The rockefeller university

Molnupiravir, a wide-spectrum antiviral that is currently in phase 2/3 clinical trials for the treatment of COVID-19, is proposed to inhibit viral replication by a mechanism known as 'lethal mutagenesis'. Two recently published studies reveal the biochemical and structural bases of how molnupiravir disrupts the fidelity of SARS-CoV-2 genome replication and prevents viral propagation by fostering error accumulation in a process referred to as 'error catastrophe'.

Patients with autosomal recessive protein kinase C delta (PKC delta) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKC delta-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40(phox) normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKC delta in activation of the NADPH oxidase complex. Our findings thus show that patients with PKC delta deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

Background: One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods: A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results: A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 =2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of similar to 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01-0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions: Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Environmental microplastics are gaining interest due to their ubiquity and the threat they pose to environmental and human health. Critical studies have revealed the abundance of microplastics in nature, while others have tested the impacts of these small plastics on organismal health in the laboratory. Yet, there is often a mismatch between these two areas of research, resulting in major discrepancies and an inability to interpret certain findings. Here, we focus on several main lines of inquiry. First, even though the majority of environmental microplastics are plastic microfibers from textiles, laboratory studies still largely use spherical microbeads. There are also inconsistencies between the measurements of microplastics in the environment as compared to the concentrations that tend to be used in experimental studies. Likewise, the period of exposure occurring in experimental studies and in the environment are vastly different. Lastly, although experimental studies often focus on a particular subset of toxic chemicals present on microplastics, textile microfibers carry other dyes and chemicals that are understudied. They also cause types of physical damage not associated with microspheres. This review will analyze the literature pertaining to these mismatches, focusing on aquatic organisms and model systems, and seek to inform a path forward for this burgeoning area of research.

Social animals display a wide range of behavioural defences against infectious diseases, some of which increase social contacts with infectious individuals (e.g. mutual grooming), while others decrease them (e.g. social exclusion). These defences often rely on the detection of infectious individuals, but this can be achieved in several ways that are difficult to differentiate. Here, we combine non-pathogenic immune challenges with automated tracking in colonies of the clonal raider ant to ask whether ants can detect the immune status of their social partners and to quantify their behavioural responses to this perceived infection risk. We first show that a key behavioural response elicited by live pathogens (allogrooming) can be qualitatively recapitulated by immune challenges alone. Automated scoring of interactions between all colony members reveals that this behavioural response increases the network centrality of immune-challenged individuals through a general increase in physical contacts. These results show that ants can detect the immune status of their nest-mates and respond with a general 'caring' strategy, rather than avoidance, towards social partners that are perceived to be infectious. Finally, we find no evidence that changes in cuticular hydrocarbon profiles drive these behavioural effects.

Hidradenitis suppurativa is a chronic inflammatory dermatosis with presentations ranging from painful nodules and abscesses to draining tunnels. Using an unbiased proteomics approach, we assessed cardiovascular-, cardiometabolic-, and inflammation-related biomarkers in the serum of patients with moderate-to-severe hidradenitis suppurativa. The serum of patients with hidradenitis suppurativa clustered separately from that of healthy controls and had an upregulation of neutrophil-related markers (Cathepsin D, IL-17A, CXCL1). Patients with histologically diagnosed dermal tunnels had higher serum lipocalin-2 levels compared with those without tunnels. Consistent with this, patients with tunnels had a more neutrophilic-rich serum signature, marked by Cathepsin D, IL-17A, and IL-17D alterations. There was a significant serum.skin correlation between proteins in the serum and the corresponding mRNA expression in skin biopsies, with healthy-appearing perilesional skin demonstrating a significant correlation with neutrophil-related proteins in the serum. CSF3 mRNA levels in lesional skin significantly correlated with neutrophil-related proteins in the serum, suggesting that CFS3 in the skin may be a driver of neutrophilic inflammation. Clinical significantly correlated with the levels of lipocalin-2 and IL-17A in the serum. Using an unbiased, large-scale proteomic approach, we demonstrate that hidradenitis suppurativa is a systemic neutrophilic dermatosis, with a specific molecular signature associated with the presence of dermal tunnels.

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and aldehyde dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes. We show DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML. SIGNIFICANCE: Aberrant gene silencing is an epigenetic hallmark of human cancer, but the functional consequences of this process are largely unknown. In this study, we show how an epigenetic alteration leads to an actionable dependency on a DNA repair pathway through the disabling of genetic redundancy.

We have read with interest the letter by Tirgan et al.1 on a group of 17 patients with keloids referred for treatment with dupilumab, according to authors with minimal or no response. However, only 8 patients were actually treated with dupilumab for 2–12 months; 3 for 2–3 months, 1 for 6 months and 4 for 10–12 months. The patients that per authors had a possible response was treated for 12 months. The responses were either evaluated by the patients or by the author (MT), with no reporting of how the response was evaluated. In addition to their effect on patients’ appearance, keloids also cause pain and itch.2 Thus, it is imperative to also evaluate for pain, itching and other symptoms in a standardized manner. Of note, evaluations were not standardized as many were self-reported. Last, while dupilumab may have been given to some patients, each received 300 mg subcutaneously every two weeks which may not be enough dosing. Also, treatment duration varied from 2 to 12 months, and often 2 months is not sufficient time to determine clinical response. Responses should be assessed by appropriate measures of dimensions and include itch and pain scores. The pictures included also have different lighting and are difficult to assess. Thus, it is difficult to ascertain response to dupilumab, based on this report. We believe it is necessary to fully assess clinical response to dupilumab in an appropriate placebo-controlled, standardized clinical trial where measures are performed by qualified personnel in the clinic. Further, we are highly experienced in treating skin disorders and know to clinically diagnose keloids and performed a biopsy that was compatible with keloids.3 The areas were biopsied to rule out skin cancer, due to the large growths, as we usually do not biopsy atopic dermatitis lesions. Furthermore, reports such as Klumpar et al.4 report development of keloids in areas of trauma. Our patient had extensive chronic scratching in the popliteal fossa, likely resulting in his keloids and had a family history of keloids.3 Our finding is further validated by a recent report by Nakashima et al.,5 about resolved fibrotic plaques in a patient treated by dupilumab. Our group has also recently shown in 3 keloid patients (compared with controls) that the Th2 immune axis is upregulated in keloid lesional and non-lesional skin.6 These findings, together with our case report and Nakashima et al.,5 provide the rationale to perform an appropriate standardized, placebo-controlled study, with relevant evaluations, and maximal dupilumab dosing (weekly), to establish clinical benefit. We hope that a controlled study, combined with mechanistic assessments, can provide a definitive answer on the clinical benefit of dupilumab and Th2 targeting in keloids. We have thus initiated a large, controlled study, with extensive assessments by a specialized team of researchers and clinicians, for patients with significant keloids, which we are hoping will not only provide an answer but may also change the treatment paradigm for patients with keloids and help with the pain caused by this condition.