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Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium–glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium–glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium–glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.Vallon and Thompson provide a tubule-centred view of diabetic kidney physiology. According to the tubular hypothesis of nephron filtration and diabetic kidney disease, early diabetes induces changes in renal tubules that alter interactions between the tubule and glomerulus, ultimately leading to diabetic kidney disease.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.

The unique avian vocal organ, the syrinx, is located at the caudal end of the trachea. Although a larynx is also present at the opposite end, birds phonate only with the syrinx. Why only birds evolved a novel sound source at this location remains unknown, and hypotheses about its origin are largely untested. Here, we test the hypothesis that the syrinx constitutes a biomechanical advantage for sound production over the larynx with combined theoretical and experimental approaches. We investigated whether the position of a sound source within the respiratory tract affects acoustic features of the vocal output, including fundamental frequency and efficiency of conversion from aerodynamic energy to sound. Theoretical data and measurements in three bird species suggest that sound frequency is influenced by the interaction between sound source and vocal tract. A physical model and a computational simulation also indicate that a sound source in a syringeal position produces sound with greater efficiency. Interestingly, the interactions between sound source and vocal tract differed between species, suggesting that the syringeal sound source is optimized for its position in the respiratory tract. These results provide compelling evidence that strong selective pressures for high vocal efficiency may have been a major driving force in the evolution of the syrinx. The longer trachea of birds compared to other tetrapods made them likely predisposed for the evolution of a syrinx. A long vocal tract downstream from the sound source improves efficiency by facilitating the tuning between fundamental frequency and the first vocal tract resonance.

Lists of species underpin many fields of human endeavour, but there are currently no universally accepted principles for deciding which biological species should be accepted when there are alternative taxonomic treatments (and, by extension, which scientific names should be applied to those species). As improvements in information technology make it easier to communicate, access, and aggregate biodiversity information, there is a need for a framework that helps taxonomists and the users of taxonomy decide which taxa and names should be used by society whilst continuing to encourage taxonomic research that leads to new species discoveries, new knowledge of species relationships, and the refinement of existing species concepts. Here, we present 10 principles that can underpin such a governance framework, namely (i) the species list must be based on science and free from nontaxonomic considerations and interference, (ii) governance of the species list must aim for community support and use, (iii) all decisions about list composition must be transparent, (iv) the governance of validated lists of species is separate from the governance of the names of taxa, (v) governance of lists of accepted species must not constrain academic freedom, (vi) the set of criteria considered sufficient to recognise species boundaries may appropriately vary between different taxonomic groups but should be consistent when possible, (vii) a global list must balance conflicting needs for currency and stability by having archived versions, (viii) contributors need appropriate recognition, (ix) list content should be traceable, and (x) a global listing process needs both to encompass global diversity and to accommodate local knowledge of that diversity. We conclude by outlining issues that must be resolved if such a system of taxonomic list governance and a unified list of accepted scientific names generated are to be universally adopted.

The biomechanics of human voice production are commonly studied using benchtop silicone vocal fold models that mimic the vibration of their in vivo counterparts. These models often have multiple layers of differing stiffness that represent human vocal fold tissue layers and are fabricated using a multi-step casting process. The purpose of the present study is to introduce and demonstrate a process for fabricating functional multi-layer vocal fold models using an alternative approach, termed embedded 3D printing, that is a hybrid of casting and 3D printing. In this paper the fabrication process is described. Analysis of the resulting geometric and stiffness characteristics of the layers, including layer elastic modulus values ranging from less than 1 kPa to approximately 40 kPa, is presented. The results of tests demonstrating that the models are capable of sustained phonomimetic vibration are given. Capabilities and limitations of the embedded 3D printing process are discussed. It is concluded that the process has the potential to contribute to voice biomechanics research by facilitating prospective improvements in the fabrication, design, and functionality of multi-layer vocal fold models.

Striking the top of a liquid-filled bottle can shatter the bottom. An intuitive interpretation of this event might label an impulsive force as the culprit in this fracturing phenomenon. However, high-speed photography reveals the formation and collapse of tiny bubbles near the bottom before fracture. This observation indicates that the damaging phenomenon of cavitation is at fault. Cavitation is well known for causing damage in various applications including pipes and ship propellers, making accurate prediction of cavitation onset vital in several industries. However, the conventional cavitation number as a function of velocity incorrectly predicts the cavitation onset caused by acceleration. This unexplained discrepancy leads to the derivation of an alternative dimensionless term from the equation of motion, predicting cavitation as a function of acceleration and fluid depth rather than velocity. Two independent research groups in different countries have tested this theory; separate series of experiments confirm that an alternative cavitation number, presented in this paper, defines the universal criteria for the onset of acceleration-induced cavitation.

The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease.

IFNs λ1, λ2, and λ3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-β gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-λ gene expression. Studies of virus induction of IFN-λ1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-λ1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-κB binding sites. Remarkably, these sites, which bind efficiently to NF-κB and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-κB RelA protein significantly reduces the level of the IFN-λ1 gene expression. We conclude that IFN-λ1 gene expression requires NF-κB, and we propose a model for IFN-λ1 gene regulation, in which IRF and NF-κB activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-λ1 and IFN-β promoters and directly implicate transposable elements in the regulation of the IFN-λ1 gene by NF-κB.

This study investigates the impact of subglottic stenosis (SGS) on voice production using a subject-specific laryngeal and airway model. Direct numerical simulations of fluid–structure–acoustic interaction were employed to analyze glottal flow dynamics, vocal fold vibration, and acoustics under realistic conditions. The model accurately captured key physiological parameters, including the glottal flow rate, vocal fold vibration patterns, and the first four formant frequencies. Simulations of varying SGS severity revealed that up to 75% stenosis, vocal function remains largely unaffected. However, at 90% severity, significant changes in glottal flow and acoustics were observed, with vocal fold vibration remaining stable. At 96%, severe reductions in glottal flow and acoustics, along with marked changes in vocal fold dynamics, were detected. Flow resistance, the ratio of glottal to stenosis area, and pressure drop across the vocal folds were identified as critical factors influencing these changes. The use of anatomically realistic airway and vocal fold geometries revealed that while anatomical variations minimally affect voice production at lower stenosis grades, they become critical at severe stenosis levels (>90%), particularly in capturing distinct anterior–posterior opening patterns and focused jet effects that alter glottal dynamics. These findings suggest that while simplified models suffice for analyzing mild to moderate stenosis, patient-specific geometric details are essential for accurate prediction of vocal fold dynamics in severe cases.