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Abstract Motility of pathogenic protozoa depends on flagella (synonymous with cilia) with axonemes containing nine doublet microtubules (DMTs) and two singlet microtubules. Microtubule inner proteins (MIPs) within DMTs influence axoneme stability and motility and provide lineage-specific adaptations, but individual MIP functions and assembly mechanisms are mostly unknown. Here, we show in the sleeping sickness parasite Trypanosoma brucei, that FAP106, a conserved MIP at the DMT inner junction, is required for trypanosome motility and functions as a critical interaction hub, directing assembly of several conserved and lineage-specific MIPs. We use comparative cryogenic electron tomography (cryoET) and quantitative proteomics to identify MIP candidates. Using RNAi knockdown together with fitting of AlphaFold models into cryoET maps, we demonstrate that one of these candidates, MC8, is a trypanosome-specific MIP required for parasite motility. Our work advances understanding of MIP assembly mechanisms and identifies lineage-specific motility proteins that are attractive targets to consider for therapeutic intervention.

Abstract Cardiac metabolic substrate preference shifts at parturition from carbohydrates to fatty acids. We hypothesized that thyroid hormone (T3) and palmitic acid (PA) stimulate fetal cardiomyocyte oxidative metabolism capacity. T3 was infused into fetal sheep to a target of 1.5 nM. Dispersed cardiomyocytes were assessed for lipid uptake and droplet formation with BODIPY‐labeled fatty acids. Myocardial expression levels were assessed PCR. Cardiomyocytes from naïve fetuses were exposed to T3 and PA, and oxygen consumption was measured with the Seahorse Bioanalyzer. Cardiomyocytes (130‐day gestational age) exposed to elevated T3 in utero accumulated 42% more long‐chain fatty acid droplets than did cells from vehicle‐infused fetuses. In utero T3 increased myocardial mRNA levels of CD36, CPT1A, CPT1B, LCAD, VLCAD, HADH, IDH, PDK4, and caspase 9. In vitro exposure to T3 increased maximal oxygen consumption rate in cultured cardiomyocytes in the absence of fatty acids, and when PA was provided as an acute (30 min) supply of cellular energy. Longer‐term exposure (24 and 48 h) to PA abrogated increased oxygen consumption rates stimulated by elevated levels of T3 in cultured cardiomyocytes. T3 contributes to metabolic maturation of fetal cardiomyocytes. Prolonged exposure of fetal cardiomyocytes to PA, however, may impair oxidative capacity.

Mutations in the small GTPase protein KRAS are one of the leading drivers of cancers including lung, pancreatic, and colorectal, as well as a group of developmental disorders termed “Rasopathies”. Recent breakthroughs in the development of mutant-specific KRAS inhibitors include the FDA approved drug Lumakras (Sotorasib, AMG510) for KRAS G12C-mutated non-small cell lung cancer (NSCLC), and MRTX1133, a promising clinical candidate for the treatment of KRAS G12D-mutated cancers. However, there are currently no FDA approved inhibitors that target KRAS mutations occurring at non-codon 12 positions. Herein, we focused on the KRAS mutant A146T, found in colorectal cancers, that exhibits a “fast-cycling” nucleotide mechanism as a driver for oncogenic activation. We developed a novel high throughput time-resolved fluorescence resonance energy transfer (TR-FRET) assay that leverages the reduced nucleotide affinity of KRAS A146T. As designed, the assay is capable of detecting small molecules that act to allosterically modulate GDP affinity or directly compete with the bound nucleotide. A pilot screen was completed to demonstrate robust statistics and reproducibility followed by a primary screen using a diversity library totaling over 83,000 compounds. Compounds yielding >50% inhibition of TR-FRET signal were selected as hits for testing in dose-response format. The most promising hit, UNC10104889, was further investigated through a structure activity relationship (SAR)-by-catalog approach in an attempt to improve potency and circumvent solubility liabilities. Overall, we present the TR-FRET platform as a robust assay to screen fast-cycling KRAS mutants enabling future discovery efforts for novel chemical probes and drug candidates.

Developmental programming of chronic adverse cardiovascular health outcomes has been studied both using numerous human populations and an array of animal models. However, the mechanisms that produce transgenerational effects have been difficult to study due to a lack of developmentally relevant models. As such, how increased disease risk is carried to the second generation has been poorly studied. We hypothesized that the endothelium which mediates many acute and chronic vascular inflammatory responses is a key player in these effects, and epidemiological studies implicate transgenerational nutritional effects on endothelial health. To study the mutigenerational effects of maternal undernutrition on offspring endothelial health, we developed a model of transgenerational nutritional stress in guinea pigs, a translationally relevant precocial species with a relatively short lifespan. First- and second-generation offspring were subjected to a high fat diet in adolescence to exacerbate negative cardiovascular health. To assess transcriptional changes, we performed bulk RNA-sequencing in carotid artery endothelial cells, with groups stratified as prenatal control or food restricted, and postnatal control or high fat diet. We detected statistically significant gene alterations for each dietary permutation, some of which were unique to treatments and other transcriptional signatures shared by multiple or all conditions. These findings highlight a core group of genes altered by high fat diet that is shared by all cohorts and a divergence of transgenerational effects between the prenatal ad libitum and dietary restriction groups. This study establishes the groundwork for this model to be used to better understand the interplay of prenatal stress and genetic reprogramming.

Introduction: The prenatal diagnosis of congenital heart disease (CHD) is a traumatic event that can cause expectant parents to experience anxiety, depression, and toxic stress. Prenatal exposure to stress may impact neonatal postoperative outcomes. In addition, expectant parents may have other psychosocial stressors that may compound maternal stress. We investigated the relationship between stress in pregnancies complicated by prenatally diagnosed CHD and their neonatal outcomes. Methods: A pilot retrospective cohort study of pregnancies with prenatally diagnosed critical CHD (2019–2021) was performed. The collected data included pregnancy characteristics and neonatal and postoperative outcomes (including the need for exogenous corticosteroid treatment (ECT)). In order to quantify prenatal stressors, a composite prenatal stress score (PSS) was established and utilized. Results: In total, 41 maternal–fetal dyads were evaluated. Thirteen (32%) neonates had single-ventricle anatomy. The need for ECT after CHD surgery was associated with higher pregnant patient PSS (p = 0.01). PSS did not correlate with birthweight, infection, or hypoglycemia in the neonatal period. Conclusions: Prenatal stress is multifactorial; higher PSS is correlates with post-bypass ECT, suggesting that a stressful intrauterine environment may be associated with worse neonatal postoperative outcomes.

Reduction of systemic autoimmunity using TNF blockers may also reduce inflammatory diseases in other organs. Here, the authors use a patient database and scRNA-seq to link autoimmune diseases to benign prostatic hyperplasia (BPH), and demonstrate that prostatic hyperplasia is reduced by TNF blockers in humans and mice.

Purpose Twenty-four hours of ambulatory blood pressure monitoring (ABPM) is recommended in several guidelines as the best method for diagnosing hypertension. In general, the prognostic value of ABPM is superior to single office blood pressure (BP) measurements. Unfortunately, some patients experience considerable discomfort during frequently repeated forceful cuff inflations. Materials and methods In this study we investigated the difference in mean daytime systolic BP (SBP) between low-frequency ABPM (LF-ABPM), measuring once every hour, and high-frequency ABPM (HF-ABPM), measuring three times an hour during daytime, and two times an hour during night-time. Results Seventy-one patients were included in the analysis. All included patients had an HF-ABPM performed first and within a few weeks they underwent an LF-ABPM. The average day time difference in SBP between the two frequencies was 3.8 mmHg (p-value = 0.07) for mild, 8.2 mmHg (p-value < 0.01) for moderate and 15 mmHg (p-value < 0.001) for severe hypertension. A similar pattern was seen for night-time SBP. This study suggests that mean BP is similar between the two measuring frequencies for normotensive and mild hypertensive patients, while HF-ABPM results in a higher 24-h mean BP for moderate- and severe hypertensive patients. Conclusion LF-ABPM may more correctly reflect the resting blood pressure in patients with moderate and severe hypertension.

Abstract The incidence of renal cell carcinoma (RCC) is increasing worldwide with an approximate 20% mortality rate. The challenge in RCC is the therapy-resistance. Cancer resistance to treatment employs multiple mechanisms due to cancer heterogeneity with multiple genetic and epigenetic alterations. These changes include aberrant overexpression of (1) anticancer cell death proteins (e.g., survivin/BIRC5), (2) DNA repair regulators (e.g., ERCC6) and (3) efflux pump proteins (e.g., ABCG2/BCRP); mutations and/or deregulation of key (4) oncogenes (e.g., MDM2, KRAS) and/or (5) tumor suppressor genes (e.g., TP5/p53); and (6) deregulation of redox-sensitive regulators (e.g., HIF, NRF2). Foci of tumor cells that have these genetic alterations and/or deregulation possess survival advantages and are selected for survival during treatment. We will review the significance of survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, TP5/p53, KRAS and AKT in treatment resistance as the potential therapeutic biomarkers and/or targets in RCC in parallel with our analized RCC-relevant TCGA genetic results from each of these gene/protein molecules. We then present our data to show the anticancer drug FL118 modulation of these protein targets and RCC cell/tumor growth. Finally, we include additional data to show a promising FL118 analogue (FL496) for treating the specialized type 2 papillary RCC.

Abstract Eukaryotic flagella (synonymous with cilia) rely on a microtubule-based axoneme, together with accessory filaments to carryout motility and signaling functions. While axoneme structures are well characterized, 3D ultrastructure of accessory filaments and their axoneme interface are mostly unknown, presenting a critical gap in understanding structural foundations of eukaryotic flagella. In the flagellum of the protozoan parasite Trypanosoma brucei (T. brucei), the axoneme is accompanied by a paraflagellar rod (PFR) that supports non-planar motility and signaling necessary for disease transmission and pathogenesis. Here, we employed cryogenic electron tomography (cryoET) with sub-tomographic averaging, to obtain structures of the PFR, PFR-axoneme connectors (PACs), and the axonemal central pair complex (CPC). The structures resolve how the 8 nm repeat of the axonemal tubulin dimer interfaces with the 54 nm repeat of the PFR, which consist of proximal, intermediate, and distal zones. In the distal zone, stacked “density scissors” connect with one another to form a “scissors stack network (SSN)” plane oriented 45° to the axoneme axis; and ~370 parallel SSN planes are connected by helix-rich wires into a paracrystalline array with ~90% empty space. Connections from these wires to the intermediate zone, then to overlapping layers of the proximal zone and to the PACs, and ultimately to the CPC, point to a contiguous pathway for signal transmission. Together, our findings provide insights into flagellum-driven, non-planar helical motility of T. brucei and have broad implications ranging from cell motility and tensegrity in biology, to engineering principles in bionics.

Applying machine learning methods to geographic data provides insights into spatial patterns in the data as well as assists in interpreting and describing environments. This paper investigates the results of k-means clustering applied to 51 geospatial layers, selected and scaled for a model of outdoor acoustic environments, in the continental United States. Silhouette and elbow analyses were performed to identify an appropriate number of clusters (eight). Cluster maps are shown and the clusters are described, using correlations between the geospatial layers and clusters to identify distinguishing characteristics for each cluster. A subclustering analysis is presented in which each of the original eight clusters is further divided into two clusters. Because the clustering analysis used geospatial layers relevant to modeling outdoor acoustics, the geospatially distinct environments corresponding to the clusters may aid in characterizing acoustically distinct environments. Therefore, the clustering analysis can guide data collection for the problem of modeling outdoor acoustic environments by identifying poorly sampled regions of the feature space (i.e., clusters which are not well-represented in the training data).

Abstract Repeated cuff‐based blood pressure (BP) measurements may cause discomfort resulting in stress and erroneous recording values. SOMNOtouch NIBP is an alternative cuff‐less BP measurement device that calculates changes in BP based on changes in pulse transit time (PTT) and a software algorithm. The device is calibrated with a single upper arm cuff‐based BP measurement. We tested the device against a validated 24‐h ambulatory BP monitoring (ABPM) device using both the previous (SomBP1) and the current software algorithm (SomBP2). In this study, 51 patients (mean age ± SD 61.5 ± 13.0 years) with essential hypertension underwent simultaneous 24‐h ABPM with the SOMNOtouch NIBP on the left arm and a standard cuff‐based oscillometric device on the right arm (OscBP). We found that mean daytime systolic BP (SBP) with OscBP was 140.8 ± 19.7 compared to 148.0 ± 25.2 (P = .008) and 146.9 ± 26.0 mmHg (P = .034) for SomBP1 and SomBP2, respectively. Nighttime SBP with OscBP was 129.5 ± 21.1 compared with 146.1 ± 25.8 (P

Abstract Phase three clinical trial evidence suggests that colorectal cancers with the KRAS G13D mutation may benefit from EGFR inhibitors, like cetuximab, in contrast to the other most common KRAS mutations. A mechanism to explain why this mutation behaves differently from other KRAS mutations had long been lacking. Two recent studies have reproduced KRAS G13D specific sensitivity to cetuximab in cellular models, and both have implicated the tumor suppressor NF1 as a critical variable in determining sensitivity and resistance. One study proposes a mechanism that focuses on the inhibition of active, GTP-bound wild-type RAS, which is proposed to occur to a greater extent in KRAS G13D tumors due to the inability of KRAS G13D to bind NF1 well. The other study suggests NF1 can convert GTP-bound KRAS G13D to inactive, GDP-bound KRAS G13D. Here, we report an inability to reproduce cellular and biophysical studies that suggested NF1 has strong GTPase activity on KRAS G13D. We also report additional data that further suggests only WT RAS-GTP levels are reduced with EGFR inhibition and that KRAS G13D is impaired in binding to NF1. These new experiments further support a mechanism in which cetuximab inhibits wild-type (HRAS and NRAS) signals in KRAS G13D colorectal cancers. Video Abstract

Abstract Background Troponin T (TnT) is a well-known risk factor for negative outcome in hemodialysis (HD) patients, but little is known about variation over time, and the impact of clinical and dialysis specific factors. This study investigated the effect of angiotensin II receptor blockade (ARB), short and long-term variation in TnT and associations with clinical parameters. Methods In this analysis based on the SAFIR-cohort (Clinical Trials ID: NCT00791830) 81 HD patients were randomized double-blind for placebo (n = 40) or angiotensin II receptor blocker (ARB) treatment (n = 41) with irbesartan (150–300 mg) and followed for 12 months with six serial measurements of TnT using a high-sensitivity assay. Results Fifty-four patients (67%) completed follow-up. Baseline TnT-medians (min-max) were (placebo/ARB): 45(14–295)/46(10–343) ng/L. ARB-treatment did not significantly affect mean TnT-levels over the 12-month study period. Median week-to-week and one-year TnT-variation (5th–95th-percentile range) using all samples regardless of intervention were: 0(− 14–10) ng/L (week-to-week) and 3(− 40–71) ng/L (12 months). Median TnT-amplitude, capturing the change from the lowest to the highest TnT-value observed during the one-year study period was 38% or 20.5 ng/L. Median ratios with 95% limits of agreement were: 1.00(0.73–1.37); P = 0.92 (1 week/baseline; n = 77) and 1.07(0.52–2.25); P = 0.19 (12 months/baseline; n = 54). Baseline TnT was positively correlated with diabetes, ultrafiltration volume, arterial stiffness, change in intradialytic total peripheral resistance and N-terminal pro b-type natriuretic peptide (NT-proBNP) and negatively correlated with hematocrit, residual renal function and change in intradialytic cardiac output. High baseline TnT was associated with a higher risk of admission and cardiovascular (CV) events during follow-up. Increase in TnT over time (ΔTnT = 12-months-baseline) was significantly associated with increase in left ventricular (LV) mass and NT-proBNP and decrease in LV ejection fraction and late intradialytic stroke volume. ΔTnT was not significantly associated with admissions, CV or intradialytic hypotensive events during follow-up. Admissions were significantly more likely with a high (TnT-amplitude> 20.5 ng/L) than a low TnT-amplitude. Peaks in TnT were less frequent in aspirin-treated patients. Conclusion ARB-treatment had no significant effect on TnT-levels. Week-to-week variation was generally low, yet over 12 months individual patients had considerable TnT fluctuations. Rise in TnT over time was significantly correlated with markers of cardiac deterioration. Trial registration ClinicalTrials.gov Identifier: NCT00791830 . Date of registration: November 17, 2008. EudraCT no: 2008–001267-11.

In this report, we present a challenging case of a 63-year-old Caucasian woman with an extreme stress response to blood pressure (BP) measurements. Office- and ambulatory BP measurements consistently found systolic BP above 200 mmHg. However, antihypertensive medication made her dizzy and extremely unwell, and she could barely tolerate treatment with a moderate dose of angiotensin-converting enzyme (ACE) inhibitor. Finger-cuff-based measurements (Finapres Finometer®) revealed extreme hypertension in relation to contact with medical professionals, but hypotension when the patient was seated alone unobserved. Months after, the patient suffered a hemorrhagic stroke possibly related to her extreme BP-fluctuations in stressful situations.

Trypanosoma brucei probably relies on chemotactic signals for movement through tsetse fly tissues, but the molecular basis is unknown. Here, the authors show that flagellar cAMP signaling is required for traversal of the peritrophic matrix and that, without it, parasites are trapped in the midgut lumen.

Sleeping sickness is a neglected tropical disease caused by the protozoan parasite Trypanosoma bruceiT. brucei

ABSTRACT To complete its infectious cycle, the protozoan parasite Trypanosoma brucei must navigate through diverse tissue environments in both its tsetse fly and mammalian hosts. This is hypothesized to be driven by yet unidentified chemotactic cues. Prior work has shown that parasites engaging in social motility in vitro alter their trajectory to avoid other groups of parasites, an example of negative chemotaxis. However, movement of T. brucei toward a stimulus, positive chemotaxis, has so far not been reported. Here, we show that upon encountering Escherichia coli, socially behaving T. brucei parasites exhibit positive chemotaxis, redirecting group movement toward the neighboring bacterial colony. This response occurs at a distance from the bacteria and involves active changes in parasite motility. By developing a quantitative chemotaxis assay, we show that the attractant is a soluble, diffusible signal dependent on actively growing E. coli. Time-lapse and live video microscopy revealed that T. brucei chemotaxis involves changes in both group and single cell motility. Groups of parasites change direction of group movement and accelerate as they approach the source of attractant, and this correlates with increasingly constrained movement of individual cells within the group. Identification of positive chemotaxis in T. brucei opens new opportunities to study mechanisms of chemotaxis in these medically and economically important pathogens. This will lead to deeper insights into how these parasites interact with and navigate through their host environments. IMPORTANCE Almost all living things need to be able to move, whether it is toward desirable environments or away from danger. For vector-borne parasites, successful transmission and infection require that these organisms be able to sense where they are and use signals from their environment to direct where they go next, a process known as chemotaxis. Here, we show that Trypanosoma brucei, the deadly protozoan parasite that causes African sleeping sickness, can sense and move toward an attractive cue. To our knowledge, this is the first report of positive chemotaxis in these organisms. In addition to describing a new behavior in T. brucei, our findings enable future studies of how chemotaxis works in these pathogens, which will lead to deeper understanding of how they move through their hosts and may lead to new therapeutic or transmission-blocking strategies.

The representativeness heuristic suggests that similarity judgments provide a basis for judgments of likelihood. We use Tversky’s (1977) contrast model of similarity to design tests of this underlying mechanism. If similarity is used to judge likelihood, factors that are known to affect similarity should also affect judgments of likelihood. In two experiments, we manipulated two such factors described in the contrast model of similarity: the nature of the task and context effects. In a between-subject design, respondents assessed either similarity of fictive citizens of 15th century Florence, or the likelihood that they belonged to the same family. The factors that affected similarity also affected the likelihood judgments. These results support the assumption that similarity is an important contributor to judgments of likelihood.

Dentin matrix protein 1 (DMP1) contains a large number of acidic domains, multiple phosphorylation sites, a functional arginine-glycine-aspartate (RGD) motif, and a DNA binding domain, and has been shown to play essential regulatory function in dentin and bone mineralization. DMP1 could also orchestrate bone matrix formation, but the ability of DMP1 on Ti to human mesenchymal stem cell (hMSC) conversion to osteoblasts has not been studied. There is importance to test if the DMP1 coated Ti surface would promote cell migration and attachment to the metal surface and promote the differentiation of the attached stem cells to an osteogenic lineage. This study aimed to study the human mesenchymal stem cells (hMSCs) attachment and proliferation on DMP1 coated titanium (Ti) disks compared to non-coated disks, and to assess possible osteoblastic differentiation of attached hMSCs. Sixty-eight Ti disks were divided into two groups. Group 1 disks were coated with dentin matrix protein 1 and group 2 disks served as control. Assessment with light microscopy was used to verify hMSC attachment and proliferation. Cell viability was confirmed through fluorescence microscopy and mitochondrial dehydrogenase activity. Real-time polymerase chain reaction analysis was done to study the gene expression. The proliferation assay showed significantly greater cell proliferation with DMP1 coated disks compared to the control group (p-value < 0.001). Cell vitality analysis showed a greater density of live cells on DMP1 coated disks compared to the control group. Alkaline phosphatase staining revealed higher enzyme activity on DMP1 coated disks and showed itself to be significantly higher than the control group (p-value < 0.001). von Kossa staining revealed higher positive areas for mineralized deposits on DMP1 coated disks than the control group (p-value < 0.05). Gene expression analysis confirmed upregulation of runt-related transcription factor 2, osteoprotegerin, osteocalcin, osteopontin, and alkaline phosphatase on DMP1 coated disks (p-value < 0.001). The dentin matrix protein promoted the adhesion, proliferation, facilitation differentiation of hMSC, and mineralized matrix formation.

Outer Hair Cells (OHCs) in the mammalian cochlea display a unique type of voltage-induced mechanical movement termed electromotility, which amplifies auditory signals and contributes to the sensitivity and frequency selectivity of mammalian hearing. Electromotility occurs in the OHC lateral wall, but it is not fully understood how the supramolecular architecture of the lateral wall enables this unique form of cellular motility. Employing electron tomography of high-pressure frozen and freeze-substituted OHCs, we visualized the 3D structure and organization of the membrane and cytoskeletal components of the OHC lateral wall. The subsurface cisterna (SSC) is a highly prominent feature, and we report that the SSC membranes and lumen possess hexagonally ordered arrays of particles. We also find the SSC is tightly connected to adjacent actin filaments by short filamentous protein connections. Pillar proteins that join the plasma membrane to the cytoskeleton appear as variable structures considerably thinner than actin filaments and significantly more flexible than actin-SSC links. The structurally rich organization and rigidity of the SSC coupled with apparently weaker mechanical connections between the plasma membrane (PM) and cytoskeleton reveal that the membrane-cytoskeletal architecture of the OHC lateral wall is more complex than previously appreciated. These observations are important for our understanding of OHC mechanics and need to be considered in computational models of OHC electromotility that incorporate subcellular features.

The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function. Methods: Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed. Results: The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance of •NO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p

Using molecular beam epitaxy, we prepared seven p-type AlGaN samples of ~25% in Al content, including six samples with Mg-doped/un-doped AlGaN alternating-layer structures of different layer-thickness combinations, for comparing their p-type performances. Lower sheet resistance and higher effective hole mobility are obtained in a layer-structured sample, when compared with the reference sample of uniform Mg doping. The improved p-type performance in a layer-structured sample is attributed to the diffusion of holes generated in an Mg-doped layer into the neighboring un-doped layers, in which hole mobility is significantly higher because of weak ionized impurity scattering. Among the layer-structured samples, that of 6/4 nm in Mg-doped/un-doped thickness results in the lowest sheet resistance (the highest effective hole mobility), which is 4.83 times lower (4.57 times higher) when compared with the sample of uniform doping. The effects of the Mg-doped/un-doped layer structure on p-type performance in AlGaN and GaN are compared.

Pre-pregnancy (pregravid) obesity has been linked to several adverse health outcomes for both mother and offspring. Complications during pregnancy include increased risk for gestational diabetes, hypertension, preeclampsia, placental abruption, and difficulties during delivery. Several studies suggest that these negative outcomes are mediated by heightened systemic inflammation as well as changes in placental development and function. However, the molecular mechanisms by which pregravid obesity affects these processes are poorly understood. In this study, we aimed to address this question by carrying out a comprehensive analysis of the systemic maternal immune system coupled with placental gene expression and microbial profiling at term delivery (11 lean and 14 obese). Specifically, we examined the impact of pregravid obesity on circulating cytokines, chemokine, adipokines, and growth factors using multiplex Luminex assay. Innate and adaptive immune cell frequencies and their cytokine production in response to stimuli were measured using flow cytometry. Finally, changes in placental transcriptome and microbiome were profiled using RNA- and 16S-sequencing, respectively. Pregravid obesity is characterized by insulin and leptin resistance, high levels of circulating inflammatory markers IL-6 and CRP, in addition to chemokine IL-8 (p < 0.01). Moreover, pregravid obesity was associated with lower frequency of naïve CD4+ T-cells (p < 0.05), increased frequency of memory CD4+ T-cells (p < 0.01), and a shift towards Th2 cytokine production (p = 0.05). Myeloid cells from the obese cohort produced higher levels of pro-inflammatory cytokines but lower levels of chemokines following TLR stimulation (p < 0.05). Lastly, pregravid obesity is associated with increased abundance of Bacteroides and changes in the expression of genes important for nutrient transport and immunity (FDR < 0.05). Collectively, these data indicate that pregravid obesity is associated with heightened systemic inflammation and of dysregulated nutrient transport in the placenta and provide insight into the basis of fetal reprogramming.

Individuals reporting episodes of breathing problems caused by re-occurring variable airflow obstructions in the larynx have been described in an increasing number of publications, with more than 40 different terms being used without consensus on definitions. This lack of an international consensus on nomenclature is a serious obstacle for the development of the area, as knowledge from different centres cannot be matched, pooled or readily utilised by others. Thus, an international Task Force has been created, led by the European Respiratory Society/European Laryngological Society/American College of Chest Physicians. This review describes the methods used to reach an international consensus on the subject and the resulting nomenclature, the 2013 international consensus conference nomenclature.

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p=0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p=0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies.