Development of Bifunctional, Raman Active Diyne-Girder Stapled α-Helical Peptides.

Stapled peptides are a unique class of cyclic α-helical peptides that are conformationally constrained via their amino acid side-chains. They have been transformative to the field of chemical biology and peptide drug discovery through addressing many of the physicochemical limitations of linear peptides. However, there are several issues with current chemical strategies to produce stapled peptides. For example, two distinct unnatural amino acids are required to synthesize i, i+7 alkene stapled peptides, leading to high production costs. Furthermore, low purified yields are obtained due to cis/trans isomers produced during ring-closing metathesis macrocyclisation. Here we report the development of a new i, i+7 diyne-girder stapling strategy that addresses these issues. The asymmetric synthesis of nine unnatural Fmoc-protected alkyne-amino acids facilitated a systematic study to determine the optimal (S,S)-stereochemistry and 14-carbon diyne-girder bridge length. Diyne-girder stapled T-STAR peptide 29 was demonstrated to have excellent helicity, cell permeability and stability to protease degradation. Finally, we demonstrate that the diyne-girder constraint is a Raman chromophore with potential use in Raman cell microscopy. Development of this highly effective, bifunctional diyne-girder stapling strategy leads us to believe that it can be used to produce other stapled peptide probes and therapeutics.

Half-sandwich nickel(II) complexes bearing 1,3-di(cycloalkyl)imidazol-2-ylidene ligands.

Two new nickel catalysts have been prepared using a convenient procedure where nickelocene, the NHC·HBF4 salts, and [Et4N]Cl were heated in THF using microwave irradiation. The resulting [NiCl(Cp)(NHC)] complexes are air- and moisture stable in the solid state, and represent two new members of this valuable and practical class of nickel catalysts. The new species were fully characterised using methods including NMR spectroscopy and X-ray crystallography. When tested in model Suzuki-Miyaura cross-coupling reactions, these complexes were found to be active for the cross-coupling of aryl bromides and aryl chlorides.

Outbreak of SARS-CoV-2 B.1.617.2 (Delta Variant) in a Youth Camp Associated With Community Spread, Nebraska, June-July 2021.

OBJECTIVES: During June-July 2021, an outbreak of SARS-CoV-2 occurred among attendees of a summer youth camp in Nebraska. We assessed the factors that contributed to onward transmission of disease. METHODS: The Four Corners Health Department conducted an outbreak investigation and recorded both laboratory-confirmed and self-reported cases of SARS-CoV-2 and mitigation measures employed. We generated sequences on positive specimens, created an epidemic curve to assist with outbreak visualization, and examined epidemiologic, genomic, and laboratory outcomes. RESULTS: Evaluation of 3 index cases led to the identification of 25 people with COVID-19 who interacted directly with the camp. Contact tracing revealed an additional 18 cases consistent with onward community transmission. Most (24 of 35, 68.5%) vaccine-eligible community cases were not vaccinated. We sequenced 8 positive specimens; all were identified as the Delta variant. Precamp planning incorporated local health officials who recommended wearing face masks, practicing social distancing, and using attendee cohorts to limit mixing of people involved in various activities. CONCLUSION: Low vaccination levels and poor face mask-wearing habits among attendees resulted in secondary and tertiary spread of SARS-CoV-2 and severe outcomes among young adults. This outbreak of COVID-19 at a youth camp highlights the importance of vaccination and use of other measures to interrupt opportunities for SARS-CoV-2 spread in the community and shows that vaccinated people remain vulnerable to infection when in an environment of high exposure to SARS-CoV-2. Proactive case identification and interruption of chains of transmission can help decrease the number of cases and avoid further severe outcomes.

Aedes aegypti Identified in York, Nebraska, Through Routine Arboviral Surveillance-August-October 2019.

On August 27, 2019, Aedes aegypti mosquitoes were identified in a neighborhood located in York, NE, through routine arboviral surveillance. Expanded surveillance using traps and morphologic identification revealed 118 adult Ae. aegypti throughout the adjacent neighborhood, including identification from larval sampling. Our findings describe the first recorded Ae. aegypti introduction in Nebraska and provide evidence of a breeding mosquito population, which suggests suitable habitat and the risk of potential establishment, raising concerns about prevention of arboviral diseases in Nebraska.

COVID-19 screening of asymptomatic patients admitted through emergency departments in Alberta: a prospective quality-improvement study.

BACKGROUND: The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among asymptomatic patients admitted to hospital has implications for personal protective equipment use, testing strategy and confidence in the safety of acute care services. Our aim was to estimate the positivity rate of reverse transcription polymerase chain reaction (RT-PCR) testing among people admitted to hospital without symptoms of coronavirus disease 2019 (COVID-19) in Alberta, Canada. METHODS: Between Apr. 9 and May 24, 2020, we screened for COVID-19 symptoms and tested for SARS-CoV-2 infection in all consecutive adult patients (≥ 18 yr) admitted via emergency department to 3 Alberta hospitals. We summarized the parameters of the epidemic curve and assessed the performance of symptom screening versus RT-PCR results on nasopharyngeal or oropharyngeal swab samples. RESULTS: The study period encompassed Alberta's initial epidemic curve, with peak active cases per 100 000 of 71.4 (0.07%) on Apr. 30, 2020, and 14.7 and 14.6 at the beginning (Apr. 9, 2020) and end (May 24, 2020), respectively. Testing for SARS-CoV-2 infection (64.9% throat and 35.1% nasopharyngeal swabs) was done on 3375 adults (mean age 51, standard deviation 21, yr; 51.5% men). None of the asymptomatic patients (n = 1814) tested positive, and 71 of those with symptoms tested positive (n = 1561; 4.5%, 95% confidence interval [CI] 3.6%-5.7%). Sensitivity of symptom screening (v. RT-PCR) was 100% (95% CI 95%-100%), and specificity was 55% (95% CI 53%-57%). Posttest probabilities for prevalence of SARS-CoV-2 infection ranging from 1.5 to 14 times the peak prevalence of active cases during the study did not change when we assumed lower sensitivity (92%). INTERPRETATION: In a region with low disease prevalence where protocolized symptom assessment was in place during the admission process, we did not identify people admitted to hospital without COVID-19 symptoms who were RT-PCR positive. There may not be additive benefit to universal testing of asymptomatic patients on hospital admission in a setting of low pretest probability and strong public health containment.

The performance and observation of action shape future behaviour.

The observation of other people's actions plays an important role in shaping the perceptual, cognitive, and motor processes of the observer. It has been suggested that these social influences occur because the observation of action evokes a representation of that response in the observer and that these codes are subsequently accessed by other cognitive systems to modify future behaviour. In the case of social search and movement tasks, the observation-evoked response code is thought to activate the same mechanisms that are activated following internally-generated response codes. In support of this hypothesis, the present study revealed that the magnitudes of the between-person inhibition of return (IOR) effects were correlated with within-person IOR effects. These findings provide substantial support for the link between observation-evoked response codes and social cognitive effects.

Enzymatically-stable oxetane-based dipeptide hydrogels.

Low molecular weight gelators that are not easily degraded by enzymes have a range of potential applications. Here, we report new Fmoc-protected dipeptides in which the amide carbonyl group has been replaced by an oxetane ring. Remarkably one of these peptidomimetics, but not the corresponding dipeptide, is an effective gelator, forming hydrogels at a concentration of 3 mg mL-1. On assembly, there is a lack of beta-sheet structure, implying that there is no requirement for this motif in such a gel. Furthermore, the modified dipeptide is also stable to proteolysis compared to the parent dipeptide.

Abnormal surround inhibition does not affect asymptomatic limbs in people with cervical dystonia.

Surround inhibition is a neural mechanism hypothesized to facilitate goal-directed action by disinhibiting agonist muscle activity while simultaneously inhibiting antagonist and other uninvolved muscle activity. The present study was designed to investigate if abnormalities in surround inhibition are found in asymptomatic body parts (the hand) of people with focal cervical dystonia (neck). Participants with (n=7) and without (n=17) cervical dystonia completed a protocol in which they abducted their index finger while EMG was recorded from the first dorsal interosseous (agonist) and abductor digiti minimi (uninvolved) muscles. Transcranial magnetic stimulation was delivered over the primary motor cortex at intervals ranging from 0 to 950+ms after the onset of agonist muscle activity. Motor-evoked potential (MEP) amplitudes from both muscles were compared. In control participants, MEPs from the uninvolved muscle were significantly lower than agonist MEPs at intervals from 0 to 480ms. Similarly, in the hands of participants with cervical dystonia - the asymptomatic body part - MEPs from the uninvolved muscle were significantly lower than agonist MEPs from 0 to 175ms. These findings suggest that surround inhibition in people with focal dystonia may be intact in asymptomatic hands. In other words, abnormalities in surround inhibition may be restricted to the dystonic limb.

Pilot study to determine safety and short-term outcome of percutaneous cryoablation in the treatment of localized prostate cancer (stages T1C-T3C NO MO).

OBJECTIVE: To assess the effectiveness of cryoablation in localized prostate cancer in our hands. Early end points are biopsy at 5 months and PSA at 12 months follow-up. METHODS: Percutaneous transperineal cryoablation was performed on 30 patients. A urethral warming catheter was used. All cases were newly diagnosed with no prior radiotherapy, or neoadjuvant hormones. A single freeze cycle was used in the first 10 cases and two cycles in the next 20 cases. RESULTS: Twenty-nine of 30 cases are eligible for follow-up. Six of the first 10 patients had negative biopsies, the 4 positive patients have had repeat cryoablation and only 1 patient remains biopsy positive. In cases 11-30, there were two patients with positive biopsies ­ both retreated. At this time, 27/29 patients (93%) have a negative biopsy after one (23 patients) or two (6 patients) treatments. At 6 months, 20/29 patients (69%) have undetectable PSA; 25/29 have PSA less than 1 ng/ml. At 12 months, 17/23 cases have an undetectable PSA (74%). Complications were minimal; 3 cases (10%) suffered urethral sloughing requiring TURP. CONCLUSION: Early results are very encouraging, showing 93% negative biopsy rate after one (23 patients) or two (6 patients) treatments; PSA is undetectable in 74% (17/23 patients) at 1 year. Early results of cryoablation for prostate cancer are encouraging.

Knowledge of response location alone is not sufficient to generate social inhibition of return.

Previous research has revealed that the inhibition of return (IOR) effect emerges when individuals respond to a target at the same location as their own previous response or the previous response of a co-actor. The latter social IOR effect is thought to occur because the observation of co-actor's response evokes a representation of that action in the observer and that the observation-evoked response code subsequently activates the inhibitory mechanisms underlying IOR. The present study was conducted to determine if knowledge of the co-actor's response alone is sufficient to evoke social IOR. Pairs of participants completed responses to targets that appeared at different button locations. Button contact generated location-contingent auditory stimuli (high and low tones in Experiment 1 and colour words in Experiment 2). In the Full condition, the observer saw the response and heard the auditory stimuli. In the Auditory Only condition, the observer did not see the co-actor's response, but heard the auditory stimuli generated via button contact to indicate response endpoint. It was found that, although significant individual and social IOR effects emerged in the Full conditions, there were no social IOR effects in the Auditory Only conditions. These findings suggest that knowledge of the co-actor's response alone via auditory information is not sufficient to activate the inhibitory processes leading to IOR. The activation of the mechanisms that lead to social IOR seems to be dependent on processing channels that code the spatial characteristics of action.

The personification of animals: coding of human and nonhuman body parts based on posture and function.

The purpose of the present research was to determine how humans represent the bodies and limbs of nonhuman mammals based on anatomical and functional properties. To this end, participants completed a series of body-part compatibility tasks in which they responded with a thumb or foot response to the color of a stimulus (red or blue, respectively) presented on different limbs of several animals. Across the studies, this compatibility task was conducted with images of human and nonhuman animals (bears, cows, and monkeys) in bipedal or quadrupedal postures. The results revealed that the coding of the limbs of nonhuman animals is strongly influenced by the posture of the body, but not the functional capacity of the limb. Specifically, body-part compatibility effects were present for both human and nonhuman animals when the figures were in a bipedal posture, but were not present when the animals were in a quadrupedal stance (Experiments 1a-c). Experiments 2a and 2b revealed that the posture-based body-part compatibility effects were not simply a vertical spatial compatibility effect or due to a mismatch between the posture of the body in the image and the participant. These data indicate that nonhuman animals in a bipedal posture are coded with respect to the "human" body representation, whereas nonhuman animals in a quadrupedal posture are not mapped to the human body representation. Overall, these studies provide new insight into the processes through which humans understand, mimic, and learn from the actions of nonhuman animals.

Negative priming in a joint selection task.

Recent studies have suggested that the observation of another individual executing a movement activates representations of the observed movement in the observer. These representations are thought to be used by other systems to facilitate a variety of social cognitive processes, such as social searches. Previous research on social searches has primarily involved contexts where targets were presented in isolation. Typical environments, however, contain targets and non-targets and one must select the correct information for task completion. To gain insight into the processes underlying social searches, participants completed negative priming tasks alone and in pairs. Results indicated that there were no differences in the negative priming effects resulting from the participants observed or performed the preceding selection task. Further, the correlations between individual and joint negative priming suggest that similar processes were activated on these tasks. The findings support the co-representation hypothesis and provide insight into the processes underlying selection in individual and social settings.

Microbial quality of water in rural communities of Trinidad

A cross-sectional study was conducted in four rural communities of northeastern Trinidad to determine the microbial quality of water supply to households and that quality's relationship to source and storage device. Of the 167 household water samples tested, total coliforms were detected in 132 of the samples (79.0 por cent), fecal coliforms in 102 (61.1 por cent), and E. coli in 111 (66.5 por cent). There were significant differences among the towns in the proportion of the samples contaminated with coliforms (P 0.001) and E. coli (P 0.001). Of 253 strains of E. coli studied, 4 (1.6 por cent) were mucoid, 9 (3.6 por cent) were hemolytic, and 37 (14.6 por cent) were nonsorbitol fermenters. Of 69 isolates of E. coli tested, 10 (14.5 por cent) were verocytotoxigenic. Twenty-eight (14.0 por cent) of 200 E. coli isolates tested belonged to enteropathogenic serogroups. Standpipe, the most common water source, was utilized by 57 (34.1 por cent) of the 167 households. Treated water (pipeborne in homes, tandpipes, or truckborne) was supplied to 119 households (71.3 por cent), while 48 households (28.7 por cent) used water from untreated sources (rain, river/stream, or well) as their primary water supply. The type of household storage device was associated with coliform contamination. Water stored in drums, barrels, or buckets was more likely to harbor fecal coliforms (74.2 por cent of samples) htan was water stored in tanks (53.3 por cent of samples), even after controlling for water source (P = 0.04). Compared with water from other sources, water piped into homes was significantly less likely to be contaminated with total coliforms (56.9 por cent) versus 88.8 por cent, P0.001) and fecal coliforms (41.2 por cent versus 69.8 por cent, P0.01), even when the type of storage device was taken into account. However, fecal contamination was not associated with whether the water came from a treated or untreated source. We concluded that the drinking water in rural communities in Trinidad was grossly unfit for human consumption, due both to contamination of vaious water sources and during household water storage

Microbial quality of water in rural communities of Trinidad / Calidad microbiológica del agua en comunidades rurales de Trinidad

A cross-sectional study was conducted in four rural communities of northeastern Trinidad to determine the microbial quality of water supply to households and that quality's relationship to source and storage device. Of the 167 household water samples tested, total coliforms were detected in 132 of the samples (79.0 por cent), fecal coliforms in 102 (61.1 por cent), and E. coli in 111 (66.5 por cent). There were significant differences among the towns in the proportion of the samples contaminated with coliforms (P < 0.001) and E. coli (P < 0.001). Of 253 strains of E. coli studied, 4 (1.6 por cent) were mucoid, 9 (3.6 por cent) were hemolytic, and 37 (14.6 por cent) were nonsorbitol fermenters. Of 69 isolates of E. coli tested, 10 (14.5 por cent) were verocytotoxigenic. Twenty-eight (14.0 por cent) of 200 E. coli isolates tested belonged to enteropathogenic serogroups. Standpipe, the most common water source, was utilized by 57 (34.1 por cent) of the 167 households. Treated water (pipeborne in homes, tandpipes, or truckborne) was supplied to 119 households (71.3 por cent), while 48 households (28.7 por cent) used water from untreated sources (rain, river/stream, or well) as their primary water supply. The type of household storage device was associated with coliform contamination. Water stored in drums, barrels, or buckets was more likely to harbor fecal coliforms (74.2 por cent of samples) htan was water stored in tanks (53.3 por cent of samples), even after controlling for water source (P = 0.04). Compared with water from other sources, water piped into homes was significantly less likely to be contaminated with total coliforms (56.9 por cent) versus 88.8 por cent, P<0.001) and fecal coliforms (41.2 por cent versus 69.8 por cent, P<0.01), even when the type of storage device was taken into account. However, fecal contamination was not associated with whether the water came from a treated or untreated source. We concluded that the drinking water in rural communities in Trinidad was grossly unfit for human consumption, due both to contamination of vaious water sources and during household water storage

Se realizó un estudio transversal en cuatro comunidades rurales del nordeste de la isla de Trinidad para determinar la calidad microbiológica de los suministros domésticos de agua y la relación entre dicha calidad y el origen del agua y los recipientes utilizados para su almacenamiento. Entre las 167 muestras de agua doméstica analizadas, se detectaron coliformes totales en 132 (79,0%), coliformes fecales en 102 (61,1%) y Escherichia coli en 111 (66,5%). Hubo diferencias significativas entre los pueblos con respecto a la proporción de muestras contaminadas con coliformes (P < 0,001) y E. coli (P < 0,001). De las 253 cepas de E. coli estudiadas, 4 (1,6%) eran mucoides, 9 (3,6%) hemolíticas y 37 (14,6%) no fermentadoras de sorbitol. De 69 aislados de E. coli en los que se analizó esta característica, 10 (14,5%) fueron citotóxicos para las células Vero. Veintiocho de 200 (14,0%) aislados de E. coli analizados pertenecían a serogrupos enteropatógenos. El origen más frecuente del agua fueron las fuentes (57 de los 167 domicilios; 34,1%). Ciento diecinueve domicilios (71,3%) recibían agua tratada (agua canalizada hasta el domicilio, de fuente o de camión cisterna), mientras que los otros 48 (28,7%) utilizaban agua no tratada (de lluvia, ríos/arroyos o pozos) como principal suministro de agua. El tipo de recipiente de almacenamiento en el domicilio se asoció con la contaminación por coliformes. El agua almacenada en bidones, barriles o cubos tenía mayores probabilidades de albergar coliformes fecales (74,2% de las muestras) que el agua almacenada en tanques (53,3% de las muestras), incluso después de controlar el efecto del origen del agua (P = 0,04). En comparación con el agua de otras fuentes, el agua canalizada hasta las casas tenía una probabilidad significativamente menor de estar contaminada por coliformes totales (56,9% frente a 88,8%; P < 0,001) y coliformes fecales (41,2% frente a 69,8%, P < 0,01), incluso después de tener en cuenta el tipo de recipiente de almacenamiento. Sin embargo, la contaminación fecal no se asoció con el origen tratado o no tratado del agua. Concluimos que el agua para beber de las comunidades rurales de Trinidad era en general no apta para el consumo humano debido a su contaminación tanto en el origen como durante el almacenamiento en el domicilio