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Immunological T follicular helper (T FH ) cells are a subpopulation of CD4 + T cells that support B cell antibody production and the establishment of B cell memory. By contrast, non-T FH cells orchestrate enhanced innate immune cell functions at sites of pathogen encounter. The factors underlying differentiation into a T FH or non-T FH cell remain poorly understood, though there is evidence to suggest that the T cell growth factor interleukin-2 (IL-2) may play a role. Using IL-2 reporter mice, DiToro et al. show that naïve CD4 + T cells that produce IL-2 are fated to become T FH cells, whereas nonproducers, which receive IL-2, become non-T FH cells. The CD4 + T cell–fate decision was linked to T cell receptor strength—only those naïve CD4 + T cells that received the highest T cell receptor signals were able to produce IL-2. Science , this issue p. eaao2933 Expression of the cytokine IL-2 is linked with cell fate choice in immunological T cells. In response to infection, naïve CD4 + T cells differentiate into two subpopulations: T follicular helper (T FH ) cells, which support B cell antibody production, and non-T FH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4 + T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become T FH cells, delivered IL-2 to nonproducers destined to become non-T FH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.

Caspases regulate and execute a spectrum of functions including cell deaths, non-apoptotic developmental functions, and stress responses. Despite these disparate roles, the same core cell-death machinery is required to enzymatically activate caspase proteolytic activities. Thus, it remains enigmatic how distinct caspase functions are differentially regulated. In this study, we show that Xeroderma pigmentosum protein XPD has a conserved function in activating the expression of stress-responsive caspases in C. elegans and human cells without triggering cell death. Using C. elegans , we show XPD-1-dependent activation of CED-3 caspase promotes survival upon genotoxic UV irradiation and inversely suppresses responses to non-genotoxic insults such as ER and osmotic stressors. Unlike the TFDP ortholog DPL-1 which is required for developmental apoptosis in C. elegans , XPD-1 only activates stress-responsive functions of caspase. This tradeoff balancing responses to genotoxic and non-genotoxic stress may explain the seemingly contradictory nature of caspase-mediated stress resilience versus sensitivity under different stressors. How caspases are differentially regulated in non-apoptotic stress responses remains enigmatic. Here, the authors show that Xeroderma pigmentosum protein XPD promotes stress specific caspase expression to balance genotoxic and non-genotoxic responses.

The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising longevity which has both cell autonomous and cell non-autonomous contributions. CED-3 caspase cleavage limits phosphorylated PMK-1. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. PMK-1 works through a complex transcriptional program to regulate lysosome formation. During early aging, the absolute phospho-p38 amount is maintained but the reservoir of non-phospho-p38 diminishes to enhance signaling without hyperactivation. Our findings show that modulating the stoichiometry of non-phospho-p38 dynamically supports tissue-homeostasis during aging without hyper-activation of stress response. The extent of phosphorylated p38 MAPK is known to determine signaling. Here, the authors show the relative pool of non-phosphorylated p38 MAPK modulates signaling output to control growth, lysosome formation and neuronal integrity during early aging.

Background Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios. Methods Whole-exome sequences (WES) were generated for 365 individuals (127 affected) and whole-genome sequences (WGS) were generated for 612 individuals (244 affected). Results Pathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected first-degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses, we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS and 4.7% of families with a negative result eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGaP. Conclusions Our data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

The zinc transporter ZIP4 (Slc39a4) is important for proper mammalian development and is an essential gene in mice. Recent studies suggest that this gene may also play a role in pancreatic cancer. Herein, we present evidence that this essential zinc transporter is expressed in hepatocellular carcinomas. Zip4 mRNA and protein were dramatically elevated in hepatocytes in the majority of human hepatocellular carcinomas relative to noncancerous surrounding tissues, as well as in hepatocytes in hepatocellular carcinomas occurring in farnesoid X receptor-knockout mice. Interestingly, meta-analysis of microarray data in the Geo and Oncomine databases suggests that Zip4 mRNA may also be elevated in many types of cancer. Potential mechanisms of action of ZIP4 were examined in cultured cell lines. RNAi knockdown of Zip4 in mouse Hepa cells significantly increased apoptosis and modestly slowed progression from G(0)/G(1) to S phase when cells were released from hydroxyurea block into zinc-deficient medium. Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration. ZIP4 may play a role in the acquisition of zinc by hepatocellular carcinomas, and potentially many different cancerous cell-types, leading to repressed apoptosis, enhanced growth rate and enhanced invasive behavior.

Genetic redundancy and pleiotropism have limited the discovery of functions associated with miRNAs and other regulatory mechanisms. To overcome this, we performed an enhancer screen for developmental defects caused by compromising both global miRISC function and individual genes in Caenorhabditis elegans. Among 126 interactors with miRNAs, we surprisingly found the CED-3 caspase that has only been well studied for its role in promoting apoptosis, mostly through protein activation. We provide evidence for a non-apoptotic function of CED-3 caspase that regulates multiple developmental events through proteolytic inactivation. Specifically, LIN-14, LIN-28, and DISL-2 proteins are known miRNA targets, key regulators of developmental timing, and/or stem cell pluripotency factors involved in miRNA processing. We show CED-3 cleaves these proteins in vitro. We also show CED-3 down-regulates LIN-28 in vivo, possibly rendering it more susceptible to proteasomal degradation. This mechanism may critically contribute to the robustness of gene expression dynamics governing proper developmental control. For an organism to develop from a single cell into a collection of many different, specialized cells, different genes must be switched on or off at particular times. However, some of these genes involved in development are ‘redundant’ and carry out the same or similar tasks. This acts like a backup system, so if one of the genes is unable to complete a task, the others can compensate and the organism will still develop correctly. To produce a protein from a gene, the DNA sequence that makes up the gene is used as a template to create another molecule called messenger RNA. Genes can also be ‘silenced’—prevented from making proteins—by small molecules called microRNAs, which bind to messenger RNA molecules and mark them for destruction. MicroRNA molecules therefore play an important role in controlling development. However, as many microRNA molecules often work together, and as many genes are redundant, it can be difficult to discover the effects of specific microRNAs. It is also difficult to discover whether any other mechanisms work alongside the microRNAs to control development. Weaver, Zabinsky et al. used mutant forms of the nematode worm Caenorhabditis elegans, in which microRNA gene regulation did not work correctly, to investigate the mechanisms that work alongside microRNAs to control development. Genes in these worms were silenced; those silenced genes that caused additional developmental defects were considered likely to work ‘redundantly’ in the same role as a microRNA molecule. This revealed over one hundred genes that were previously unknown to work with microRNA molecules. Weaver, Zabinsky et al. focused on one of these genes, called ced-3. The CED-3 protein produced from this gene is known to execute programmed cell death, a carefully controlled process also known as apoptosis, but was not known to have other developmental functions. However, the worms with mutant forms of the ced-3 gene already have problems performing apoptosis but are otherwise relatively normal, so Weaver, Zabinsky et al. reasoned that the CED-3 protein must also have another role in development. Further investigation revealed that ced-3 mutations most severely disrupt development when they are combined with mutations in one particular family of microRNAs. These microRNAs are particularly important for controlling both when cells specialize into a particular type of cell, and the timing of when certain stages of development happen. Experiments using purified proteins showed that CED-3 breaks down three proteins that are produced from genes controlled by this family of microRNA molecules, and one of these proteins was also broken down by CED-3 in experiments with mutant worms. Weaver, Zabinsky et al. therefore propose that CED-3 is part of a semi-redundant system that ensures the proteins are produced at the right level and at the right time even if the microRNAs insufficiently regulate them. This finding demonstrated both a specific role and specific targets for the CED-3 protein during development, entirely distinct from its role in apoptosis. Although Weaver, Zabinsky et al. have identified a large number of genes that work alongside microRNAs to control development, these are only the genes that cause obvious developmental defects in healthy worms. Further experiments using similar techniques performed on worms under stress may reveal yet more such genes.

Chronic stress and inflammation are both outcomes and major drivers of many human diseases. Sustained responsiveness despite mitigation suggests a failure to sense resolution of the stressor. Here we show that a proteolytic cleavage event of fatty acid synthase (FASN) activates a global cue for stress resolution in Caenorhabditis   elegans . FASN is well established for biosynthesis of the fatty acid palmitate. Our results demonstrate FASN promoting an anti-inflammatory profile apart from palmitate synthesis. Redox-dependent proteolysis of limited amounts of FASN by caspase activates a C-terminal fragment sufficient to downregulate multiple aspects of stress responsiveness, including gene expression, metabolic programs and lipid droplets. The FASN C-terminal fragment signals stress resolution in a cell non-autonomous manner. Consistent with these findings, FASN processing is also seen in well-fed but not fasted male mouse liver. As downregulation of stress responses is critical to health, our findings provide a potential pathway to control diverse aspects of stress responses. Wei et al. show that proteolytic cleavage of fatty acid synthase (FASN) upon stress contributes to stress resolution. This role in stress resolution of the resulting C-terminal fragment of FASN is independent of its canonical function in fatty acid synthesis.

Translation of the basolateral zinc transporter ZIP5 is repressed during zinc deficiency but Zip5 mRNA remains associated with polysomes and can be rapidly translated when zinc is repleted. Herein, we examined the mechanisms regulating translation of Zip5 . The 3′-untranslated region (UTR) of Zip5 mRNA is well conserved among mammals and is predicted by mFOLD to form a very stable stem-loop structure. Three algorithms predict this structure to be flanked by repeated seed sites for miR-328 and miR-193a. RNAse footprinting supports the notion that a stable stem-loop structure exists in this 3′-UTR and electrophoretic mobility shift assays detect polysomal protein(s) binding specifically to the stem-loop structure in the Zip5 3′-UTR. miR-328 and miR-193a are expressed in tissues known to regulate Zip5 mRNA translation in response to zinc availability and both are polysome-associated consistent with Zip5 mRNA localization. Transient transfection assays using native and mutant Zip5 3′-UTRs cloned 3′ to luciferase cDNA revealed that the miRNA seed sites and the stem-loop function together to augment translation of Zip5 mRNA when zinc is replete.

The Sloan Digital Sky Survey (SDSS) has been active for approximately 15 years as of this writing. SDSS continues to produce large amounts of data, effectively daily. SDSS needs an effective system for data transfer and management that can operate essentially free of human intervention. In 2008, with the commencement of the third phase of SDSS, SDSS-III, new needs and opportunities motivated a fresh look at the data transfer infrastructure. We have constructed and are releasing a Python package, transfer, that contains all the automation needed for daily data transfer operations. This package has been tested and used successfully for several years. Significant portions of this code will continue to be used as SDSS transitions to its fourth phase, SDSS-IV.

The Dark Energy Spectroscopic Instrument (DESI) is under construction to measure the expansion history of the universe using the baryon acoustic oscillations technique. The spectra of 35 million galaxies and quasars over 14,000 square degrees will be measured during a 5-year survey. A new prime focus corrector for the Mayall telescope at Kitt Peak National Observatory will deliver light to 5,000 individually targeted fiber-fed robotic positioners. The fibers in turn feed ten broadband multi-object spectrographs. We describe the ProtoDESI experiment, that was installed and commissioned on the 4-m Mayall telescope from 2016 August 14 to September 30. ProtoDESI was an on-sky technology demonstration with the goal to reduce technical risks associated with aligning optical fibers with targets using robotic fiber positioners and maintaining the stability required to operate DESI. The ProtoDESI prime focus instrument, consisting of three fiber positioners, illuminated fiducials, and a guide camera, was installed behind the existing Mosaic corrector on the Mayall telescope. A fiber view camera was mounted in the Cassegrain cage of the telescope and provided feedback metrology for positioning the fibers. ProtoDESI also provided a platform for early integration of hardware with the DESI Instrument Control System that controls the subsystems, provides communication with the Telescope Control System, and collects instrument telemetry data. Lacking a spectrograph, ProtoDESI monitored the output of the fibers using a fiber photometry camera mounted on the prime focus instrument. ProtoDESI was successful in acquiring targets with the robotically positioned fibers and demonstrated that the DESI guiding requirements can be met.