Biosynthetic pathways containing multiple core enzymes have potential to produce structurally complex natural products. Here we mined a fungal gene cluster that contains two predicted terpene ...cyclases (TCs) and a nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1, an alkaloidal terpenoid. The core of 1 is a tetracyclic, cage-like, and oxygenated sesquiterpene that is connected to dimethylcadaverine via a C–N bond and is acylated with 5,5-dimethyl-l-pipecolate. The roles of all flv enzymes are established on the basis of metabolite analysis from heterologous expression.
Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential
. However, access to large ...quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis
along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.
Background
Critically ill patients with diabetes mellitus (DM) are at increased risk of in‐hospital complications and the optimal glycemic target for such patients remains unclear. A more liberal ...approach to glucose control has recently been suggested for patients with DM, but uncertainty remains regarding its impact on complications.
Methods
We aimed to test the hypothesis that complications would be more common with a liberal glycemic target in ICU patients with DM. Thus, we compared hospital‐acquired complications in the first 400 critically ill patients with DM included in a sequential before‐and‐after trial of liberal (glucose target: 10‐14 mmol/L) vs conventional (glucose target: 6‐10 mmol/L) glucose control.
Results
Of the 400 patients studied, 165 (82.5%) patients in the liberal and 177 (88.5%) in the conventional‐control group were coded for at least one hospital‐acquired complication (P = 0.09). When comparing clinically relevant complications diagnosed between ICU admission and hospital discharge, we found no difference in the odds for infectious (adjusted odds ratio aOR for liberal‐control: 1.15 95% CI: 0.68‐1.96, P = 0.60), cardiovascular (aOR 1.40 95% CI: 0.63‐3.12, P = 0.41) or neurological complications (aOR: 1.07 95% CI: 0.61‐1.86, P = 0.81), acute kidney injury (aOR 0.83 95% CI: 0.43‐1.58, P = 0.56) or hospital mortality (aOR: 1.09 95% CI: 0.59‐2.02, P = 0.77) between the liberal and the conventional‐control group.
Conclusion
In this prospective before‐and‐after study, liberal glucose control was not associated with an increased risk of hospital‐acquired infectious, cardiovascular, renal or neurological complications in critically ill patients with diabetes.
nasal carriage is transient in most humans and usually benign, but dissemination of
to extranasal sites causes the majority of clinical infections, and
is a major cause of serious infections in the ...United States. A better understanding of innate nasal decolonization mechanisms is urgently needed, as are relevant models for studying
clearance. Here, we screened a population of healthy smokers for nasal
carriage and compared the participants' abilities to clear experimentally applied nasal
before and after completion of a smoking cessation program. We determined that cigarette smoking increases the mean nasal
load (2.6 × 10
CFU/swab) compared to the load observed in healthy nonsmokers (1.7 × 10
CFU/swab) and might increase the rate of
nasal carriage in otherwise-healthy adults: 22 of 99 smokers carried
at the screening visit, while only 4 of 30 nonsmokers screened positive during the same time period. Only 6 of 19 experimental inoculation studies in active smokers resulted in
clearance within the month of follow-up, while in the cessation group, 6 of 9 subjects cleared nasal
and carriage duration averaged 21 ± 4 days. Smoking cessation associated with enhanced expression of
-associated interleukin-1β (IL-1β) and granulocyte colony-stimulating factor (G-CSF) in nasal fluids. Participants who failed to clear
exhibited a higher nasal
load and elevated nasal interleukin-1 receptor antagonist (IL-1RA) expression at the preexperiment study visits. We conclude that smokers exhibit higher
loads than nonsmokers and that innate immune pathways, including G-CSF expression and signaling through the IL-1 axis, are important mediators of nasal
clearance.
We report the case of a man with severe Guillain‐Barré syndrome who developed a persistent tracheocutaneous fistula (TCF) following prolonged tracheostomy and mechanical ventilation. Following ...tracheostomy decannulation, the TCF had a deleterious effect on non‐invasive positive pressure ventilation efficacy and ability to effectively clear airway secretions due to air leaking from the patent stoma. This case highlights a non‐surgical approach to TCF management that is not well‐described in the literature and presents an alternative management option for cohorts of patients in which the risk associated with surgical interventions may be undesirable.
Most published management strategies of tracheocutaneous fistulas typically focus on surgical approaches. However, in certain scenarios such as patients with respiratory insufficiency or chronic respiratory failure, surgical management poses an unacceptable perioperative risk. This case highlights a non‐surgical approach to TCF management that is not well‐described in the literature and presents an alternative management option for cohorts of patients in which the risk associated with surgical interventions may be undesirable.
While extensive research efforts have decreased human immunodeficiency virus (HIV) transmissions and mortalities, new challenges have arisen in the fight to eradicate HIV. Drug resistance to ...antiretroviral therapy threatens infected individuals, while the prevalence of heterosexual transmission creates an urgent need for therapies effective in the female reproductive tract (FRT) mucosa. We screened a library of 2095 small molecule compounds comprising a unique chemical space, purchased from Asinex Corporation, for antiviral activity against human immunodeficiency virus type 1 (HIV-1) strain BaL and identified several molecular representatives of a unique class of HIV-1 inhibitors, which we termed "Avirulins." We determined that Avirulins were active against clinical isolates of HIV-1 from genetically variant subtypes, several of which have reduced sensitivity to other antivirals. Avirulins displayed specific dose-dependent inhibition of the HIV-1 drug target, reverse transcriptase (RT). Avirulins were effective against several nucleoside RT-inhibitor resistant strains of HIV-1, as well as one nonnucleoside RT-inhibitor resistant strain containing a 106A mutation, suggesting a noncompetitive mechanism of action. Drugs, which are damaging to the FRT, can increase the risk of HIV-1 transmission. We therefore explored the cytotoxicity of Avirulins against epithelial cells derived from the FRT and found no significant toxicity, even at the highest concentrations tested. Importantly, Avirulin antiviral activity was not diminished in human cervico-vaginal fluid, suggesting retained potency in the milieu of the FRT. Based on these promising results, Avirulins should be valuable chemical scaffolds for development into next-generation treatments and preventatives that target HIV-1.
nasal carriage is a common condition affecting both healthy and immunocompromised populations and provides a reservoir for dissemination of potentially infectious strains by casual contact. The ...factors regulating the onset and duration of nasal
colonization are mostly unknown, and a human-relevant animal model is needed. Here, we screened 17 pig-tailed macaques (
) for
carriage, and 14 of 17 animals tested positive in the nose at one or both screening sessions (8 weeks apart), while the other 3 animals were negative in the nose but positive in the pharynx at least once. As in humans,
colonization was densest in the nose, and treatment of the nostrils with mupirocin ointment effectively cleared the nostrils and 6 extranasal body sites. Experimental nasal
colonization was established with 10
CFU/nostril, and both autologous and nonautologous strains survived over 40 days without any apparent adverse effects. A human nasal
isolate (strain D579, sequence type 398) was carried in 4 of 6 animals for over 3 weeks. Nostrils that did eradicate experimentally applied
exhibited neutrophilic innate immunity marked by elevated nasal interleukin-1β (IL-1β), IL-8, and monocyte chemotactic protein 1 levels and a 10-fold decreased IL-1 receptor antagonist/IL-1β ratio within 7 days postinoculation, analogous to the human condition. Taken together, pig-tailed macaques represent a physiological model of human
nasal carriage that may be utilized for testing natural colonization and decolonization mechanisms as well as novel classes of anti-
therapeutics.
A bribe-giving function was tested for Malaysia using data on 449 convicted bribe givers. Both the size of bribes and the probability of paying a large bribe were found to be positively and ...significantly associated with the size of fines and length of imprisonment
through bribery. Both the size of bribes and the probability of paying a large bribe increased with fines for bribery, however, but decreased with length of imprisonment. Our findings suggest that a reduction in human involvement in apprehending bribe givers, stricter enforcement, higher conviction rates, and more severe punishments could discourage bribes.
Multiple medical records may exist for a particular individual based on the various health services he or she receives. Maintaining updated, accurate records remains the responsibility of both ...practitioners and patients. Medication reconciliation, defined as the process to accurately depict the patient’s current orders and medications, 2 seeks to avoid errors in duplicity, interactions and dosing errors. Medication histories at Moses Cone Hospital are currently recorded by pharmacy technicians who follow specific standards, for instance they cannot remove “house meds”, which are prescribed medications with an active prescription attached. Technicians instead mark these medications for removal, leaving reconciliation to the physician. The physicians in the emergency department are not required to complete a full reconciliation for patient's profiles as this is a task left for the admitting physician. This leads to the question whether the reconciliation process in the emergency department (ED) needs to be re-evaluated. Patients’ “After Visit Summary” reports were used to analyze patient profiles in determining medication reconciliation statuses (whether fully reconciled, partially reconciled, or unreconciled). 280 patients’ profiles were used. 243 records (86.79%) were found unreconciled, 18 (6.43%) were partially reconciled, and 19 (6.79%) were fully reconciled.
Conflict of Interest
We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties
Type: Student Project
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