The response of precipitation extremes to climate change is considered using results from theory, modeling, and observations, with a focus on the physical factors that control the response. ...Observations and simulations with climate models show that precipitation extremes intensify in response to a warming climate. However, the sensitivity of precipitation extremes to warming remains uncertain when convection is important, and it may be higher in the tropics than the extratropics. Several physical contributions govern the response of precipitation extremes. The thermodynamic contribution is robust and well understood, but theoretical understanding of the microphysical and dynamical contributions is still being developed. Orographic precipitation extremes and snowfall extremes respond differently from other precipitation extremes and require particular attention. Outstanding research challenges include the influence of mesoscale convective organization, the dependence on the duration considered, and the need to better constrain the sensitivity of tropical precipitation extremes to warming.
Purpose of Review
To discuss the current understanding of “β cell identity” and factors underlying altered identity of pancreatic β cells in diabetes, especially in humans.
Recent Findings
Altered ...identity of β cells due to dedifferentiation and/or transdifferentiation has been proposed as a mechanism of loss of β cells in diabetes. In dedifferentiation, β cells do not undergo apoptosis; rather, they lose their identity and function. Dedifferentiation is well characterized by the decrease in expression of key β cell markers such as genes encoding major transcription factors, e.g., MafA, NeuroD1, Nkx6.1, and Foxo1, and an increase in atypical or “disallowed” genes for β cells such as lactate dehydrogenase, monocarboxylate transporter MCT1, or progenitor cell genes (Neurog3, Pax4, or Sox9). Moreover, altered identity of mature β cells in diabetes also involves transdifferentiation of β cells into other islet hormone producing cells. For example, overexpression of α cell specific transcription factor Arx or ablation of Pdx1 resulted in an increase of α cell numbers and a decrease in β cell numbers in rodents. The frequency of α-β double-positive cells was also prominent in human subjects with T2D. These altered identities of β cells likely serve as a compensatory response to enhance function/expand cell numbers and may also camouflage/protect cells from ongoing stress. However, it is equally likely that this may be a reflection of new cell formation as a frank regenerative response to ongoing tissue injury. Physiologically, all these responses are complementary.
Summary
In diabetes, (1) endocrine identity recapitulates the less mature/less-differentiated fetal/neonatal cell type, possibly representing an adaptive mechanism; (2) residual β cells may be altered in their subtype proportions or other molecular features; (3) in humans, “altered identity” is a preferable term to dedifferentiation as their cellular fate (differentiated cells losing identity or progenitors becoming more differentiated) is unclear as yet.
The high reverse-recovery charge ( Q rr ) of the Si superjunction (SJ) mosfet s' body diode leads to exacerbated switching loss and even destructive dynamic avalanche. In this article, we propose a ...GaN/Si-SJ cascode structure that combines the high-voltage Si SJ- mosfet s with a low-voltage GaN HEMT. Benefiting from introducing GaN HEMT, the GaN/Si-SJ cascode structure features zero Q rr at moderate current levels and substantially suppressed Q rr at high current levels. Such a significant improvement in the reverse-recovery process leads to a more than 50% reduction in switching loss and significantly enhanced hard-commutation robustness simultaneously.
Purpose of Review
Obstructive sleep apnea (OSA) is an underdiagnosed illness linked to essential hypertension (HTN), resistant hypertension (r-HTN), and cardiovascular disease (CVD). This review ...provides updates on the epidemiology, pathophysiology, and treatments of OSA-associated HTN.
Recent Findings
Mild sleep apnea increases the risk for HTN. Eighty-nine percent of young patients aged 18–35 with HTN not attributed to secondary causes have underlying OSA. Home sleep studies are noninferior to formal polysomnography for OSA diagnosis. Nocturnal oxygen desaturation rate is positively correlated with HTN severity. Gut microbiome neo-colonization in response to high-fat diet cravings in patients with OSA alters immune function and worsens HTN. Carbonic anhydrase inhibitors and probiotics show newfound potential for OSA-associated HTN treatment. OSA recognition improves hospital outcomes after a STEMI. Hypoxia-inducible factor (HIF) transcription increases in a dose-dependent manner to hypoxia, and HIFs are strongly linked to cancer growth.
Summary
OSA and HTN are comorbid conditions with adversely connected pathophysiology including sympathetic hyperactivity, gut dysbiosis, proinflammation, endothelial damage, rostral fluid shifts, pharyngeal collapse, intravascular fluid retention, nocturnal energy expenditure, and metabolic derangements. The dose–response effect of OSA on HTN severity challenges blood pressure (
BP
) control, so those with refractory HTN should be screened for OSA.
A comprehensive analysis consisting of computational fluid dynamics (CFD) and machine learning algorithms (MLAs) is conducted to study the effect of geometrical and operational parameters on ...nanofluid heat transfer in a microchannel heat sink (MCHS) with double synthetic jets (SJs). A parametric CFD study is initially carried out on insert types (dimple/protrusion), insert arrangements (inline/staggered), insert diameters, and jet phase actuation (in-phase/180° out-of-phase actuation). Four popular regression models used to save the computational cost are k-nearest neighbor (k−NN), random forest (RF), Gaussian process regression (GPR), and Multi-layer perceptron (MLP). In the MCHS with inactive jets, the heat transfer coefficient (HTC) is enhanced by 104.8% by adding 5% alumina particles and inline protrusions (D = 0.26 mm). Staggered arrangements also show a higher heat transfer rate and pressure drop ratio. In the case of active jets, adding nanoparticles and staggered dimples significantly reduces the maximum temperature. The k-NN regression model shows more accurate predictions than the other MLAs. The conductive heat transfer rate is maximized by 53.99% in the in-phase actuation cases. The optimum results are obtained at the inline dimple set with D = 0.265 mm in the in-phase actuation case.
•Combining CFD and MLAs is studied to predict nanofluid heat transfer in an MCHS.•The k-NN model is more accurate than RF, GPR, and MLP regression models.•Tmax drops by 15 K with active SJs, nanofluids, and staggered dimples.•104.8% HTC enhancement is obtained at inline dimples when SJs are inactive.•The conductive heat transfer rate is maximized by 54.896% in in-phase actuation.
Purpose of the Review
The aim of this review is to discuss recent data pointing at an involvement of human endogenous retroviruses (HERVs) in type 1 diabetes (T1D) onset and progression.
Recent ...Findings
The envelope protein of HERV-W family, named HERV-W-Env, was detected in pancreata from T1D patients and was shown to display pro-inflammatory properties and direct toxicity toward pancreatic beta cells.
Summary
The etiopathogenesis of T1D remains elusive, even if conventional environmental viral infections have been recurrently involved. Nonetheless, a new category of pathogens may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. A number of studies have now shown that HERV sequences, which are normally inactivated or repressed in the human genome, could be activated by environmental viruses. Thus, if similarly activated by viruses associated with T1D, disregarded HERV genes may underlie T1D genetic susceptibility. Moreover, once expressed, HERV elements may display broad pathogenic properties, which identify them as potential new therapeutic targets.
Chronic migraine (CM) and episodic migraine (EM) are part of the spectrum of migraine disorders, but they are distinct clinical entities. Population-based studies have shown that those with CM ...demonstrate higher individual and societal burden because they are significantly more disabled than those with EM and have greater impaired quality of life both inside and outside the home. Proper diagnosis of both conditions requires clearly defined clinical criteria. Diagnosis enables the initiation of appropriate treatments and risk-factor modification, which ultimately improve functional status and quality of life for persons with migraine. Recognizing that both disorders are on the spectrum of migraine, this review serves as a guide to define the disease state of CM as distinct from EM in terms of clinical, epidemiological, sociodemographic, and comorbidity profiles.
Renal Fanconi syndrome (FS) is rare in primary Sjӧgren's syndrome (pSS). We aimed to describe the clinicopathological characteristics of pSS associated FS (pSS-FS) and its responses to treatment.
We ...reported 25 cases of pSS-FS patients and retrospectively reviewed their clinical records, kidney pathology and follow-up data.
The 25 pSS-FS patients were mainly female (92.0%) and the mean age at diagnosis was 43.6±11.3 years. They showed different degrees of proximal tubular dysfunctions and eGFR decline (60.9±32.3 ml/min/1.73m2). Kidney pathology of pSS-FS patients showed tubulo-interstitial nephritis with defective brush border and lymphoplasmacytic infiltrates. After glucocorticoid treatment, the eGFR levels were significantly improved from 48.3±20.6 ml/min/1.73m2 to 55.0±19.9 ml/min/1.73m2 (P = 0.012) at the third month of follow-up. They also acquired good tubular (88.2%) and immunological (90.0%) responses. pSS-FS patients with young-onset pSS presented with a higher prevalence of positive anti-SSB antibody and hypocomplementemia, more severe hypokalemia, and better eGFR levels.
In pSS-FS patients, use of glucocorticoids could improve eGFR and tubular functions. The young-onset pSS group presented with a particular pattern in immunological features and kidney involvement.
Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly ...recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue.
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Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that primarily affects exocrine glands. The expression of mitochondrial double-stranded RNAs (mt-dsRNAs) was significantly elevated in the saliva/tear of patients. In this context, mt-dsRNAs were acting as positive-feedback amplifiers of the innate immune system, and downregulating mt-dsRNAs rescued the glandular phenotypes of SS.
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