Biotin attachment domain-containing proteins mediate hydroxy fatty acid-dependent inhibition of acetyl CoA carboxylase.

Hundreds of naturally occurring specialized fatty acids (FAs) have potential as desirable chemical feedstocks if they could be produced at large scale by crop plants; however, transgenic expression of their biosynthetic genes has generally been accompanied by dramatic reductions in oil yield. For example, expression of castor (Ricinus communis) FA hydroxylase (FAH) in the Arabidopsis thaliana FA elongation mutant fae1 resulted in a 50% reduction of FA synthesis rate that was attributed to inhibition of acetyl-CoA carboxylase (ACCase) by an undefined mechanism. Here, we tested the hypothesis that the ricinoleic acid-dependent decrease in ACCase activity is mediated by biotin attachment domain-containing (BADC) proteins. BADCs are inactive homologs of biotin carboxy carrier protein that lack a biotin cofactor and can inhibit ACCase. Arabidopsis contains three BADC genes. To reduce expression levels of BADC1 and BADC3 in fae1/FAH plants, a homozygous badc1,3/fae1/FAH line was created. The rate of FA synthesis in badc1,3/fae1/FAH seeds doubled relative to fae1/FAH, restoring it to fae1 levels, increasing both native FA and HFA accumulation. Total FA per seed, seed oil content, and seed yield per plant all increased in badc1,3/fae1/FAH, to 5.8 µg, 37%, and 162 mg, respectively, relative to 4.9 µg, 33%, and 126 mg, respectively, for fae1/FAH. Transcript levels of FA synthesis-related genes, including those encoding ACCase subunits, did not significantly differ between badc1,3/fae1/FAH and fae1/FAH. These results demonstrate that BADC1 and BADC3 mediate ricinoleic acid-dependent inhibition of FA synthesis. We propose that BADC-mediated FAS inhibition as a general mechanism that limits FA accumulation in specialized FA-accumulating seeds.

Scoping review: The state of research on cryptogenic organizing pneumonia therapeutics.

Cryptogenic organizing pneumonia is a diffuse interstitial lung disease that starts in the alveolar wall and subsequently expands to the alveolar ducts and respiratory bronchioles. Randomized controlled trials are lacking to guide the treatment of cryptogenic organizing pneumonia, so treatment decisions and practice guidelines are often based upon observations from case series or expert clinical opinions. The backbone of treatment involves immunosuppression via corticosteroids. In refractory cases, cytotoxic therapy is considered. The evidence that supports the use of these regimens are limited. The goal of this scoping review is to conduct a systematic search of the literature to determine what regimens have been utilized to treat steroid refractory organizing pneumonia and to characterize the evidence supporting their use.

Functional profiling of the Toxoplasma genome during acute mouse infection.

Within a host, pathogens encounter a diverse and changing landscape of cell types, nutrients, and immune responses. Examining host-pathogen interactions in animal models can therefore reveal aspects of infection absent from cell culture. We use CRISPR-based screens to functionally profile the entire genome of the model apicomplexan parasite Toxoplasma gondii during mouse infection. Barcoded gRNAs were used to track mutant parasite lineages, enabling detection of bottlenecks and mapping of population structures. We uncovered over 300 genes that modulate parasite fitness in mice with previously unknown roles in infection. These candidates span multiple axes of host-parasite interaction, including determinants of tropism, host organelle remodeling, and metabolic rewiring. We mechanistically characterized three novel candidates, including GTP cyclohydrolase I, against which a small-molecule inhibitor could be repurposed as an antiparasitic compound. This compound exhibited antiparasitic activity against T. gondii and Plasmodium falciparum, the most lethal agent of malaria. Taken together, we present the first complete survey of an apicomplexan genome during infection of an animal host, and point to novel interfaces of host-parasite interaction that may offer new avenues for treatment.

Statin Use and Mortality among Patients Hospitalized with Sepsis: A Retrospective Cohort Study within Southern California, 2008-2018.

Background: Despite early goal-directed therapy, sepsis mortality remains high. Statins exhibit pleiotropic effects. Objective: We sought to compare mortality outcomes among statin users versus nonusers who were hospitalized with sepsis. Methods: Retrospective cohort study of patients (age ≥18 years) during 1/1/2008-9/30/2018. Mortality was compared between statin users and nonusers and within statin users (hydrophilic versus lipophilic, fungal versus synthetic derivation, and individual statins head-to-head). Multivariable Cox regression models were used to estimate hazard ratios (HR) for 30-day and 90-day mortality. Inverse probability treatment weighting (IPTW) analysis was performed to account for indication bias. Results: Among 128,161 sepsis patients, 34,088 (26.6%) were prescribed statin drugs prior to admission. Statin users compared to nonusers had a 30-day and 90-day mortality HR (95% CI) of 0.80 (0.77-0.83) and 0.79 (0.77-0.81), respectively. Synthetic derived statin users compared to fungal derived users had a 30- and 90-day mortality HR (95% CI) of 0.86 (0.81-0.91) and 0.85 (0.81-0.89), respectively. Hydrophilic statin users compared to lipophilic users had a 30-day and 90-day mortality HR (95% CI) of 0.90 (0.81-1.01) and 0.86 (0.78-0.94), respectively. Compared to simvastatin, 30-day mortality HRs (95% CI) were 0.85 (0.66-1.10), 0.87 (0.82-0.92), 0.87 (0.76-0.98), and 1.22 (1.10-1.36) for rosuvastatin, atorvastatin, pravastatin, and lovastatin, respectively. Conclusion: Statin use was associated with lower mortality in patients hospitalized with sepsis. Hydrophilic and synthetic statins were associated with better outcomes than lipophilic and fungal-based preparations.

Characteristics of patients discharged and readmitted after COVID-19 hospitalisation within a large integrated health system in the United States.

BACKGROUND: Limited studies have explored post-discharge outcomes following Coronavirus Disease 2019 (COVID-19) hospitalisation. We sought to characterise patients discharged following a COVID-19 hospitalisation within a large integrated health system in the United States. METHODS: We performed a retrospective study of 2180 COVID-19 patients discharged between 1 April 2020 and 31 July 2020. The primary endpoint was all-cause observation stay or inpatient readmission within 30 days from discharge. Bivariate and multivariable logistic regression analyses were performed to estimate the association between key socio-demographic and clinical characteristics with risk of 30-day readmission. RESULTS: The 30-day readmission rate was 7.6% (n = 166); 30-day mortality rate was 1% (n = 19). Most readmissions were respiratory-related (58%) and occurred at a median time of 5 days post discharge. Adjusted models showed that prior hospitalisations (Odds Ratio = 2.36, [95% Confidence Interval: 1.59-3.50]), chronic pulmonary disease (1.57 [1.09-2.28]), and discharge to home health (1.46 [1.01-2.11]) were significantly associated with 30-day readmission. Longer duration from diagnosis to index admission was borderline associated with lower odds of readmission (0.95 [0.91-1.00]). CONCLUSION: Readmission and mortality rates for COVID-19 following discharge are low. Most readmissions occur early and are due to respiratory causes and may reflect the prolonged acute disease course.

Minihelix-loop RNAs: minimal structures for aminoacylation catalysts.

We report here an in vitro selected ribozyme, KL17, which is active in charging amino acids on its own 5'-OH group. The ribozyme consists of two catalytic domains, one of which (consisting of P5/P6/L6) recognizes amino acid substrates based on the steric environment of the side chain, whereas the other recognizes an aminoacylated oligonucleotide. The secondary structure of this ambidextrous ribozyme arranges into a pseudoknot, where L6 docks onto the 3'-terminal single-stranded region. The formation of this pseudoknot structure brings the P6 region, in which the essential catalytic core is most likely embedded, into the proximity of the 5'-OH group. Our studies show that the P6-L6 domain can be separated from the main body of KL17 and the derived P6-L6 minihelix-loop RNA can act as a trans-aminoacylation catalyst. In this report, we also compare this ribozyme with an analogous aminoacylation system previously characterized in our laboratory and illuminate the similarities and differences between these catalytic systems.

Epidemiology and clinical significance of pneumocystis colonization.

Pneumocystis pneumonia has long been recognized as a cause of morbidity and mortality in immunocompromised populations, particularly those with HIV infection. Pneumocystis colonization-that is, detection of the organism or its DNA, without signs or symptoms of pneumonia-has recently been described, and accumulating evidence suggests that it may be an important clinical phenomenon. Sensitive molecular techniques such as polymerase chain reaction are frequently used to identify Pneumocystis colonization. Low levels of Pneumocystis in the lungs may stimulate pulmonary inflammation and may play a role in the development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss evidence for the occurrence of Pneumocystis colonization in animals as well as the epidemiology and risk factors for Pneumocystis colonization in various human populations. We also evaluate the clinical significance of Pneumocystis colonization and its relationship to lung disease.