Nephropathy in Pparg-null mice highlights PPARγ systemic activities in metabolism and in the immune system.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response, and development. Total-body deletion of the two Pparg alleles provoked generalized lipoatrophy along with severe type 2 diabetes. Herein, we explore the appearance and development of structural and functional alterations of the kidney, comparing Pparg null-mice to their littermate controls (carrying Pparg floxed alleles). We show that renal hypertrophy and functional alterations with increased glucosuria and albuminuria are already present in 3 weeks-old Pparg null-mice. Renal insufficiency with decreased creatinine clearance progress at 7 weeks of age, with the advance of the type 2 diabetes. At 52 weeks of age, these alterations are accompanied by signs of fibrosis and mesangial expansion. More intriguingly, aged Pparg null-mice concomitantly present an anti-phospholipid syndrome (APS), characterized by the late appearance of microthrombi and a mesangioproliferative pattern of glomerular injury, associated with significant plasmatic levels of anti-β2- glycoprotein1 antibodies and renal deposition of IgG, IgM, and C3. Thus, in line with the role of PPARγ in metabolic homeostasis, Pparg null-mice first represent a potent model for studying the initiation and the development of diabetic nephropathy. Second, and in relation with the important PPARγ activity in inflammation and in immune system, these mice also highlight a new role for PPARγ signaling in the promotion of APS, a syndrome whose pathogenesis is poorly known and whose current treatment is limited to prevention of thrombosis events

One Health proof of concept: Bringing a transdisciplinary approach to surveillance for zoonotic viruses at the human-wild animal interface.

As the world continues to react and respond inefficiently to emerging infectious diseases, such as Middle Eastern Respiratory Syndrome and the Ebola and Zika viruses, a growing transdisciplinary community has called for a more proactive and holistic approach to prevention and preparedness - One Health. Such an approach presents important opportunities to reduce the impact of disease emergence events and also to mitigate future emergence through improved cross-sectoral coordination. In an attempt to provide proof of concept of the utility of the One Health approach, the US Agency for International Development's PREDICT project consortium designed and implemented a targeted, risk-based surveillance strategy based not on humans as sentinels of disease but on detecting viruses early, at their source, where intervention strategies can be implemented before there is opportunity for spillover and spread in people or food animals. Here, we share One Health approaches used by consortium members to illustrate the potential for successful One Health outcomes that can be achieved through collaborative, transdisciplinary partnerships. PREDICT's collaboration with partners around the world on strengthening local capacity to detect hundreds of viruses in wild animals, coupled with a series of cutting-edge virological and analytical activities, have significantly improved our baseline knowledge on the zoonotic pool of viruses and the risk of exposure to people. Further testament to the success of the project's One Health approach and the work of its team of dedicated One Health professionals are the resulting 90 peer-reviewed, scientific publications in under 5 years that improve our understanding of zoonoses and the factors influencing their emergence. The findings are assisting in global health improvements, including surveillance science, diagnostic technologies, understanding of viral evolution, and ecological driver identification. Through its One Health leadership and multi-disciplinary partnerships, PREDICT has forged new networks of professionals from the human, animal, and environmental health sectors to promote global health, improving our understanding of viral disease spillover from wildlife and implementing strategies for preventing and controlling emerging disease threats

Magnetic-field-induced spin excitations and renormalized spin gap of the underdoped superconductor La1.895_{1.895}Sr0.105_{0.105}CuO4_{4}

High-resolution neutron inelastic scattering experiments in applied magnetic fields have been performed on La$_{1.895}$Sr$_{0.105}$CuO$_{4}$ (LSCO). In zero field, the temperature dependence of the low-energy peak intensity at the incommensurate momentum-transfer $\mathbf{Q}^{\ }_{\mathrm{IC}}=(0.5,0.5\pm\delta,0),(0.5\pm\delta,0.5,0)$exhibits an anomaly at the superconducting$T^{\}_{c}$ which broadens and shifts to lower temperature upon the application of a magnetic field along the c-axis. A field-induced enhancement of the spectral weight is observed, but only at finite energy transfers and in an intermediate temperature range. These observations establish the opening of a strongly downward renormalized spin gap in the underdoped regime of LSCO. This behavior contrasts with the observed doping dependence of most electronic energy features.Comment: accepted for publication in Phys. Rev. Let

Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC

Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice.

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargF <sup>Δ/Δ</sup> ) and whole-body PPARγ-null (Pparg <sup>Δ/Δ</sup> ) mice. We identified a clear sex dimorphism occurring only in Pparg <sup>Δ/Δ</sup> mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized Pparg <sup>Δ/Δ</sup> mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans

Renal mineralocorticoid receptor expression is reduced in lipoatrophy.

Obesity is a condition characterized by adipose tissue hypertrophy; it is estimated that the obesity epidemic accounted for 4 million deaths in 2015 and that 70% of these were due to cardiovascular disease (CVD). One of the mechanisms linking obesity to CVD is the ability of adipose tissue to secrete circulating factors. We hypothesized that adipose tissue and its secretory products may influence mineralocorticoid receptor (MR) expression. Here, we showed that expression of MR and its downstream targets (Cnksr3, Scnn1b, and Sgk1) were significantly reduced in the kidneys of peroxisome proliferator-activated receptor-γ null (Pparg <sup> Δ/Δ </sup> ) and A-ZIP/F-1 (AZIP <sup>tg/+</sup> ) lipoatrophic mice with respect to their controls. Intriguingly, MR expression was also found to be significantly reduced in the kidneys of genetically obese ob/ob mice. Our data suggest that adipose tissue contributes to the regulation of MR expression. Given that leptin deficiency seems to be the major feature shared by Pparg <sup> Δ/Δ </sup> , AZIP <sup>tg/+</sup> , and ob/ob mice, we speculate that adipose tissue modulates MR expression through the leptin system

Effect of a magnetic field on long-range magnetic order in stage-4 and stage-6 superconducting La2CuO(4+y)

We have measured the enhancement of the static incommensurate spin-density wave (SDW) order by an applied magnetic field in stage-4 and stage-6 samples of superconducting La2CuO(4+y). We show that the stage-6 La2CuO(4+y) (Tc=32 K) forms static long-range SDW order with the same wave-vector as that in the previously studied stage-4 material. We have measured the field dependence of the SDW magnetic Bragg peaks in both stage-4 and stage-6 materials at fields up to 14.5 T. A recent model of competing SDW order and superconductivity describes these data well.Comment: Published version. 6 pages. 1 figure adde