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BackgroundCancer treatment of prepubertal patients impacts future fertility due to the abolition of spermatogonial stem cells (SSCs). In macaques, spermatogenesis could be regenerated by intratesticular transplantation of SSCs, but no studies have involved cytotoxic treatment before puberty and transplantation after puberty, which would be the most likely clinical scenario.ObjectivesTo evaluate donor-derived functional sperm production after SSC transplantation to adult monkeys that had received testicular irradiation during the prepubertal period.Materials and methodsWe obtained prepubertal testis tissue by unilaterally castrating six prepubertal monkeys and 2 weeks later irradiated the remaining testes with 6.9 Gy. However, because spermatogenic recovery was observed, we irradiated them again 14 months later with 7 Gy. Three of the monkeys were treated with GnRH-antagonist (GnRH-ant) for 8 weeks. The cryopreserved testis cells from the castrated testes were then allogeneically transplanted into the intact testes of all monkeys. Tissues were harvested 10 months later for analyses.ResultsIn three of the six monkeys, 61%, 38%, and 11% of the epididymal sperm DNA were of the donor genotype. The ability to recover donor-derived sperm production was not enhanced by the GnRH-ant pretreatment. However, the extent of filling seminiferous tubules during the transplantation procedure was correlated with the eventual production of donor spermatozoa. The donor epididymal spermatozoa from the recipient with 61% donor contribution were capable of fertilizing rhesus eggs and forming embryos. Although the transplantation was done into the rete testis, two GnRH-ant-treated monkeys, which did not produce donor-derived epididymal spermatozoa, displayed irregular tubular cords in the interstitium containing testicular spermatozoa derived from the transplanted donor cells.Discussion and conclusionThe results further support that sperm production can be restored in non-human primates from tissues cryopreserved prior to prepubertal and post-pubertal gonadotoxic treatment by transplantation of these testicular cells after puberty into seminiferous tubules.

Abstract Background Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained. Methods Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8’s involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement. Results GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content. Conclusions Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes. Graphical abstract

During cold exposure, white adipose tissue can remodel to dissipate energy as heat under cold similar to thermogenic brown adipose tissue. This “browning” and the regulation of body temperature is under the control of neural and hormonal signaling. It was recently discovered that neurotensin, a small neuropeptide, not only acts to inhibit thermogenesis, but also that lymphatic vessels may be a surprisingly potent source of neurotensin production. We hypothesized that the induction of adipose tissue lymphangiogenesis would therefore increase tissue neurotensin levels and impair thermogenesis.Methods: We utilized AdipoVD mice that have inducible expression of vascular endothelial growth factor (VEGF)-D, a potent lymphangiogenic stimulator, specifically in adipose tissue. Overexpression of VEGF-D induced significant lymphangiogenesis in both white and brown adipose tissues of AdipoVD mice.Results: Obese Adipo-VD mice demonstrated no differences in adipose morphology or browning under room temperature conditions compared to controls but did express significantly higher levels of neurotensin in their adipose tissues. Upon acute cold exposure, AdipoVD mice were markedly cold intolerant; inhibition of neurotensin signaling ameliorated this cold intolerance as AdipoVD mice were then able to maintain body temperature on cold challenge equivalent to their littermates.Conclusion: In total, these data demonstrate that adipose tissue lymphatic vessels are a potent paracrine source of neurotensin and that lymphangiogenesis therefore impairs the tissues’ thermogenic ability.

Transcranial alternating current stimulation (tACS) can modulate cortical oscillations and associated long-lasting cognitive and behavioral functions in humans. Here, the authors provide in vivo evidence in ferrets on the mechanism of how weak electric fields in tACS can entrain neuronal activity.

Twelve common density functional methods and seven basis sets for geometry optimization were evaluated on the accuracy of 1H/13C NMR chemical shift calculations for biaryls. For these functionals, 1H shifts calculations for gas phase optimized geometries were significantly less accurate than those for in-solution optimized structures, while 13C results were not strongly influenced by geometry optimization methods and solvent effects. B3LYP, B3PW91, mPW1PW91 and ωB97XD were the best-performing functionals with lowest errors; among seven basis sets, DGDZVP2 and 6-31G(d,p) outperformed the others. The combination of these functionals and basis sets resulted in high accuracy with CMAEmin = 0.0327 ppm (0.76%) and 0.888 ppm (0.58%) for 1H and 13C, respectively. The selected functionals and basis set were validated when consistently producing optimized structures with high accuracy results for 1H and 13C chemical shift calculations of two other biaryls. This study highly recommends the IEFPCM/B3LYP, B3PW91, mPW1PW91 or ωB97XD/DGDZVP2 or 6-31G(d,p) level of theory for the geometry optimization step, especially the solvent incorporation, which would lead to high accuracy 1H/13C calculation. This work would assist in the fully structural assignments of biaryls and provide insights into in-solution biaryl conformations.

The electric-field gradient (EFG) at nuclei in solids is a sensitive probe of the charge distribution. Experimental data, which previously only existed in insulators, have been available for metals with the development of nuclear measuring techniques since about 1970. An early, systematic investigation of the temperature dependence of the EFG in metals, originally based on results for Cd, but then also extended to various other systems, has suggested a proportionality to T3/2. However, later measurements in the structurally and electronically similar material Zn, which demonstrated much more complex behavior, were largely ignored at the time. The present experimental effort has confirmed the reliability of this unexpected behavior, which was previously unexplained.

The debt-to-GDP ratio negatively predicts cumulative nominal consumption growth up to a 10-year horizon, resulting from the ratio's ability to forecast lower inflation and real growth. Moreover, the debt-to-GDP ratio is positively associated with yield spreads. I rationalize these facts in a model in which positive shocks to government debt cause lower inflation and growth, making bonds attractive assets. Furthermore, because longer-term bonds are less exposed to current debt shock than are shorter-term bonds, they are better hedges, resulting in high yield spreads in high-debt states. The model highlights the importance of fiscal risk in understanding the Treasury bond market. Authors have furnished an Internet Appendix , which is available on the Oxford University Press Web site next to the link to the final published paper online. [ABSTRACT FROM AUTHOR]

Introduction: Access site vascular complications in transfemoral transcatheter aortic valve implantation (TF-TAVI) are still a major concern. Recently, a novel collagen plug based closure device (Manta) was introduced. The results from the first reports on Manta are very promising, but not much is known about the long-term patency. Report: A case of late pseudoaneurysm after access site arterial closure with Manta in TF-TAVI is described. The patient presented five weeks after left sided TF-TAVI with pain and claudication like symptoms in the left leg. CT angiography revealed a pseudoaneurysm at the puncture site. The patient was successfully treated by vascular surgery. Discussion: The results from recent peri-operative reports on the Manta vascular closure device (VCD) are promising, but not much is known about the long-term patency. In the present report a patient is described who developed a pseudoaneurysm several weeks after access site closure with Manta. To the authors’ knowledge, no such late access site complications after use of the Manta VCD have been reported previously. Keywords: TAVI, Access site closure, Manta, Pseudoaneurysm

Microsatellite sequences were isolated from both non-enriched and enriched genomic libraries of California spiny lobster, Panulirus interruptus. Eight consistently amplifying, scorable and polymorphic loci were characterized for 79 individuals collected at Santa Cruz and San Clemente Islands, California, and tested for cross-species amplification in four closely related Panulirus spp., as well as four other species of the order Achelata. The number of alleles observed per locus ranged from three to 54 and observed heterozygosities ranged from 0.57 to 0.98. Quality control testing shows that all loci were reliably scorable, independently segregating, inherited in Mendelian ratios, and had low to moderate (≤14.4%) frequencies of null alleles and high statistical power for detecting fine scale genetic structure.