Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

Biology has taught us that a protein as abundantly made and conserved among species as Tamm–Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic inter-organ signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP’s physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes

Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI

Effect of drinking saline water on food and water intake, food digestibility, and nitrogen and mineral balances of rusa deer stags (Cervus timorensis russa)

The salinity tolerance of Javan rusa deer (Cervus timorensis russa) was investigated with seven stags, aged 4-5 years. Animals were offered a medium-quality chaffed lucerne hay and given five different levels of water salinity: (a) control (570 mg/kg of total dissolved salts (TDS)) and (b) 'saline' water with TDS contents of 1000, 3500, 6000 and 8500 mg/kg. Food intake, food digestibility and nitrogen balance were not affected by increasing salt concentration in drinking water, however the drinking water (DW) intake, the total (food plus drinking) water intake and the DW:dry-matter ratio increased with increasing salt concentration. Some deer given water containing 8500 mg TDS per kg showed signs of stress which included large between-day fluctuations in water intake, opening of the orbital gland, head shaking, and rapid breathing. Rusa deer can tolerate drinking water containing 6000 mg TDS per kg for at least 9 days without harmful effect but may be unable to tolerate water with 8500 mg TDS per kg

Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality

Brown Carbon in Primary and Aged Coal Combustion Emission

Smog chamber experiments were conducted to characterize the light absorption of brown carbon (BrC) from primary and photochemically aged coal combustion emissions. Light absorption was measured by the UV-visible spectrophotometric analysis of water and methanol extracts of filter samples. The single-scattering albedo at 450 nm was 0.73 ± 0.10 for primary emissions and 0.75 ± 0.13 for aged emissions. The light absorption coefficient at 365 nm of methanol extracts was higher than that of water extracts by a factor of 10 for primary emissions and a factor of 7 for aged emissions. This suggests that the majority of BrC is water-insoluble even after aging. The mass absorption efficiency of this BrC (MAE365) for primary OA (POA) was dependent on combustion conditions, with an average of 0.84 ± 0.54 m2 g-1, which was significantly higher than that for aged OA (0.24 ± 0.18 m2 g-1). Secondary OA (SOA) dominated aged OA and the decreased MAE365 after aging indicates that SOA is less light absorbing than POA and/or that BrC is bleached (oxidized) with aging. The estimated MAE365 of SOA (0.14 ± 0.08 m2 g-1) was much lower than that of POA. A comparison of MAE365 of residential coal combustion with other anthropogenic sources suggests that residential coal combustion emissions are among the strongest absorbing BrC organics

The stylomastoid artery as an anatomical landmark to the facial nerve during parotid surgery: a clinico-anatomic study

BACKGROUND: The identification of the facial nerve can be difficult in a bloody operative field or by an incision that limits exposure; hence anatomical landmarks and adequate operative exposure can aid such identification and preservation. In this clinico-anatomic study, we examined the stylomastoid artery (SMA) and its relation to the facial nerve trunk; the origin of the artery was identified on cadavers and its nature was confirmed histologically. METHODS: The clinical component of the study included prospective reviewing of 100 consecutive routine parotidectomies; while, the anatomical component of the study involved dissecting 50 cadaveric hemifaces. RESULTS: We could consistently identify a supplying vessel, stylomastoid artery, which tends to vary less in position than the facial nerve. Following this vessel, a few millimetres inferiorly and medially, we have gone on to identify the facial nerve trunk, which it supplies, with relative ease. The origin of the stylomastoid artery, in our study, was either from the occipital artery or the posterior auricular artery. CONCLUSION: This anatomical aid, the stylomastoid artery, when supplemented by the other more commonly known anatomical landmarks and intra-operative facial nerve monitoring further reduces the risk of iatrogenic facial nerve damage and operative time

Gradient elasticity: a transformative stress analysis tool to design notched components against uniaxial/multiaxial high-cycle fatigue

This paper investigates the accuracy of gradient elasticity in estimating high-cycle fatigue strength of notched components subjected to both uniaxial and multiaxial fatigue loading. A novel design methodology is formulated by combining Ru and Aifantis’ gradient elasticity with the Theory of Critical Distances and the Modified Wöhler Curve Method. The keyfeature of this innovative design methodology is that, via the Theory of Critical Distances, gradient elasticity’s length scale parameter is directly estimated from conventional material fatigue properties (i.e., the plain fatigue limit and the threshold value of the stress intensity factor). From a stress analysis point of view, the proposed approach directly post-processes the gradient-enriched stress states determined, at the hot-spots, on the surface of the component under investigation (and independently of the sharpness of the stress concentrator being assessed). The accuracy and reliability of this design method was checked by using a large number of experimental results taken from the literature and generated by testing notched metallic samples under uniaxial as well as under multiaxial fatigue loading. This comprehensive validation exercise demonstrates that the systematic usage of this transformative design approach leads to the same level of accuracy as the one which is obtained by applying the classic Theory of Critical Distances. This result is certainly remarkable since the proposed approach is not only very efficient from a computational point of view, but it also allows high-cycle fatigue damage to be assessed by directly postprocessing gradient-enriched stress states determined on the surface of the component being assessed

Memorias de la Primera Reunión Internacional de Administración Rural Gerencia de Empresas Agropecuarias

261 páginasLa reunión se concentra en intercambiar experiencias sobre sistemas de manejo de las empresas agropecuarias en Colombia, Inglaterra, Francia, Brasil y Costa Rica; generalizar el uso continuado y coordinado de las técnicas y métodos administrativos en la agricultura colombiana; plantear aspectos de organización, planificación y dirección de la empresa agropecuaria

Microstructural length scale parameters to model the high-cycle fatigue behaviour of notched plain concrete

The present paper investigates the importance and relevance of using microstructural length scale parameters in estimating the high-cycle fatigue strength of notched plain concrete. In particular, the accuracy and reliability of the Theory of Critical Distances and Gradient Elasticity are checked against a number of experimental results generated by testing, under cyclic bending, square section beams of plain concrete containing stress concentrators of different sharpness. The common feature of these two modelling approaches is that the required effective stress is calculated by using a length scale which depends on the microstructural material morphology. The performed validation exercise demonstrates that microstructural length scale parameters are successful in modelling the behaviour of notched plain concrete in the high-cycle fatigue regime

Serum-Nutrient Starvation Induces Cell Death Mediated by Bax and Puma That Is Counteracted by p21 and Unmasked by Bcl-xL Inhibition

The cyclin-dependent kinase inhibitor p21 (p21WAF1/Cip1) is a multifunctional protein known to promote cell cycle arrest and survival in response to p53-dependent and p53 independent stimuli. We herein investigated whether and how it might contribute to the survival of cancer cells that are in low-nutrient conditions during tumour growth, by culturing isogenic human colorectal cancer cell lines (HCT116) and breast cancer cell lines in a medium deprived in amino acids and serum. We show that such starvation enhances, independently from p53, the expression of p21 and that of the pro-apoptotic BH3-only protein Puma. Under these conditions, p21 prevents Puma and its downstream effector Bax from triggering the mitochondrial apoptotic pathway. This anti-apoptotic effect is exerted from the cytosol but it is unrelated to the ability of p21 to interfere with the effector caspase 3. The survival function of p21 is, however, overcome by RNA interference mediated Bcl-xL depletion, or by the pharmacological inhibitor ABT-737. Thus, an insufficient supply in nutrients may not have an overt effect on cancer cell viability due to p21 induction, but it primes these cells to die, and sensitizes them to the deleterious effects of Bcl-xL inhibitors regardless of their p53 status