Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscapes of human spermatogenesis remain unknown. Here, we performed single-cell RNA sequencing (scRNA-seq) analysis for 2,854 testicular cells from donors with normal spermatogenesis and 174 testicular cells from one nonobstructive azoospermia (NOA) donor. A hierarchical model was established, which was characterized by the sequential and stepwise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes. Further analysis identified several stage-specific marker genes of human germ cells, such as HMGA1, PIWIL4, TEX29, SCML1, and CCDC112. Moreover, we identified altered gene expression patterns in the testicular somatic cells of one NOA patient via scRNA-seq analysis, paving the way for further diagnosis of male infertility. Our work allows for the reconstruction of transcriptional programs inherent to sequential cell fate transition during human spermatogenesis and has implications for deciphering male-related reproductive disorders.
Spatial and temporal variations of atmospheric CO 2 concentrations contain information about surface sources and sinks, which can be quantitatively interpreted through tracer transport inversion. Previous CO 2 inversion calculations obtained differing results due to different data, methods and transport models used. To isolate the sources of uncertainty, we have conducted a set of annual mean inversion experiments in which 17 different transport models or model variants were used to calculate regional carbon sources and sinks from the same data with a standardized method. Simulated transport is a significant source of uncertainty in these calculations, particularly in the response to prescribed "background" fluxes due to fossil fuel combustion, a balanced terrestrial biosphere, and air-sea gas exchange. Individual model-estimated fluxes are often a direct reflection of their response to these background fluxes. Models that generate strong surface maxima near background exchange locations tend to require larger uptake near those locations. Models with weak surface maxima tend to have less uptake in those same regions but may infer small sources downwind. In some cases, individual model flux estimates cannot be analyzed through simple relationships to background flux responses but are
[1] Using an atmospheric inversion approach, we estimate methane surface emissions for different methane regional sources between 1996 and 2001. Data from 13 high-frequency and 79 low-frequency CH 4 observing sites have been averaged into monthly mean values with associated errors arising from instrumental precision, mismatch error, and sampling frequency. Simulated methane mole fractions are generated using the 3-D global chemical transport model (MATCH), driven by NCEP analyzed observed meteorology (T62 resolution), which accounts for the impact of synoptic and interannually varying transport on methane observations. We adapted the Kalman filter to optimally estimate methane flux magnitudes and uncertainties from seven seasonally varying (monthly varying flux) and two aseasonal sources (constant flux). We further tested the sensitivity of the inversion to different observing sites, filtered versus unfiltered observations, different model sampling strategies, and alternative emitting regions. Over the 1996-2001 period the inversion reduces energy emissions and increases rice and biomass burning emissions relative to the a priori emissions. The global seasonal emission peak is shifted from August to July because of increased rice and wetland emissions from southeast Asia. The inversion also attributes the large 1998 increase in atmospheric CH 4 to global wetland emissions. The current CH 4 observational network can significantly constrain northern emitting regions but not tropical emitting regions. Better estimates of global OH fluctuations are also necessary to fully describe interannual methane observations. This is evident in the inability of the optimized emissions to fully reproduce the observations at Samoa.
Neddylation, the covalent attachment of ubiquitin-like protein Nedd8, of the Cullin-RING E3 ligase family regulates their ubiquitylation activity. However, regulation of HECT ligases by neddylation has not been reported to date. Here we show that the C2-WW-HECT ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and then catalyses its own neddylation on multiple lysine residues. Intriguingly, this autoneddylation needs an active site at C426 in the HECT N-lobe. Neddylation of Smurf1 potently enhances ubiquitin E2 recruitment and augments the ubiquitin ligase activity of Smurf1. The regulatory role of neddylation is conserved in human Smurf1 and yeast Rsp5. Furthermore, in human colorectal cancers, the elevated expression of Smurf1, Nedd8, NAE1 and Ubc12 correlates with cancer progression and poor prognosis. These findings provide evidence that neddylation is important in HECT ubiquitin ligase activation and shed new light on the tumour-promoting role of Smurf1.
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