Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase.

Reverse transcriptase (RT) is one of three key proteins responsible for the replication cycle of HIV-1 in the host. Several classes of inhibitors have been developed to target the enzyme, with non-nucleoside reverse transcriptase inhibitors forming first-line treatment. Previously, covalent RT inhibitors have been identified and found to bind irreversibly to commonly mutated residues such as Y181C. In this work we aim to circumvent the issue of NNRTI resistance through targeting K102, which has not yet been identified to confer drug resistance. As reported here, 34 compounds were synthesized and characterized biochemically and structurally with wild-type (WT) HIV-1 RT. Two of these inhibitors demonstrate covalent inhibition as evidenced by protein crystallography, enzyme kinetics, mass spectrometry, and antiviral potency in HIV-1 infected human T-cell assays.

Design, synthesis, and biological testing of biphenylmethyloxazole inhibitors targeting HIV-1 reverse transcriptase.

We report non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) using a biphenylmethyloxazole pharmacophore. A crystal structure of benzyloxazole 1 was obtained and suggested the potential viability of biphenyl analogues. In particular, 6a, 6b, and 7 turned out to be potent NNRTIs with low-nanomolar activity in enzyme inhibition and infected T-cell assays, and with low cytotoxicity. Though modeling further suggested that analogues with fluorosulfate and epoxide warheads might provide covalent modification of Tyr188, synthesis and testing did not find evidence for this outcome.

Building a synthesis of economic costs of biological invasions in New Zealand.

Biological invasions are a major component of anthropogenic environmental change, incurring substantial economic costs across all sectors of society and ecosystems. There have been recent syntheses of costs for a number of countries using the newly compiled InvaCost database, but New Zealand-a country renowned for its approach to invasive species management-has so far not been examined. Here we analyse reported economic damage and management costs incurred by biological invasions in New Zealand from 1968 to 2020. In total, US$69 billion (NZ$97 billion) is currently reported over this ∼50-year period, with approximately US$9 billion of this considered highly reliable, observed (c.f. projected) costs. Most (82%) of these observed economic costs are associated with damage, with comparatively little invested in management (18%). Reported costs are increasing over time, with damage averaging US$120 million per year and exceeding management expenditure in all decades. Where specified, most reported costs are from terrestrial plants and animals, with damages principally borne by primary industries such as agriculture and forestry. Management costs are more often associated with interventions by authorities and stakeholders. Relative to other countries present in the InvaCost database, New Zealand was found to spend considerably more than expected from its Gross Domestic Product on pre- and post-invasion management costs. However, some known ecologically (c.f. economically) impactful invasive species are notably absent from estimated damage costs, and management costs are not reported for a number of game animals and agricultural pathogens. Given these gaps for known and potentially damaging invaders, we urge improved cost reporting at the national scale, including improving public accessibility through increased access and digitisation of records, particularly in overlooked socioeconomic sectors and habitats. This also further highlights the importance of investment in management to curtail future damages across all sectors.

The global contribution of invasive vertebrate eradication as a key island restoration tool.

Islands are global hotspots for biodiversity and extinction, representing ~ 5% of Earth's land area alongside 40% of globally threatened vertebrates and 61% of global extinctions since the 1500s. Invasive species are the primary driver of native biodiversity loss on islands, though eradication of invasive species from islands has been effective at halting or reversing these trends. A global compendium of this conservation tool is essential for scaling best-practices and enabling innovations to maximize biodiversity outcomes. Here, we synthesize over 100 years of invasive vertebrate eradications from islands, comprising 1550 eradication attempts on 998 islands, with an 88% success rate. We show a significant growth in eradication activity since the 1980s, primarily driven by rodent eradications. The annual number of eradications on islands peaked in the mid-2000s, but the annual area treated continues to rise dramatically. This trend reflects increases in removal efficacy and project complexity, generating increased conservation gains. Our synthesis demonstrates the collective contribution of national interventions towards global biodiversity outcomes. Further investment in invasive vertebrate eradications from islands will expand biodiversity conservation while strengthening biodiversity resilience to climate change and creating co-benefits for human societies.

Acute effects of radiation treatment to submental muscles on burrowing and swallowing behaviors in a rat model.

Swallowing impairments are a major complication of radiation treatment for oropharyngeal cancers, influencing oral intake and quality of life. The timing and functional consequences of radiation treatment on the swallowing process is not clearly understood. A rodent radiation injury model was used to investigate the onset of oral and pharyngeal dysfunctions in deglutition related to radiation treatment. This study tested the hypothesis that (Wall et al., 2013) alterations in normal biting, licking, and swallowing performance would be measurable following 64Gy of fractionated radiation to the submental muscles; and (Kotz et al., 2004) radiation will affect the animal's general well-being as measured via burrowing activity. Seven rats received radiation using a clinical linear accelerator given in 8 fractions of 8Gy and another seven animals received sham anesthesia only treatment. Swallowing bolus transit/size was assessed via videofluoroscopy, tongue movement during drinking was measured via an electrical lick sensor, and biting was analyzed from acoustic recordings of a vermicelli pasta test. Burrowing activity was measured by the amount of gravel substrate displaced within a container. Measurements were taken at baseline, during treatment (1-4 weeks), and after completion of treatment (weeks 5 & 6). Decreases in licking frequency and increases in inter-lick interval were observed 5- and 6-weeks post-treatment. Significant decreases in burrowing performance, swallowing frequency, and inter-swallow interval were observed starting the last week of treatment and continuing up to 2-weeks after completion. Results suggest that tongue dysfunction is one of the first treatment related feeding problems to present immediately after the completion of radiation to the submental muscles.

Swallowing dysfunction following radiation to the rat mylohyoid muscle is associated with sensory neuron injury.

Radiation-based treatments for oropharyngeal and hypopharyngeal cancers result in impairments in swallowing mobility, but the mechanisms behind the dysfunction are not clear. The purpose of this study was to determine if we could establish an animal model of radiation-induced dysphagia in which mechanisms could be examined. We hypothesized that 1) radiation focused at the depth of the mylohyoid muscle would alter normal bolus transport and bolus size and 2) radiation to the mylohyoid muscle will induce an injury/stress-like response in trigeminal sensory neurons whose input might modulate swallow. Rats were exposed to 48 or 64 Gy of radiation to the mylohyoid given 8 Gy in 6 or 8 fractions. Swallowing function was evaluated by videofluoroscopy 2 and 4 wk following treatment. Neuronal injury/stress was analyzed in trigeminal ganglion by assessing activating transcription factor (ATF)3 and GAP-43 mRNAs at 2, 4, and 8 wk post treatment. Irradiated rats exhibited decreases in bolus movement through the pharynx and alterations in bolus clearance. In addition, ATF3 and GAP-43 mRNAs were upregulated in trigeminal ganglion in irradiated rats, suggesting that radiation to mylohyoid muscle induced an injury/stress response in neurons with cell bodies that are remote from the irradiated tissue. These results suggest that radiation-induced dysphagia can be assessed in the rat and radiation induces injury/stress-like responses in sensory neurons.NEW & NOTEWORTHY Radiation-based treatments for head and neck cancer can cause significant impairments in swallowing mobility. This study provides new evidence supporting the possibility of a neural contribution to the mechanisms of swallowing dysfunction in postradiation dysphagia. Our data demonstrated that radiation to the mylohyoid muscle, which induces functional deficits in swallowing, also provokes an injury/stress-like response in the ganglion, innervating the irradiated muscle.

Covalent Inhibition of Wild-Type HIV-1 Reverse Transcriptase Using a Fluorosulfate Warhead.

Covalent inhibitors of wild-type HIV-1 reverse transcriptase (CRTIs) are reported. Three compounds derived from catechol diether non-nucleoside inhibitors (NNRTIs) with addition of a fluorosulfate warhead are demonstrated to covalently modify Tyr181 of HIV-RT. X-ray crystal structures for complexes of the CRTIs with the enzyme are provided, which fully demonstrate the covalent attachment, and confirmation is provided by appropriate mass shifts in ESI-TOF mass spectra. The three CRTIs and six noncovalent analogues are found to be potent inhibitors with both IC50 values for in vitro inhibition of WT RT and EC50 values for cytopathic protection of HIV-1-infected human T-cells in the 5-320 nM range.

The clock is ticking: Temporally prioritizing eradications on islands.

Achieving conservation objectives is time critical, but the vast number of threats and potential actions means some form of ranking is necessary to aid prioritization. Objective methods for ranking conservation actions based on when they are differentially likely to become feasible, or to succeed, are currently unavailable within existing decision-making frameworks but are critical for making informed management decisions. We demonstrate how statistical tools developed for survival (or time-to-event) analysis can be used to rank conservation actions over time, through the lens of invasive mammal eradications on islands. Here we forecast the probability of eradicating commensal rat species (Rattus rattus, R. norvegicus, R. exulans) from the New Zealand archipelago by the government's stated target of year 2050. Our methods provide temporally ranked eradication trajectories for the entire country, thus facilitating meeting nationwide policy goals. This demonstration highlights the relevance and applicability of such an approach and its utility for prioritizing globally effective conservation actions.

Rapid and temporary improvement of depression and anxiety observed following niraparib administration: a case report.

BACKGROUND: Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. CASE PRESENTATION: A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. CONCLUSIONS: This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.

Bedside diagnostics in dermatology: Viral, bacterial, and fungal infections.

Viral, bacterial, and fungal infections are frequently encountered in clinical practice, resulting in numerous cutaneous manifestations. Although diagnosis of these infections has changed over time because of technological advancements, such as polymerase chain reaction, bedside diagnostic techniques still play an important role in diagnosis and management, enabling rapid and low-cost diagnosis and implementation of appropriate therapies. This 2-part article will review both common and infrequent uses of bedside diagnostic techniques that dermatologists can incorporate into daily practice. This article examines the utility of bedside tests for the diagnosis of viral, bacterial, and fungal infections. The second article in this series reviews the use of bedside diagnostics for parasitic and noninfectious disorders.

Creation of an Internal Teledermatology Store-and-Forward System in an Existing Electronic Health Record: A Pilot Study in a Safety-Net Public Health and Hospital System.

Importance: External store-and-forward (SAF) teledermatology systems operate separately from the primary health record and have many limitations, including care fragmentation, inadequate communication among clinicians, and privacy and security concerns, among others. Development of internal SAF workflows within existing electronic health records (EHRs) should be the standard for large health care organizations for delivering high-quality dermatologic care, improving access, and capturing other telemedicine benchmark data. Epic EHR software (Epic Systems Corporation) is currently one of the most widely used EHR system in the United States, and development of a successful SAF workflow within it is needed. Objectives: To develop an SAF teledermatology workflow within the Epic system, the existing EHR system of Parkland Health and Hospital System (Dallas, Texas), assess its effectiveness in improving access to care, and validate its reliability; and to evaluate the system's ability to capture meaningful outcomes. Design, Setting, and Participants: Electronic consults were independently evaluated by 2 board-certified dermatologists, who provided diagnoses and treatment plans to primary care physicians (PCPs). Results were compared with in-person referrals from May to December 2013 from the same clinic (a community outpatient clinic in a safety-net public hospital system). Patients were those 18 years or older with dermatologic complaints who would have otherwise been referred to dermatology clinic. Main Outcomes and Measures: Median time to evaluation; percentage of patients evaluated by a dermatologist through either teledermatology or in-person compared with the previous year. Results: Seventy-nine teledermatology consults were placed by 6 PCPs from an outpatient clinic between May and December 2014; 57 (74%) were female and their mean (SD) age was 47.0 (12.4) years. Teledermatology reduced median time to evaluation from 70.0 days (interquartile range [IQR], 33.25-83.0 days) to 0.5 days (IQR, 0.172-0.94 days) and median time to treatment from 73.5 to 3.0 days compared with in-person dermatology visits. Overall, a greater percentage of patients (120 of 144 [83.3%]) were evaluated by a dermatologist through either teledermatology or in-person during the 2014 study period compared with the previous year (111 of 173 [64.2%]). Primary care physicians followed management recommendations 93% of the time. Conclusions and Relevance: Epic-based SAF teledermatology can improve access to dermatologic care in a public safety-net hospital setting. We hope that the system will serve as a model for other health care organizations wanting to create SAF teledermatology workflows within the Epic EHR system.