Structural insights into the complex of oncogenic KRas4BG12V and Rgl2, a RalA/B activator.

About a quarter of total human cancers carry mutations in Ras isoforms. Accumulating evidence suggests that small GTPases, RalA, and RalB, and their activators, Ral guanine nucleotide exchange factors (RalGEFs), play an essential role in oncogenic Ras-induced signalling. We studied the interaction between human KRas4B and the Ras association (RA) domain of Rgl2 (Rgl2RA), one of the RA-containing RalGEFs. We show that the G12V oncogenic KRas4B mutation changes the interaction kinetics with Rgl2RA The crystal structure of the KRas4BG12V: Rgl2RA complex shows a 2:2 heterotetramer where the switch I and switch II regions of each KRasG12V interact with both Rgl2RA molecules. This structural arrangement is highly similar to the HRasE31K:RALGDSRA crystal structure and is distinct from the well-characterised Ras:Raf complex. Interestingly, the G12V mutation was found at the dimer interface of KRas4BG12V with its partner. Our study reveals a potentially distinct mode of Ras:effector complex formation by RalGEFs and offers a possible mechanistic explanation for how the oncogenic KRas4BG12V hyperactivates the RalA/B pathway.

Antiviral Used among Non-Severe COVID-19 Cases in Relation to Time till Viral Clearance: A Retrospective Cohort Study.

(1) Background: The WHO identified COVID-19 as a fast-growing epidemic worldwide. A few antivirals have shown promising effectiveness in treating COVID-19. This study aimed to assess the correlation between antiviral drugs and the time until viral clearance of SARS-CoV-2. (2) Methods: This was a retrospective cohort study that included 1731 non-severe COVID-19 patients treated in NMC Royal Hospital, UAE. (3) Results: A total of 1446 patients received symptomatic treatment only (mean age of 35.6 ± 9.0 years). The analyzed antiviral treatment protocols were azithromycin, hydroxychloroquine, lopinavir/ritonavir, and favipiravir. The produced Kaplan-Meier plots showed no significant differences in the time until viral clearance among the compared protocols, which showed overlapping confidence intervals, which were determined by performing the log-rank and adjusted pairwise log-rank tests (p = 0.2, log-rank = 9.3). The age and gender of patients did not significantly affect the rate of viral clearance regardless of the antiviral therapy administered, even when compared to patients who received symptomatic treatment only, with the exception of hydroxychloroquine (HCQ), azithromycin, and favipiravir, which increased the odds of a faster rate of viral clearance by 46% after adjustments. (4) Conclusions: No significant differences were observed regarding the time until viral clearance among non-severe COVID-19 patients following the prescription of different antiviral drugs.

ABO Blood Group in Relation to COVID-19 Susceptibility and Clinical Outcomes: A Retrospective Observational Study in the United Arab Emirates.

(1) Background: The association between ABO blood groups and COVID-19 outcomes was investigated in several studies. The results were controversial. This study aimed to explore the association between ABO blood groups and COVID-19 outcomes. (2) Methods: This retrospective study included 303 COVID-19 patients treated at the NMC Royal Hospital in the United Arab Emirates between 8 April 2020 and 30 June 2020. (3) Results: The mean age of patients included in the study was 39.3 ± 10.7 years, and 72.9% of patients were males. The prevalence of blood groups O, A, B, and AB was 40.3%, 27.7%, 25.1%, and 6.9%, respectively. The correlation between ABO blood groups and COVID-19 outcomes was insignificant except in the AB group, with significantly higher odds of disease severity. Increased age, higher body mass index (BMI), and being of male gender increased the risk for pneumonia among all blood groups. Both increased age and higher BMI increased the risk of mortality, and increased age increased the risk of disease severity. Troponin and platelet counts were significantly different in the A group compared to the non-A groups. Time to viral clearance was not different among blood groups. However, adjustment for Rh groups resulted in a significantly shorter time in the B group. (4) Conclusions: There was no significant association between ABO blood groups and COVID-19 outcomes, with the exception of group AB.