Nuclear GRP75 Binds Retinoic Acid Receptors to Promote Neuronal Differentiation of Neuroblastoma

Retinoic acid (RA) has been approved for the differentiation therapy of neuroblastoma (NB). Previous work revealed a correlation between glucose-regulated protein 75 (GRP75) and the RA-elicited neuronal differentiation of NB cells. The present study further demonstrated that GRP75 translocates into the nucleus and physically interacts with retinoid receptors (RARα and RXRα) to augment RA-elicited neuronal differentiation. GRP75 was required for RARα/RXRα-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARα/RXRαin a RA-dependent manner. More intriguingly, the level of GRP75/RARα/RXRα tripartite complexes was tightly associated with the RA-induced suppression of tumor growth in animals and the histological grade of differentiation in human NB tumors. The formation of GRP75/RARα/RXRα complexes was intimately correlated with a normal MYCN copy number of NB tumors, possibly implicating a favorable prognosis of NB tumors. The present findings reveal a novel function of nucleus-localized GRP75 in actively promoting neuronal differentiation, delineating the mode of action for the differentiation therapy of NB by RA

Dynamics of O2 and pCO2 in a Southeast Asia seagrass meadow: Metabolic rates and carbon sink capacity

Dissolved oxygen (DO) and partial pressure of CO2 (pCO2) were measured at half-hourly intervals from June 29 to September 9, 2019, in a seagrass meadow in the Southeast Asia archipelagos region. The open water mass balance of the O2 approach was used to calculate metabolic rates (i.e., gross primary production (GPP), community respiration (CR), and net community production (NCP). The calculations show that GPP and CR rates in the seagrass meadow of Dongsha Island were approximately 2.5 times higher than the global means (GPP, 507 ± 173 vs. 225 ± 11 mmol O2 m-2 d-1; CR, 497 ± 171 vs. 188 ± 10 mmol O2 m-2 d-1), while NCP was similar to the global mean (8 ± 61 vs. 27 ± 6 mmol O2 m-2 d-1), suggesting that seagrass meadows with high GPP may not necessarily hold high potential for carbon sequestration. The current data set also reveal that NCP tended to increase with GPP only at lower GPP levels, while NCP did not increase with GPP anymore at higher GPP levels. Moreover, the autotrophic/heterotrophic status did not correspond well to the sink/source behavior of CO2, suggesting that organic carbon metabolism could not be the only dominant factor in determining the sink/source status in a typical seagrass meadow underlain by carbonate sediments, which was further supported by the observed decrease in the trend of pCO2 with a relatively stable NCP level over the study period. These results demonstrate that the metabolism and the relationship between NCP and pCO2 in the seagrass meadows of Dongsha Island may deviate greatly from the global mean condition. To obtain a better assessment of the global potential of seagrass meadows as a nature-based solution for carbon sequestration, more regional-specific studies are still needed in the key regions, such as Indonesia and the Pacific archipelagos, that support extensive seagrass meadows but have not been charted

Mortality risk factors in patients with Acinetobacter baumannii ventilator-associated pneumonia

Background/PurposeVentilator-associated pneumonia (VAP) caused by Acinetobacter baumannii has contributed to high mortality rate, prolonged stays in the intensive care unit, and the rapid development of antimicrobial resistance to commonly used antimicrobials. This study sought to determine predictors of mortality and carbapenem resistance for patients with A baumannii VAP.MethodsWe retrospectively reviewed 541 adult patients with A baumannii pneumonia, who were admitted to a medical center between 2005 and 2007; of which 180 (33.3%) had been treated with mechanical ventilation. Of the 180 patients, 98 (54.4%) who survived were categorized as the survivor group, and 82 (45.6%) who died as the mortality group. Eighty-seven (48.3%) with imipenem-sensitive A baumannii VAP were categorized as the IS-AB group, and the remaining 93 (51.7%) with imipenem-resistant VAP as the IR-AB group.ResultsCompared with the survivor group, the mortality group had significantly higher Charlson comorbidity index scores, and more neoplastic disease, other sites of infection, bloodstream infections, altered mental status, confusion, urea >7 mmol/L, respiratory rate >30/min, low blood pressure (systolic <90 mmHg or diastolic <60 mmHg), age >65 years (CURB-65) ≥ 3, creatinine > 1.6 mg/dL, C-reactive protein ≥ 100 mg/L, and imipenem resistance. The survivor group had more cases of tracheostomy and diabetes mellitus than the mortality group had. Compared with the IS-AB group, the IR-AB group had higher Charlson comorbidity index scores, longer stays before VAP onset, an increase in other sites of infection, white blood cell count <4/μL or >1.1 × 104/μL, and higher hospital mortality rates.ConclusionInadequate initial empiric antimicrobial therapy and higher disease severity scores, including CURB ≥ 3 and C-reactive protein ≥ 120 mg/L, were independent risk factors associated with higher mortality rates for A baumannii pneumonia. Length of stay before VAP and white blood cell count <4/μL or >1.1 × 104/μL were independent risk factors for carbapenem resistance

A cytoplasmic RNA virus generates functional viral small RNAs and regulates viral IRES activity in mammalian cells

The roles of virus-derived small RNAs (vsRNAs) have been studied in plants and insects. However, the generation and function of small RNAs from cytoplasmic RNA viruses in mammalian cells remain unexplored. This study describes four vsRNAs that were detected in enterovirus 71-infected cells using next-generation sequencing and northern blots. Viral infection produced substantial levels (\u3e105 copy numbers per cell) of vsRNA1, one of the four vsRNAs. We also demonstrated that Dicer is involved in vsRNA1 generation in infected cells. vsRNA1 overexpression inhibited viral translation and internal ribosomal entry site (IRES) activity in infected cells. Conversely, blocking vsRNA1 enhanced viral yield and viral protein synthesis. We also present evidence that vsRNA1 targets stem-loop II of the viral 5′ untranslated region and inhibits the activity of the IRES through this sequence-specific targeting. Our study demonstrates the ability of a cytoplasmic RNA virus to generate functional vsRNA in mammalian cells. In addition, we also demonstrate a potential novel mechanism for a positive-stranded RNA virus to regulate viral translation: generating a vsRNA that targets the IRES