HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis.

Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains poorly understood, as are approaches to restore hematopoietic stem cell (HSC) function loss because of defective ribosome biogenesis. Here we reveal a role of the E3 ubiquitin ligase HectD1 in regulating HSC function via ribosome assembly and protein translation. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and ex vivo maintenance concomitant with reduced protein synthesis and growth rate under stress conditions. Mechanistically, HectD1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Hectd1 loss leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, resulting in 60S/40S joining defects. Importantly, Znf622 depletion in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. These findings highlight the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration

Penaeid shrimp genome provides insights into benthic adaptation and frequent molting

Crustacea, the subphylum of Arthropoda which dominates the aquatic environment, is of major importance in ecology and fisheries. Here we report the genome sequence of the Pacific white shrimp Litopenaeus vannamei, covering similar to 1.66 Gb (scaffold N50 605.56 Kb) with 25,596 protein-coding genes and a high proportion of simple sequence repeats (>23.93%). The expansion of genes related to vision and locomotion is probably central to its benthic adaptation. Frequent molting of the shrimp may be explained by an intensified ecdysone signal pathway through gene expansion and positive selection. As an important aquaculture organism, L. vannamei has been subjected to high selection pressure during the past 30 years of breeding, and this has had a considerable impact on its genome. Decoding the L. vannamei genome not only provides an insight into the genetic underpinnings of specific biological processes, but also provides valuable information for enhancing crustacean aquaculture

Paleophysical Oceanography with an Emphasis on Transport Rates

Paleophysical oceanography is the study of the behavior of the fluid ocean of the past, with a specific emphasis on its climate implications, leading to a focus on the general circulation. Even if the circulation is not of primary concern, heavy reliance on deep-sea cores for past climate information means that knowledge of the oceanic state when the sediments were laid down is a necessity. Like the modern problem, paleoceanography depends heavily on observations, and central difficulties lie with the very limited data types and coverage that are, and perhaps ever will be, available. An approximate separation can be made into static descriptors of the circulation (e.g., its water-mass properties and volumes) and the more difficult problem of determining transport rates of mass and other properties. Determination of the circulation of the Last Glacial Maximum is used to outline some of the main challenges to progress. Apart from sampling issues, major difficulties lie with physical interpretation of the proxies, transferring core depths to an accurate timescale (the “age-model problem”), and understanding the accuracy of time-stepping oceanic or coupled-climate models when run unconstrained by observations. Despite the existence of many plausible explanatory scenarios, few features of the paleocirculation in any period are yet known with certainty.National Science Foundation (U.S.) (grant OCE-0645936

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors

INTRODUCTION: Treatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors. BACKGROUND: METHODS: Patients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event. CONCLUSIONS: Treatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25

Urgent care centers in the U.S.: Findings from a national survey

<p>Abstract</p> <p>Background</p> <p>Due to long waits for primary care appointments and extended emergency department wait times, newer sites for episodic primary care services, such as urgent care centers, have developed. However, little is known about these centers. The purpose of this study is to provide information about the organization and functioning of urgent care centers based on a nationally representative U.S. sample.</p> <p>Methods</p> <p>We conducted a mail survey with telephone follow-up of urgent care centers identified via health insurers' websites, internet searches, and a trade association mailing list. Descriptive statistics are presented.</p> <p>Results</p> <p>Urgent care centers are open beyond typical office hours, and their scope of services is broader than that of many primary care offices. While these characteristics are similar to hospital emergency departments, such centers employ significant numbers of family physicians. The payer distribution is similar to that of primary care, and physicians' average salaries are comparable to those for family physicians overall. Urgent care centers report early adoption of electronic health records, though our findings are qualified by a lack of strictly comparable data.</p> <p>Conclusion</p> <p>While their hours and scope of services reflect some characteristics of emergency departments, urgent care centers are in many ways similar to family medicine practices. As the health care system evolves to cope with expanding demands in the face of limited resources, it is unclear how patients with episodic care needs will be treated, and what role urgent care centers will play in their care.</p

Environmental and diagenetic controls on the morphology and calcification of the Ediacaran metazoan Cloudina

Abstract Cloudina is a globally distributed Ediacaran metazoan, with a tubular, funnel-in-funnel form built of thin laminae (ca. 1–10 μm). To what degree local environmental controlled morphology, and whether early diagenesis controlled the degree of calcification of Cloudina, is debated. Here we test these hypotheses by considering assemblages from four, coeval localities from the Upper Omkyk Member, Nama Group, Namibia, from inner ramp to mid-ramp reef across the Zaris Subbasin. We show that sinuosity of the Cloudina tube is variable between sites, as is the relative thickness of the tube wall, suggesting these features were environmentally controlled. Walls are thickest in high-energy reef settings, and thinnest in the low-energy, inner ramp. While local diagenesis controls preservation, all diagenetic expressions are consistent with the presence of weakly calcified, organic-rich laminae, and lamina thicknesses are broadly constant. Finally, internal ‘cements’ within Cloudina are found in all sites, and pre-date skeletal breakage, transport, as well as syn-sedimentary botryoidal cement precipitation. Best preservation shows these to be formed by fine, pseudomorphed aragonitic acicular crystals. Sr concentrations and Mg/Ca show no statistically significant differences between internal Cloudina cements and botryoidal cements, but we infer all internal cements to have precipitated when Cloudina was still in-situ and added considerable mechanical strength, but may have formed post-mortem or in abandoned parts of the skeleton

Improved eradication of Clostridium difficile spores from toilets of hospitalized patients using an accelerated hydrogen peroxide as the cleaning agent

<p>Abstract</p> <p>Background</p> <p><it>C. difficle </it>spores in the environment of patients with <it>C. difficile </it>associated disease (CDAD) are difficult to eliminate. Bleach (5000 ppm) has been advocated as an effective disinfectant for the environmental surfaces of patients with CDAD. Few alternatives to bleach for non-outbreak conditions have been evaluated in controlled healthcare studies.</p> <p>Methods</p> <p>This study was a prospective clinical comparison during non-outbreak conditions of the efficacy of an accelerated hydrogen peroxide cleaner (0.5% AHP) to the currently used stabilized hydrogen peroxide cleaner (0.05% SHP at manufacturer recommended use-dilution) with respect to spore removal from toilets in a tertiary care facility. The toilets used by patients who had diarrhea with and without <it>C. difficile </it>associated disease (CDAD) were cultured for <it>C. difficile </it>and were monitored using an ultraviolet mark (UVM) to assess cleaning compliance on a daily basis 5 days per week. A total of 243 patients and 714 samples were analysed. The culture results were included in the analysis only if the UVM audit from the same day confirmed that the toilet had been cleaned.</p> <p>Results</p> <p>Our data demonstrated that the efficacy of spore killing is formulation specific and cannot be generalized. The Oxivir_TB^®AHP formulation resulted in statistically significantly (p = 0.0023) lower levels of toxigenic <it>C. difficile </it>spores in toilets of patients with CDAD compared to the SHP formulation that was routinely being used (28% vs 45% culture positive). The background level of toxigenic <it>C. difficile </it>spores was 10% in toilets of patients with diarrhea not due to CDAD. The UVM audit indicated that despite the enhanced twice-daily cleaning protocol for CDAD patients cleaning was not achieved on approximately 30 - 40% of the days tested.</p> <p>Conclusion</p> <p>Our data indicate that the AHP formulation evaluated that has some sporicidal activity was significantly better than the currently used SHP formulation. This AHP formulation provides a one-step process that significantly lowers the <it>C. difficile </it>spore level in toilets during non-outbreak conditions without the workplace safety concerns associated with 5000 ppm bleach.</p

Highlights of the 2nd International Symposium on Tribbles and Diseases: Tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles (TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2nd International Symposium on Tribbles and Diseases held on May 7‒9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases

Molecular Mechanism of a Green-Shifted, pH-Dependent Red Fluorescent Protein mKate Variant

Fluorescent proteins that can switch between distinct colors have contributed significantly to modern biomedical imaging technologies and molecular cell biology. Here we report the identification and biochemical analysis of a green-shifted red fluorescent protein variant GmKate, produced by the introduction of two mutations into mKate. Although the mutations decrease the overall brightness of the protein, GmKate is subject to pH-dependent, reversible green-to-red color conversion. At physiological pH, GmKate absorbs blue light (445 nm) and emits green fluorescence (525 nm). At pH above 9.0, GmKate absorbs 598 nm light and emits 646 nm, far-red fluorescence, similar to its sequence homolog mNeptune. Based on optical spectra and crystal structures of GmKate in its green and red states, the reversible color transition is attributed to the different protonation states of the cis-chromophore, an interpretation that was confirmed by quantum chemical calculations. Crystal structures reveal potential hydrogen bond networks around the chromophore that may facilitate the protonation switch, and indicate a molecular basis for the unusual bathochromic shift observed at high pH. This study provides mechanistic insights into the color tuning of mKate variants, which may aid the development of green-to-red color-convertible fluorescent sensors, and suggests GmKate as a prototype of genetically encoded pH sensors for biological studies