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The COP9 signalosome (CSN) is a highly conserved eukaryotic multi-subunit enzyme, regulating cullin RING ligase activities and accordingly, substrate ubiquitination and degradation. We showed that the CSN complex of Saccharomyces cerevisiae that is deviated in subunit composition and in sequence homology harbors a highly conserved cullin deneddylase enzymatic core complex. We took advantage of the non-essentiality of the S. cerevisiae CSN-NEDD8/Rub1 axis, together with the enzyme-substrate cross-species activity, to develop a sensitive fluorescence readout assay, suitable for biochemical assessment of cullin deneddylation by CSNs from various origins. We also demonstrated that the yeast catalytic subunit, CSN5/Jab1, is targeted by an inhibitor that was selected for the human orthologue. Treatment of yeast by the inhibitor led to the accumulation of neddylated cullins and the formation of reactive oxygen species. Overall, our data revealed S. cerevisiae as a general platform that can be used for studies of CSN deneddylation and for testing the efficacy of selected CSN inhibitors.

Background The gold standard for COVID-19 diagnosis is detection of viral RNA through PCR. Due to global limitations in testing capacity, effective prioritization of individuals for testing is essential. Methods We devised a model estimating the probability of an individual to test positive for COVID-19 based on answers to 9 simple questions that have been associated with COVID-19 infection. Our model was devised from a subsample of a national symptom survey that was answered over 2 million times in Israel in its first 2 months and a targeted survey distributed to all residents of several cities in Israel. Overall, 43,752 adults were included, from which 498 self-reported as being COVID-19 positive. Findings Our model was validated on a held-out set of individuals from Israel where it achieved an auROC of 0.737 (CI: 0.712-0.759), auPR of 0.144 (CI: 0.119-0.177) and demonstrated its applicability outside of Israel in an independently-collected symptom survey dataset from the U.S., U.K. and Sweden. Our analyses revealed interactions between several symptoms and age, suggesting variation in the clinical manifestation of the disease in different age groups. Conclusions our tool can be used online and without exposure to suspected patients, thus suggesting worldwide utility in combating COVID-19 by better directing the limited testing resources through prioritization of individuals for testing, thereby increasing the rate at which positive individuals can be identified. Moreover, individuals at high risk for a positive test result can be isolated prior to testing., Graphical Abstract

The gold standard for COVID-19 diagnosis is detection of viral RNA in a reverse transcription PCR test. Due to global limitations in testing capacity, effective prioritization of individuals for testing is essential. Here, we devised a model that estimates the probability of an individual to test positive for COVID-19 based on answers to 9 simple questions regarding age, gender, presence of prior medical conditions, general feeling, and the symptoms fever, cough, shortness of breath, sore throat and loss of taste or smell, all of which have been associated with COVID-19 infection. Our model was devised from a subsample of a national symptom survey that was answered over 2 million times in Israel over the past 2 months and a targeted survey distributed to all residents of several cities in Israel. Overall, 43,752 adults were included, from which 498 self-reported as being COVID-19 positive. We successfully validated the model on held-out individuals from Israel where it achieved a positive predictive value (PPV) of 46.3% at a 10% sensitivity and demonstrated its applicability outside of Israel by further validating it on an independently collected symptom survey dataset from the U.K., U.S. and Sweden, where it achieved a PPV of 34.7% at 10% sensitivity. Moreover, evaluating the model’s performance on this latter independent dataset on entries collected one week prior to the PCR test and up to the day of the test we found the highest performance on the day of the test. As our tool can be used online and without the need of exposure to suspected patients, it may have worldwide utility in combating COVID-19 by better directing the limited testing resources through prioritization of individuals for testing, thereby increasing the rate at which positive individuals can be identified and isolated.

The vast and rapid spread of COVID-19 calls for immediate action from policy-makers, and indeed various lockdown measures were implemented in many countries. Here, we utilized nationwide surveys that assess COVID-19 associated symptoms to analyze the effect of the lockdown policy in Israel on the prevalence of clinical symptoms in the population. Daily symptom surveys were distributed online and included fever, respiratory symptoms, gastrointestinal symptoms, anosmia and Ageusia. A total of 1,456,461 survey responses were analyzed. We defined a single measure of symptoms, Symptoms Average (SA), as the mean number of symptoms reported by responders. Data were collected between March 15th to May 11th, 2020. Notably, following severe lockdown measures, we found that between March 15th and April 20th, SA sharply declined by 83.8%, as did every individual symptom, including the most common symptoms reported by our responders, cough and rhinorrhea and\or nasal congestion, which decreased by 74.1% and 69.6%, respectively. Individual symptoms exhibit differences in reduction dynamics, suggesting differences in the medical conditions that they represent or in the nature of the symptoms themselves. The reduction in symptoms was observed in all the cities in Israel, and in several stratifications of demographic characteristics. Between April 20th and May 11th, following several subsequent lockdown relief measures, the decrease in SA and individual symptoms halted and they remain relatively stable with no significant change. Overall, these results demonstrate a profound decrease in a variety of clinical symptoms following the implementation of a lockdown in Israel. As our survey symptoms are not specific to COVID-19 infection, this effect likely represents an overall nationwide reduction in the prevalence of infectious diseases, including COVID-19. This quantification may be of major interest for COVID-19 pandemic, as many countries consider implementation of lockdown strategies.