective PKC inhibitor chelerythrine chloride, a specific PKCα inhibitor Go6976, or a PKCα siRNA, and the aldosterone-induced increase in O(2)(-) production was blocked. These data indicate that aldosterone-stimulated O(2)(-) production in the MD buffers the effect of NO in control of TGF response, an effect that was mediated by PKCα.

Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors.

Chronic aldosterone administration increases glomerular filtration rate, whereas inhibition of mineralocorticoid receptors (MRs) markedly attenuates glomerular hyperfiltration and hypertension associated with primary aldosteronism or obesity. However, the mechanisms by which aldosterone alters glomerular filtration rate regulation are poorly understood. In the present study, we hypothesized that aldosterone suppresses tubuloglomerular feedback (TGF) via activation of macula densa MR. First, we observed the expression of MR in macula densa cells isolated by laser capture microdissection and by immunofluorescence in rat kidneys. Second, to investigate the effects of aldosterone on TGF in vitro, we microdissected the juxtaglomerular apparatus from rabbit kidneys and perfused the afferent arteriole and distal tubule simultaneously. Under control conditions, TGF was 2.8±0.2 µm. In the presence of aldosterone (10(-8) mol/L), TGF was reduced by 50%. The effect of aldosterone to attenuate TGF was blocked by the MR antagonist eplerenone (10(-5) mol/L). Third, to investigate the effect of aldosterone on TGF in vivo, we performed micropuncture, and TGF was determined by maximal changes in stop-flow pressure P(sf) when tubular perfusion rate was increased from 0 to 40 nL/min. Aldosterone (10(-7) mol/L) decreased ΔP(sf) from 10.1±1.4 to 7.7±1.2 mm Hg. In the presence of l-NG-monomethyl arginine citrate (10(-3) mol/L), this effect was blocked. We conclude that MRs are expressed in macula densa cells and can be activated by aldosterone, which increases nitric oxide production in the macula densa and blunts the TGF response.

Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) study.

Progressive renal fibrosis is a characteristic of all the diseases that cause renal failure and is invariably accompanied by a prominent leukocyte infiltration in the kidney. The goal of this study was to determine the association between the circulating specific leukocyte types and incident chronic kidney disease (CKD). In a cohort of 10,056 middle-aged white and African American adults, levels of circulating neutrophils, lymphocytes, and monocytes were measured at baseline; blood pressure (BP) and serum creatinine were measured and estimated glomerular filtration rate (eGFR) was calculated at baseline and 3 and 9 years later; and surveillance for first hospitalization or death with CKD was carried out over a mean follow-up of 7.4 years (maximum, 11.9 years). Increased neutrophil levels and decreased lymphocyte levels were significantly associated with greater CKD incidence after adjustment for covariates. African Americans tended to have similar but stronger patterns of association between circulating leukocytes and CKD incidence than whites, although the differences between race groups were not statistically significant. We also found that eGFR and BP were higher at each visit in African Americans than whites between ages 45 and 65. These findings support a potential role for circulating specific leukocytes in the pathogenesis of kidney dysfunction, especially in African Americans, indicating the leukocyte-related renal mechanism of essential hypertension (HT).

Pregnancy in type 2B VWD: a case series.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

Phase discrimination and simultaneous frequency conversion of the orthogonal components of an optical signal by four-wave mixing in an SOA.

Simultaneous conversion of the two orthogonal phase components of an optical input to different output frequencies has been demonstrated by simulation and experiment. A single stage of four-wave mixing between the input signal and four pumps derived from a frequency comb was employed. The nonlinear device was a semiconductor optical amplifier, which provided overall signal gain and sufficient contrast for phase sensitive signal processing. The decomposition of a quadrature phase-shift keyed signal into a pair of binary phase-shift keyed outputs at different frequencies was also demonstrated by simulation.

Aldosterone stimulates superoxide production in macula densa cells.

Two major factors which regulate tubuloglomerular feedback (TGF)-mediated constriction of the afferent arteriole are release of superoxide (O(2)(-)) and nitric oxide (NO) by macula densa (MD) cells. MD O(2)(-) inactivates NO; however, among the factors that increase MD O(2)(-) release, the role of aldosterone is unclear. We hypothesize that aldosterone activates the mineralocorticoid receptor (MR) on MD cells, resulting in increased O(2)(-) production due to upregulation of cyclooxygenase-1 (COX-2) and NOX-2, and NOX-4, isoforms of NAD(P)H oxidase. Studies were performed on MMDD1 cells, a renal epithelial cell line with properties of MD cells. RT-PCR and Western blotting confirmed the expression of MR. Aldosterone (10(-8) mol/l for 30 min) doubled MMDD1 cell O(2)(-) production, and this was completely blocked by MR inhibition with 10(-5) mol/l eplerenone. RT-PCR, real-time PCR, and Western blotting demonstrated aldosterone-induced increases in COX-2, NOX-2, and NOX-4 expression. Inhibition of COX-2 (NS398), NADPH oxidase (apocynin), or a combination blocked aldosterone-induced O(2)(-) production to the same degree. These data suggest that aldosterone-stimulated MD O(2)(-) production is mediated by COX-2 and NADPH oxidase. Next, COX-2 small-interfering RNA (siRNA) specifically decreased COX-2 mRNA without affecting NOX-2 or NOX-4 mRNAs. In the presence of the COX-2 siRNA, the aldosterone-induced increases in COX-2, NOX-2, and NOX-4 mRNAs and O(2)(-) production were completely blocked, suggesting that COX-2 causes increased expression of NOX-2 and NOX-4. In conclusion 1) MD cells express MR; 2) aldosterone increases O(2)(-) production by activating MR; and 3) aldosterone stimulates COX-2, which further activates NOX-2 and NOX-4 and generates O(2)(-). The resulting balance between O(2)(-) and NO in the MD is important in modulating TGF.

Generation of 21.3 Gbaud 8PSK signal using an SOA-based all-optical phase modulator.

We describe a novel SOA-based all-optical pure-phase modulator, and show how deleterious cross-gain modulation from the SOAs can be suppressed by utilizing an integrated interferometer structure. We experimentally demonstrate the use of the optical gate as a π/4 phase modulator producing 21.3 Gbaud 8PSK from 21.3 Gbit/s OOK and 21.3 Gbaud QPSK inputs. The modulator produces 3 dB of gain and coherent detection-based bit error rate measurements indicate a 2.4 dB excess penalty.

All-optical technique for modulation format conversion from on-off-keying to alternate-mark-inversion.

We propose and numerically investigate for the first time a novel all-optical on-off-keying to alternate-mark-inversion modulation format converter operating at 40 Gbps employing a semiconductor optical amplifier (SOA)-based Mach-Zehnder interferometer (MZI). We demonstrate that this SOA-MZI operates as a pulse subtractor, and in the absence of patterning will produce perfectly phase inverted pulses regardless of the individual SOA phase excursions. We use a comprehensive computer model to illustrate the impact of patterning on the output phase modulation, which is quantified through the definition of the phase compression factor.

Association between circulating specific leukocyte types and blood pressure: the atherosclerosis risk in communities (ARIC) study.

Although total white blood cell (WBC) count has been associated with hypertension, the association between specific WBC types and blood pressure (BP) levels has not been studied. In a cohort of 5746 middle-age African-American and white adults free of clinical cardiovascular disease and cancer and not taking hypertension or anti-inflammatory medications, BP was measured at baseline and 3, 6, and 9 years later. Levels of circulating neutrophils, lymphocytes, and monocytes were measured at baseline. In African-Americans, but much less so in whites, increased neutrophil levels and decreased lymphocyte levels were significantly associated with elevation of BP but did not influence the rate of change of BP over time. The mean BP difference between the highest and lowest quartiles of neutrophils was approximately 8 mm Hg for systolic BP (SBP), 4 mm Hg for mean arterial pressure (MAP), and 5 mm Hg for pulse pressure (PP). The mean BP difference between the lowest and highest quartiles of lymphocytes was approximately 6 mm Hg for SBP, 2 mm Hg for diastolic BP (DBP), 3 mm Hg for MAP, and 4 mm Hg for PP. Increased neutrophils and decreased lymphocytes are significantly correlated with the regulation of BP and the development of hypertension, especially in African-Americans.

Pattern compensation in SOA-based gates.

We propose a novel scheme employing complementary data inputs to overcome the patterning normally associated with semiconductor optical amplifier based gates and demonstrate the scheme experimentally at 42.6Gb/s. The scheme not only avoids introducing patterning during switching, but also compensates for much of the patterning present on the input data. A novel gate was developed for the experiment to provide the complementary signals required for the scheme.