bluuebunny/crossref_metadata_2025 huggingface dataset:
Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse
Authors: Ledein Laetitia , Léger Bertrand , Dees Clara , Beyer Christian , Distler Alfiya , Vettori Serena , Boukaiba Rachid , Bidouard Jean Pierre , Schaefer Matthias , Pernerstorfer Josef , Ruetten Hartmut , Jagerschmidt Alexandre , Janiak Philip , Distler Jörg H.W. , Distler Oliver , Illiano Stéphane
Published: July 2020

Background and Purpose

Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid (LPA1) receptor in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA1 receptor antagonist using dermal fibroblasts from patients and an animal model of skin fibrosis.

Experimental Approach

Dermal fibroblast and skin biopsies from systemic sclerosis patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Pharmacolgical effect of SAR100842 was assessed in the tight skin 1 (Tsk1) mouse model.

Key Results

SAR100842 is equipotent against various LPA isoforms. Dermal fibroblasts and skin biopsies from patients with systemic sclerosis expressed high levels of LPA1 receptor. The LPA functional response (Ca2+) in systemic sclerosis dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in systemic sclerosis dermal and idiopathic pulmonary fibrosis lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from systemic sclerosis dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice.

Conclusion and Implications

The effects of SAR100842 on LPA‐induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA1 receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA1 receptor antagonists in systemic sclerosis.
Effects of local forearm skin heating on skin properties
Authors: Mayrovitz Harvey N.
Published: July 2020

This study investigated impacts of local skin heating on skin properties and tested whether skin changes depended on heat‐induced hyperaemia. It was reasoned that heat‐induced vasodilation impacts accompanying interstitial fluid changes. Forearm skin was locally heated from a baseline of 35°C to 40–42°C in 30 young adults (15 females, 15 males, 24.9 ± 2.1 years) and non‐heated in 10 others (5 females, 5 males, 25.2 ± 1.3 years. Skin blood flow (SBF) was continuously measured using a laser Doppler method and skin tissue dielectric constant (TDC), stratum corneum capacitance (SCC) and transepidermal water loss (TEWL) were measured before and after maintained heat for 12 min. TDC values were determined to effective measurement depths of 1.5 mm (TDC15) and 2.5 mm (TDC25). Results showed a large heat‐induced hyperaemia, with SBF increasing on average 8.8‐fold from its baseline of 35°C. Heating also caused significant increases in TDC, SCC and TEWL that, compared to preheating, increased approximately 1.1‐fold, 3.1‐fold and 4.5‐fold. None of these skin changes correlated with the magnitude of the SBF hyperaemic response. Absence of this correlation may indicate that in young healthy adults, increased capillary filtration due to heat‐induced arteriolar vasodilation is rapidly accommodated by postcapillary reabsorption, enhanced lymphatic activity and TEWL processes. An alternate explanation is that heating caused increased red cell oscillations that were detected as part of the laser Doppler increase without representing increased capillary flux. The major determinant of the Increases in TDC, SCC and TEWL is likely a consequence of heat‐induced eccrine gland activation. Studies of older persons or those with depressed function are warranted.
Effect of setmelanotide, a melanocortin‐4 receptor agonist, on obesity in Bardet‐Biedl syndrome
Authors: Haws Robert , Brady Sheila , Davis Elisabeth , Fletty Kristina , Yuan Guojun , Gordon Gregory , Stewart Murray , Yanovski Jack
Published: July 2020

Aim

To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet‐Biedl syndrome (BBS).

Materials and methods

Individuals aged 12 years and older with BBS received once‐daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52‐week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes.

Results

From February 2017 and February 2018, 10 individuals were screened; eight completed the 3‐month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was −5.5% (90% CI, −9.3% to −1.6%; n = 8); change from baseline was −11.3% (90% CI, −15.5% to −7.0%; n = 8) at 6 months and −16.3% (90% CI, −19.9% to −12.8%; n = 7) at 12 months. All participants reported at least one treatment‐emergent adverse event (AE), most commonly injection‐site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points.

Conclusions

Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS‐associated obesity and hyperphagia.
Using a newly introduced framework to measure ecological stressor interactions
Authors: Tekin Elif , Diamant Eleanor S. , Cruz‐Loya Mauricio , Enriquez Vivien , Singh Nina , Savage Van M. , Yeh Pamela J.
Published: July 2020

Understanding how stressors combine to affect population abundances and trajectories is a fundamental ecological problem with increasingly important implications worldwide. Generalisations about interactions among stressors are challenging due to different categorisation methods and how stressors vary across species and systems. Here, we propose using a newly introduced framework to analyse data from the last 25 years on ecological stressor interactions, for example combined effects of temperature, salinity and nutrients on population survival and growth. We contrast our results with the most commonly used existing method – analysis of variance (ANOVA) – and show that ANOVA assumptions are often violated and have inherent limitations for detecting interactions. Moreover, we argue that rescaling – examining relative rather than absolute responses – is critical for ensuring that any interaction measure is independent of the strength of single‐stressor effects. In contrast, non‐rescaled measures – like ANOVA – find fewer interactions when single‐stressor effects are weak. After re‐examining 840 two‐stressor combinations, we conclude that antagonism and additivity are the most frequent interaction types, in strong contrast to previous reports that synergy dominates yet supportive of more recent studies that find more antagonism. Consequently, measuring and re‐assessing the frequency of stressor interaction types is imperative for a better understanding of how stressors affect populations.
P‐glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)‐[11C]verapamil PET
Authors: Ilyas‐Feldmann Maria , Asselin Marie‐Claude , Wang Shaonan , McMahon Adam , Anton‐Rodriguez José , Brown Gavin , Hinz Rainer , Duncan John S. , Sisodiya Sanjay M. , Koepp Matthias
Published: July 2020

Objective

Overexpression of the drug transporter P‐glycoprotein (P‐gp) is thought to be involved in drug‐resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P‐gp substrate radiotracer (R)‐[11C]verapamil (VPM) together with the third‐generation P‐gp inhibitor tariquidar (TQD) to evaluate P‐gp function in individuals with drug‐resistant epileptogenic developmental lesions.

Methods

Twelve healthy controls (7 male, median age 45, range 35‐55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM‐PET scans before and 60 minutes after a 30‐minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM‐K1, was estimated from the first 10 minutes of dynamic data using a single‐tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls.

Results

At baseline, SPM voxel‐based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P‐gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002).

Significance

This study provides further evidence of P‐gp overactivity in patients with drug‐resistant epilepsy, irrespective of the type of lesion. Identifying P‐gp overactivity as an underlying contributor to drug‐resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P‐gp overactivity.
Microtubule‐associated proteins and emerging links to primary cilium structure, assembly, maintenance, and disassembly
Authors: Conkar Deniz , Firat‐Karalar Elif Nur
Published: July 2020

The primary cilium is a microtubule‐based structure that protrudes from the cell surface in diverse eukaryotic organisms. It functions as a key signaling center that decodes a variety of mechanical and chemical stimuli and plays fundamental roles in development and homeostasis. Accordingly, structural and functional defects of the primary cilium have profound effects on the physiology of multiple organ systems including kidney, retina, and central nervous system. At the core of the primary cilium is the microtubule‐based axoneme, which supports the cilium shape and acts as the scaffold for bidirectional transport of cargoes into and out of cilium. Advances in imaging, proteomics, and structural biology have revealed new insights into the ultrastructural organization and composition of the primary cilium, the mechanisms that underlie its biogenesis and functions, and the pathologies that result from their deregulation termed ciliopathies. In this viewpoint, we first discuss the recent studies that identified the three‐dimensional native architecture of the ciliary axoneme and revealed that it is considerably different from the well‐known '9 + 0' paradigm. Moving forward, we explore emerging themes in the assembly and maintenance of the axoneme, with a focus on how microtubule‐associated proteins regulate its structure, length, and stability. This far more complex picture of the primary cilium structure and composition, as well as the recent technological advances, open up new avenues for future research.
Preclinical insights into the gut‐skeletal muscle axis in chronic gastrointestinal diseases
Authors: Ehlers Luise , Bannert Karen , Rohde Sarah , Berlin Peggy , Reiner Johannes , Wiese Mats , Doller Julia , Lerch Markus M. , Aghdassi Ali A. , Meyer Fatuma , Valentini Luzia , Agrifoglio Ottavia , Metges Cornelia C. , Lamprecht Georg , Jaster Robert
Published: July 2020

Muscle wasting represents a constant pathological feature of common chronic gastrointestinal diseases, including liver cirrhosis (LC), inflammatory bowel diseases (IBD), chronic pancreatitis (CP) and pancreatic cancer (PC), and is associated with increased morbidity and mortality. Recent clinical and experimental studies point to the existence of a gut‐skeletal muscle axis that is constituted by specific gut‐derived mediators which activate pro‐ and anti‐sarcopenic signalling pathways in skeletal muscle cells. A pathophysiological link between both organs is also provided by low‐grade systemic inflammation. Animal models of LC, IBD, CP and PC represent an important resource for mechanistic and preclinical studies on disease‐associated muscle wasting. They are also required to test and validate specific anti‐sarcopenic therapies prior to clinical application. In this article, we review frequently used rodent models of muscle wasting in the context of chronic gastrointestinal diseases, survey their specific advantages and limitations and discuss possibilities for further research activities in the field. We conclude that animal models of LC‐, IBD‐ and PC‐associated sarcopenia are an essential supplement to clinical studies because they may provide additional mechanistic insights and help to identify molecular targets for therapeutic interventions in humans.
The systemic inflammatory response following hand instrumentation versus ultrasonic instrumentation—A randomized controlled trial
Authors: Johnston William , Paterson Michael , Piela Krystyna , Davison Emily , Simpson Annabel , Goulding Marilyn , Ramage Gordon , Sherriff Andrea , Culshaw Shauna
Published: July 2020

Objective

This study sought to investigate whether the immediate systemic inflammatory response following full‐mouth debridement differs following use of hand compared with ultrasonic instruments.

Methods

Thirty‐nine periodontitis patients were randomized to treatment with full‐mouth debridement using either hand or ultrasonic instrumentation completed within 24 hr. Serum and periodontal clinical parameters were collected at baseline, day 1, day 7 and day 90 post‐treatment. Differences in systemic inflammatory markers were assessed using general linear models at each timepoint, corrected for age, gender, smoking status, body mass index and baseline levels of each marker.

Results

Across all patients, serum C‐reactive protein increased at day 1, with no differences between hand and ultrasonic groups (p(adjusted) = .22). There was no difference between groups in interleukin‐6 (p(adjusted) = .29) or tumour necrosis factor α (p(adjusted) = .53) at day 1. Inflammatory markers returned to baseline levels by day 7. Treatment resulted in equal and marked improvements in clinical parameters in both groups; however, total treatment time was on average shorter for ultrasonic instruments (p(adjusted) = .002).

Conclusions

Ultrasonic instrumentation resulted in shorter treatment time with comparable clinical outcomes. Levels of serum C‐reactive protein at day 1 were similar following debridement with hand or ultrasonic instruments.
Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases
Authors: Jeon Jae‐Han , Thoudam Themis , Choi Eun Jung , Kim Min‐Ji , Harris Robert A , Lee In‐Kyu
Published: July 2020

Good health depends on the maintenance of metabolic flexibility, which in turn is dependent on the maintenance of regulatory flexibility of a large number of regulatory enzymes, but especially the pyruvate dehydrogenase complex (PDC), because of its central role in carbohydrate metabolism. Flexibility in regulation of PDC is dependent on rapid changes in the phosphorylation state of PDC determined by the relative activities of the pyruvate dehydrogenase kinases (PDKs) and the pyruvate dehydrogenase phosphatases. Inactivation of the PDC by overexpression of PDK4 contributes to hyperglycemia, and therefore the serious health problems associated with diabetes. Loss of regulatory flexibility of PDC occurs in other disease states and pathological conditions that have received less attention than diabetes. These include cancers, non‐alcoholic fatty liver disease, cancer‐induced cachexia, diabetes‐induced nephropathy, sepsis and amyotrophic lateral sclerosis. Overexpression of PDK4, and in some situations, the other PDKs, as well as under expression of the pyruvate dehydrogenase phosphatases, leads to inactivation of the PDC, mitochondrial dysfunction and deleterious effects with health consequences. The possible basis for this phenomenon, along with evidence that overexpression of PDK4 results in phosphorylation of “off‐target” proteins and promotes excessive transport of Ca2+ into mitochondria through mitochondria‐associated endoplasmic reticulum membranes are discussed. Recent efforts to find small molecule PDK inhibitors with therapeutic potential are also reviewed.
Sex differences in sarcopenia and frailty among community‐dwelling Korean older adults with diabetes: The Korean Frailty and Aging Cohort Study
Authors: Kang Sunyoung , Oh Tae Jung , Cho Be Long , Park Yong Soon , Roh Eun , Kim Hyeon Ju , Lee Sam‐Gyu , Kim Bong Jo , Kim Miji , Won Chang Won , Jang Hak Chul
Published: July 2020

Aims/Introduction

We aimed to examine the prevalence of sarcopenia and frailty in Korean older adults with diabetes compared with individuals without diabetes.

Materials and Methods

We analyzed the data of 2,403 participants aged 70–84 years enrolled in the Korean Frailty and Aging Cohort Study. Sarcopenia was defined using the Asian Working Group for Sarcopenia and the Foundation for the National Institutes of Health. Frailty was assessed by the Cardiovascular Health Study frailty phenotype criteria.

Results

The mean age of the participants was 76.0 ± 3.9 years, and 47.2% were men. The prevalence of diabetes was 30.2% in men and 25.8% in women. Adults with diabetes showed a lower muscle mass index (appendicular skeletal muscle mass/body mass index) and handgrip strength in both sexes, but only the women showed decreased physical performance. Women with diabetes presented a higher prevalence of sarcopenia diagnosed by the Foundation for the National Institutes of Health criteria, and frailty compared with participants without diabetes (sarcopenia 14.7% vs 8.5%, P = 0.001; frailty 9.5% vs 4.9%, P = 0.003). Men in the high and middle tertiles for homeostatic model assessment of insulin resistance presented a significantly higher prevalence of sarcopenia, compared with men in the low tertile homeostatic model assessment of insulin resistance (high tertile 16.6%, middle tertile 13.3%, low tertile 8.6%).

Conclusions

In older adults with diabetes, muscle mass index and muscle strength were lower than in those without diabetes. However, the prevalence of sarcopenia and frailty was higher and physical performance was lower only in women with diabetes.
Nesidiocoris tenuis as a pest in Northwest Europe: Intervention threshold and influence of Pepino mosaic virus
Authors: Moerkens Rob , Pekas Apostolos , Bellinkx Stijn , Hanssen Inge , Huysmans Marlies , Bosmans Lien , Wäckers Felix
Published: July 2020

The use of Nesidiocoris tenuis (Hemiptera: Miridae) as a biocontrol agent is controversial as it is considered a pest in Northwest European tomato greenhouses, due to its tendency to damage the plant and fruit. Necessary chemical plant protection products to control N. tenuis have toxic side effects on important beneficials like Macrolophus pygmaeus (Hemiptera: Miridae), which jeopardizes the whole IPM programme. In this study, several commercial tomato greenhouses were monitored for mirid populations. The relationship between the number of N. tenuis individuals and plant damage was assessed in function of availability of prey and interaction with M. pygmaeus. These greenhouse data were used to determine a practical density intervention threshold. Next, the hypothesis that a Pepino mosaic virus (PepMV) infection increases plant and fruit damage by N. tenuis (as has been shown for M. pygmaeus) was tested. Plant damage occurred when the average number of predatory bugs in the head of the plant exceeded 16 per ten plants. Plant damage increased in severity at increasing predatory bug densities, independent of the availability of prey and M. pygmaeus presence. Plant and fruit damage were not affected by the presence of PepMV, as was shown for fruit damage in previous studies for M. pygmaeus. Our study provides a practical density intervention threshold for growers in greenhouse crops. Simple monitoring of the number of predatory bugs in the head of the plant can be used to take specific biocontrol actions. It was also shown that only the predatory bug N. tenuis itself causes damage, and there is no interaction with PepMV.
Epidemiology of Polypodium hydriforme in American Paddlefish
Authors: Okamura Beth , Hartigan Ashlie , Long Paul F. , Ruggeri Paolo , Smith‐Easter Katie , Schooley Jason D.
Published: July 2020

Polypodium hydriforme is a parasitic cnidarian that develops within the eggs of acipenseriform fish in the Old and New Worlds. Currently regarded as monotypic, P. hydriforme has been studied largely in the context of caviar production in Russian sturgeon species. We report the first robust epidemiological study of P. hydriforme in North American acipenseriform fish. We sampled infection prevalences (in 2017 and 2018) and intensities (in 2017) during annual surveys of American Paddlefish, Polyodon spathula, caught during spawning migration in north‐eastern Oklahoma. Egg masses were characterized for the presence and intensity of P. hydriforme infection. Prevalences were similar in 2017 and 2018 (49% and 45%, respectively). Generally, a small number of eggs were infected per egg mass, but a few were heavily infected. Longer, heavier and older fish are more likely to be infected and to harbour more severe infections. In addition, infection is linked to decreases in roe fat weight independently of fish length, weight, age or roe weight. Infection thus diminishes Paddlefish energy reserves (roe fat) which could in turn impact host fitness. Our results raise questions about the impacts of infection on caviar production and Paddlefish conservation and suggest insights on infection dynamics and parasite strategies.
Puffed rice: A materialistic understanding of rice puffing and its associated changes in physicochemical and nutritional characteristics
Authors: Saha Sreyajit , Roy Anupam
Published: July 2020

Puffed rice is an expanded breakfast cereal obtained by high temperature short time heat treatment of salt‐treated parboiled rice. This intense heat results in deformation and phase transition within the grain and delivers an expanded porous structure. Such transformations essentially govern the final puffed rice quality and its physicochemical attributes. They commence during pretreatment and proceeds till puffing. These properties of rice such as expansion, hardness, degree of gelatinization, glass transition temperature, crystallinity, color, nutrient content, porosity, and microstructure are altered during the processing of puffed rice from pretreated parboiled rice. This review attempts to address such materialistic changes in the rice matrix during puffed rice production that would help a researcher to understand the associated changes in physicochemical and nutritional characteristics.

Practical applications

Studying the changes in the material properties associated with processing conditions is a useful approach to understand final quality of puffed rice. The review is a detailed study of parameters like expansion, hardness, degree of gelatinization, glass transition temperature, crystallinity, color, nutrient content, porosity, and microstructure that influence the final product characteristics of puffed rice and help a manufacturer to produce an acceptable product by exercising strict control on them. Insight on changes brought about by alteration in these characteristics are thus of paramount importance. This is because it can help individuals to produce puffed rice of optimized quality, correct product defects, and cause alterations in the end‐product. Researchers working on possible future applications can have a thorough background knowhow. Thus, the work would bear extreme commercial and scientific importance.
Neurolymphomatosis, a rare manifestation of peripheral nerve involvement in lymphomas: Suggestive features and diagnostic challenges
Authors: Campagnolo Marta , Cacciavillani Mario , Cavallaro Tiziana , Ferrari Sergio , Gasparotti Roberto , Zambello Renato , Briani Chiara
Published: July 2020

Neurolymphomatosis, the infiltration of the peripheral nervous system from lymphoid cells, represents an uncommon manifestation of lymphomas. We describe the challenging diagnostic work‐up in a patient with neurolymphomatosis. A 58‐year‐old woman with previous breast diffuse large B‐cell lymphoma treated with chemo‐ and radiation‐therapy, presented with dysesthesias, neuropathic pain at left abdomen and thigh, and weakness at left lower limb 9 years after disease remission. Neurophysiology revealed left T10‐L4 radiculo‐plexopathy with no abnormalities at cerebrospinal fluid (CSF), nerve ultrasound, and 18fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). MR‐neurography disclosed left rectus abdominis muscle atrophy, neurogenic edema, and denervation. Radiation‐induced damage, paraneoplastic, infectious radiculo‐plexopathies, and atypical chronic inflammatory demyelinating polyradiculoneuropathy were ruled out. Neurolymphomatosis was suspected, and the patient treated with rituximab with improvement. Despite treatment, the radiculo‐plexopathy eventually extended to the right side and sacral roots. Later in the disease course, sural nerve biopsy confirmed the diagnosis. Maintenance therapy was continued, until cutaneous localizations occurred, requiring salvage therapy and autologous stem cell transplant. Although rare, neurolymphomatosis should be considered in all patients with lymphomas and unexplained peripheral nervous system involvement. Hematological, CSF, and neuroimaging findings may be unremarkable, and a high index of suspicion required in order to achieve the diagnosis.
Immunocompromised cutaneous district, isotopic, and isopathic phenomena—Systematic review
Authors: Tabosa Gabriel V. B. S. , Stelini Rafael F. , Souza Elemir M. , Velho Paulo E. N. F. , Cintra Maria L. , Florence Michelle E. B.
Published: July 2020

Background

Although the development of lesions in skin areas that have undergone injury has long been known, understanding of its pathogenesis is limited. Depending on their peculiarities, those events have been described as isomorphic, reverse isomorphic, pseudoisomorphic, isotopic, and isopathic phenomena. Ruocco's immunocompromised cutaneous district (ICD) concept was proposed to include all those phenomena.

Aims

We performed a systematic review and critically evaluated the current understanding about ICD and its relationship with the isotopic and isopathic phenomena.

Methods

To illustrate the complexity of the theme, we present a case of subclinical leprosy, whose manifestation was brisk in an old tattoo. The possible interaction between the approached phenomena, acting in the genesis of the disease, made this a pertinent study. The research was conducted under the PRISMA‐P guidelines, in seven biomedical databases between 1996 and 2018. The eligibility criteria were systematic reviews, meta‐analyses, clinical studies, and case series, written in English, French, Italian, Portuguese, or Spanish.

Results

Using standardized keywords, 1220 articles were identified. After applying the eligibility criteria, 53 studies were selected.

Conclusion

This review ratifies that all these phenomena are aspects of one single condition. They can be integrated into the ICD concept with the pathogenesis including: (a) neural damage (peripheral or central) and (b) chronic lymphedema. Both may change the local neuroimmune interaction. The identification of these phenomena and the understanding of their pathogenesis are of paramount importance, to define the diagnosis and choose the therapeutic strategy.
Dental patients' functional, pain‐related, aesthetic, and psychosocial impact of oral conditions on quality of life—Project overview, data collection, quality assessment, and publication bias
Authors: Sekulic Stella , John Mike T. , Häggman‐Henrikson Birgitta , Theis‐Mahon Nicole
Published: July 2020

Background

Knowledge about the magnitude of Oral Health‐Related Quality of Life (OHRQoL) impairment across dental patient populations is essential for clinical practice, public health and research. Within the project Mapping Oral Disease Impact with a Common Metric, this systematic review aimed to describe functional, pain‐related, aesthetic and broader psychosocial impact of oral conditions with a single metric using OHRQoL dimensions Oral Function, Oro facial Pain, Oro facial Appearance and Psychosocial Impact.

Methods

A search using PubMed, EMBASE, Cochrane, CINAHL and PsycINFO was performed on 8 June 2017, and updated on 14 January 2019. Only publications in the English language were considered. To characterise the extent of available standardised and clinically relevant OHRQoL information, we determined the number of publications, dental patient populations, which are clinically similar, and patient samples within each population with four‐dimensional OHRQoL information using the Oral Health Impact Profile (OHIP) questionnaire. A quality assessment and a publication bias assessment were performed.

Results

We identified 171 publications that characterised 199 dental populations and 329 patient samples with four‐dimensional OHRQoL information. The vast majority of populations were only characterised by one patient sample. Study quality was not related to OHRQoL magnitude, and substantial publication bias could be excluded.

Conclusions

Standardised and clinically relevant information using the four OHRQoL dimensions Oral Function, Oro facial Pain, Oro facial Appearance and Psychosocial Impact was available for a significant number of dental patient populations. Findings can provide a framework to interpret OHRQoL impairment of individual patients, or groups of patients, for clinical practice, public health and research.
How Free Is Sow Stall Free? Incremental Regulatory Reform and Industry Co‐optation of Activism
Authors: Carey RACHEL , Parker Christine , Scrinis Gyorgy
Published: July 2020

This article critically examines how interactions between social movement activism, supermarkets, and the pork industry led to the voluntary adoption of “sow stall free” standards in Australia. We “backwards map” the regulatory space behind “sow stall free” products to show how the movement against factory farming became selectively focused on the abolition of one form of confinement for sows rather than on other forms of confinement and the conditions of the sows’ offspring, the piglets that are consumed. We argue that this facilitated an incremental shift to “sow stall free” production, allowing the concept of pig welfare to be corporatized in a way that maintains the dominant model of factory farmed pig meat production.
Accounting for cryptic population substructure enhances detection of inbreeding depression with genomic inbreeding coefficients: an example from a critically endangered marsupial
Authors: Zilko Joseph P , Harley Dan , Hansen Birgita , Pavlova Alexandra , Sunnucks Paul
Published: July 2020

Characterizing inbreeding depression in wildlife populations can be critical to their conservation. Coefficients of individual inbreeding can be estimated from genome‐wide marker data. The degree to which sensitivity of inbreeding coefficients to population genetic substructure alters estimates of inbreeding depression in wild populations is not well understood. Using generalized linear models, we tested the power of two frequently used inbreeding coefficients that are calculated from genome‐wide SNP markers, FH and F^III, to predict four fitness traits estimated over two decades in an isolated population of the critically endangered Leadbeater's possum. FH estimates inbreeding as excess observed homozygotes relative to equilibrium expectations, whereas F^III quantifies allelic similarity between the gametes that formed an individual, and upweights rare homozygotes. We estimated FH and F^III from 1,575 genome‐wide SNP loci in individuals with fitness trait data (N = 179–237 per trait), and computed revised coefficients, FHby group and F^IIIby group, adjusted for population genetic substructure by calculating them separately within two different genetic groups of individuals identified in the population. Using FH or F^III in the models, inbreeding depression was detected for survival to sexual maturity, longevity and whether individuals bred during their lifetime. F^IIIby group (but not FHby group) additionally revealed significant inbreeding depression for lifetime reproductive output (total offspring assigned to each individual). Estimates of numbers of lethal equivalents indicated substantial inbreeding load, but differing between inbreeding estimators. Inbreeding depression, declining population size, and low and declining genetic diversity suggest that genetic rescue may assist in preventing extinction of this unique Leadbeater's possum population.
Three novel HLA‐DQB1*05 variants identified in Brazilian individuals
Authors: Vianna Romulo , Secco Danielle , Santos Angela , Porto Luís Cristóvão
Published: July 2020

Characterization of three novel HLA‐DQB1*05 variants, HLA‐DQB1*05:01:01:08, ‐DQB1*05:02:01:07 and ‐DQB1*05:03:01:05.
Is Dickie's Account of Aboutness‐Fixing Explanatory?
Authors: Pepp Jessica
Published: July 2020

Imogen Dickie's book Fixing Reference promises to reframe the investigation of mental intentionality, or what makes thoughts be about particular things. Dickie focuses on beliefs, and argues that if we can show how our ordinary means of belief formation sustain a certain connection between what our beliefs are about and how they are justified, we will have explained the ability of these ordinary means of belief formation to generate beliefs that are about particular objects. A worry about Dickie's approach is that the explanation it offers is circular and thus not a genuine explanation of mental aboutness. This article develops a version of that worry in detail and turns it aside. Nonetheless, I argue that the explanatory value of the account remains unclear. While it does promise a dialectical advance over traditional theorizing about aboutness, it does not reveal how our ordinary means of belief formation make beliefs be about what they are about.
Obligatory role for PKCδ in PIP2‐mediated activation of store‐operated TRPC1 channels in vascular smooth muscle cells
Authors: Martín‐Aragón Baudel Miguel A. S. , Shi Jian , Large William A. , Albert Anthony P.
Published: July 2020

Key points

In vascular smooth muscle cells (VSMCs), activation of Ca2+‐permeable store‐operated channels (SOCs) composed of canonical transient receptor potential channel 1 (TRPC1) subunits mediates Ca2+ entry pathways that regulate contraction, proliferation and migration, which are processes associated with vascular disease.

Activation of TRPC1‐based SOCs requires protein kinase C (PKC) activity, which is proposed to phosphorylate TRPC1 proteins to promote channel opening by phosphatidylinositol 4,5‐bisphosphate (PIP2). We investigated the identity of the PKC isoform involved in activating TRPC1‐based SOCs in rat mesenteric artery VSMCs.

TRPC1‐based SOCs were reduced by PKCδ inhibitors and knockdown of PKCδ expression. Store depletion induced interactions between TRPC1 and PKCδ and PKCδ‐dependent phosphorylation of TRPC1. Furthermore, generation of store‐operated interactions between PIP2 and TRPC1 and activation of TRPC1‐based SOCs by PIP2 required PKCδ.

These findings reveal that PKCδ activity has an obligatory role in activating TRPC1‐based SOCs, through regulating PIP2‐mediated channel opening.

In vascular smooth muscle cells (VMSCs), stimulation of Ca2+‐permeable canonical transient receptor potential channel 1 (TRPC1)‐based store‐operated channels (SOCs) mediates Ca2+ entry pathways that regulate cell contraction, proliferation and migration, which are processes associated with vascular disease. It is therefore important to understand how TRPC1‐based SOCs are activated. Stimulation of TRPC1‐based SOCs requires protein kinase C (PKC) activity, with store‐operated PKC‐dependent phosphorylation of TRPC1 essential for channel opening by phosphatidylinositol 4,5‐bisphosphate (PIP2). Experimental protocols used to activate TRPC1‐based SOCs suggest that the PKC isoform involved requires diacylglycerol (DAG) but is Ca2+‐insensitive, which are characteristics of the novel group of PKC isoforms (δ, ε, η, θ). Hence, the present study examined whether a novel PKC isoform(s) is involved in activating TRPC1‐based SOCs in contractile rat mesenteric artery VSMCs. Store‐operated whole‐cell cation currents were blocked by Pico145, a highly selective and potent TRPC1/4/5 channel blocker and T1E3, a TRPC1 blocking antibody. PKCδ was expressed in VSMCs, and selective PKCδ inhibitory peptides and knockdown of PKCδ expression with morpholinos oligomers inhibited TRPC1‐based SOCs. TRPC1 and PKCδ interactions and phosphorylation of TRPC1 induced by store depletion were both reduced by pharmacological inhibition and PKCδ knockdown. In addition, store‐operated PIP2 and TRPC1 interactions were blocked by PKCδ inhibition, and PKCδ was required for PIP2‐mediated activation of TRPC1 currents. These results identify the involvement of PKCδ in stimulation of TRPC1‐based SOCs and highlight that store‐operated PKCδ activity is obligatory for channel opening by PIP2, the probable activating ligand.
10 Smart Startups
Authors: Jeffrey Winters
Published: July 2020

Superstar Cities are known for their technology startups, but innovative companies are popping up all over the United States. To show the diversity of innovation outside the so-called innovation hubs, this article spotlights 10 startups or young companies developing products in a variety of engineering fields. Some of these companies are located in small towns, others in large cities not necessarily known for their entrepreneurship. Some are tapping into local universities or resources; almost all are in cities that can offer a high quality of life at an affordable cost.
The Thirst Quenchers
Authors: Kelly Caitlin
Published: July 2020

Scientists are developing a wide variety of technologies to solve the urgent problem of water shortages across the world. In fact, many have been working for decades on finding better and more economical ways to turn non-traditional sources of water into potable water for drinking and cooking. This article focus on early-stage research and development of energy-efficient and cost-competitive technologies to tap nontraditional water sources for a variety of uses.
Clean Fuel from Nuclear Power
Authors: Hank Hogan
Published: July 2020

The current commercial hydrogen production has a significant carbon footprint. Now, projects co-funded by the U.S. Department of Energy and commercial nuclear utilities with operating nuclear power facilities aim to change that by exploiting the capabilities of nuclear power plants. This article delves into four projects aimed at demonstrating technology to make hydrogen from water on an industrial scale using energy from an operating commercial nuclear power plant.
Strain-dependent luminescence and piezoelectricity in monolayer transition metal dichalcogenides
Authors: De Palma Alex C. , Cossio Gabriel , Jones Kayleigh , Quan Jiamin , Li Xiaoqin , Yu Edward T.
Published: July 2020

The modification of optical and electronic properties of transition metal dichalcogenides via mechanical deformation has been widely studied. Their ability to withstand large deformations before rupture has enabled large tunability of the bandgap, and further, the spatially varying strain has been shown to control the spatial distribution of the bandgap and lead to effects such as carrier funneling. Monolayer transition metal dichalcogenides exhibit a significant piezoelectric effect that could couple to a spatially inhomogeneous strain distribution to influence electronic and optical behavior. We investigate both experimentally and theoretically an example case of photoluminescence in structures with a strain distribution similar to that employed in single-photon emitters but generated here via nanoindentation. Using a mechanical model for strain induced by nanoindentation, we show that piezoelectricity can result in charge densities reaching 1012 e/cm2 and can generate electrostatic potential variations on the order of ±0.1 V across the suspended monolayer. We analyze the implications of these results for luminescence and exciton transport in monolayer transition metal dichalcogenides with spatially varying strain.
Design, fabrication, and characterization of broad beam transducers for fragmenting large renal calculi with burst wave lithotripsy
Authors: Randad Akshay , Ghanem Mohamed A. , Bailey Michael R. , Maxwell Adam D.
Published: July 2020

Burst wave lithotripsy (BWL) is a technology for comminuting urinary stones. A BWL transducer's requirements of high-pressure output, limited acoustic window, specific focal depth, and frequency to produce fragments of passable size constrain focal beamwidth. However, BWL is most effective with a beam wider than the stone. To produce a broad-beam, an iterative angular spectrum approach was used to calculate a phase screen that was realized with a rapid prototyped lens. The technique did not accurately replicate a target beam profile when an axisymmetric profile was chosen. Adding asymmetric weighting functions to the target profile achieved appropriate beamwidth. Lenses were designed to create a spherically focused narrow-beam (6 mm) and a broad-beam (11 mm) with a 350-kHz transducer and 84-mm focal depth. Both lenses were used to fragment artificial stones (11 mm long) in a water bath, and fragmentation rates were compared. The linearly simulated and measured broad beamwidths that were 12 mm and 11 mm, respectively, with a 2-mm-wide null at center. The broad-beam and the narrow-beam lenses fragmented 44 ± 9% and 16 ± 4% (p = 0.007, N = 3) of a stone by weight, respectively, in the same duration at the same peak negative pressure. The method broadened the focus and improved the BWL rate of fragmentation of large stones.
The Arginine Deiminase Pathway Impacts Antibiotic Tolerance during Biofilm-Mediated Streptococcus pyogenes Infections
Authors: Freiberg Jeffrey A. , Le Breton Yoann , Harro Janette M. , Allison Devon L. , McIver Kevin S. , Shirtliff Mark E.
Published: July 2020

Biofilm-mediated bacterial infections are a major threat to human health because of their recalcitrance to antibiotic treatment. Through the study of
Streptococcus pyogenes
, a significant human pathogen that is known to form antibiotic-tolerant biofilms, we demonstrated the role that a bacterial pathway known for responding to acid stress plays in biofilm growth and antibiotic tolerance. This not only provides some insight into antibiotic treatment failure in
S. pyogenes
infections but also, given the widespread nature of this pathway, provides a potentially broad target for antibiofilm therapies. This discovery has the potential to impact the treatment of many different types of recalcitrant biofilm infections.
Parallel Analysis of Cystic Fibrosis Sputum and Saliva Reveals Overlapping Communities and an Opportunity for Sample Decontamination
Authors: Lu Junnan , Carmody Lisa A. , Opron Kristopher , Simon Richard H. , Kalikin Linda M. , Caverly Lindsay J. , LiPuma John J.
Published: July 2020

Cystic fibrosis is an inherited disease characterized by chronic respiratory tract infection and progressive lung disease. Studies of cystic fibrosis lung microbiology often rely on expectorated sputum to reflect the microbiota present in the lower airways. Passage of sputum through the oropharynx during collection, however, contributes microbes present in saliva to the sample, which could confound interpretation of results. Using culture-independent DNA sequencing-based analyses, we characterized the bacterial communities in pairs of expectorated sputum and saliva samples to generate a model for “decontaminating” sputum
in silico
. Our results demonstrate that salivary contamination of expectorated sputum does not have a large effect on most sputum samples and that observations of high bacterial diversity likely accurately reflect taxa present in cystic fibrosis lower airways.
A Comprehensive Coexpression Network Analysis in Vibrio cholerae
Authors: DuPai Cory D. , Wilke Claus O. , Davies Bryan W.
Published: July 2020

Cholera is a devastating illness that kills tens of thousands of people annually.
Vibrio cholerae
, the causative agent of cholera, is an important model organism to investigate both bacterial pathogenesis and the impact of horizontal gene transfer on the emergence and dissemination of new virulent strains. Despite the importance of this pathogen, roughly one-third of
V. cholerae
genes are functionally unannotated, leaving large gaps in our understanding of this microbe. Through coexpression network analysis of existing RNA sequencing data, this work develops an approach to uncover novel gene-gene relationships and contextualize genes with no known function, which will advance our understanding of
V. cholerae
virulence and evolution.
Supplemental Material: Coarse sediment dynamics in a large glaciated river system: Holocene history and storage dynamics dictate contemporary climate sensitivity
Authors: Anderson S.W. , Jaeger KL.
Published: July 2020

Description of ancillary data collection methods and supporting figures.
Activation of Notch1 signaling in podocytes by glucose-derived AGEs contributes to proteinuria
Authors: Nishad Rajkishor , Meshram Prajakta , Singh Ashish Kumar , Reddy G Bhanuprakash , Pasupulati Anil Kumar
Published: July 2020

Introduction

Advanced glycation end-products (AGEs) are implicated in the pathogenesis of diabetic nephropathy (DN). Previous studies have shown that AGEs contribute to glomerulosclerosis and proteinuria. Podocytes, terminally differentiated epithelial cells of the glomerulus and the critical component of the glomerular filtration barrier, express the receptor for AGEs (RAGE). Podocytes are susceptible to severe injury during DN. In this study, we investigated the mechanism by which AGEs contribute to podocyte injury.

Research design and methods

Glucose-derived AGEs were prepared in vitro. Reactivation of Notch signaling was examined in AGE-treated human podocytes (in vitro) and glomeruli from AGE-injected mice (in vivo) by quantitative reverse transcription-PCR, western blot analysis, ELISA and immunohistochemical staining. Further, the effects of AGEs on epithelial to mesenchymal transition (EMT) of podocytes and expression of fibrotic markers were evaluated.

Results

Using human podocytes and a mouse model, we demonstrated that AGEs activate Notch1 signaling in podocytes and provoke EMT. Inhibition of RAGE and Notch1 by FPS-ZM1 (N-Benzyl-4-chloro-N-cyclohexylbenzamide) and DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenyl glycine t-butylester), respectively, abrogates AGE-induced Notch activation and EMT. Inhibition of RAGE and Notch1 prevents AGE-induced glomerular fibrosis, thickening of the glomerular basement membrane, foot process effacement, and proteinuria. Furthermore, kidney biopsy sections from people with DN revealed the accumulation of AGEs in the glomerulus with elevated RAGE expression and activated Notch signaling.

Conclusion

The data suggest that AGEs activate Notch signaling in the glomerular podocytes. Pharmacological inhibition of Notch signaling by DAPT ameliorates AGE-induced podocytopathy and fibrosis. Our observations suggest that AGE-induced Notch reactivation in mature podocytes could be a novel mechanism in glomerular disease and thus could represent a novel therapeutic target.