Cysteine S-acetylation is a post-translational modification involved in metabolic regulation.

Cysteine is a reactive amino acid central to the catalytic activities of many enzymes. It is also a common target of post-translational modifications (PTMs), such as palmitoylation. This longchain acyl PTM can modify cysteine residues and induce changes in protein subcellular localization. We hypothesized that cysteine could also be modified by short-chain acyl groups, such as cysteine S-acetylation. To test this, we developed sample preparation and non-targeted mass spectrometry protocols to analyze the mouse liver proteome for cysteine acetylation. Our findings revealed hundreds of sites of cysteine acetylation across multiple tissue types, revealing a previously uncharacterized cysteine acetylome. Cysteine acetylation shows a marked cytoplasmic subcellular localization signature, with tissue-specific acetylome patterns and specific changes upon metabolic stress. This study uncovers a novel aspect of cysteine biochemistry, highlighting short-chain modifications alongside known long-chain acyl PTMs. These findings enrich our understanding of the landscape of acyl modifications and suggest new research directions in enzyme activity regulation and cellular signaling in metabolism.

Impact of COVID-19 & Response Measures on HIV-HCV Prevention Services and Social Determinants in People Who Inject Drugs in 13 Sites with Recent HIV Outbreaks in Europe, North America and Israel.

HIV/HCV prevention among people who inject drugs (PWID) is of key public health importance. We aimed to assess the impact of COVID-19 and associated response measures on HIV/HCV prevention services and socio-economic status of PWID in high-HIV-risk sites. Sites with recent (2011-2019) HIV outbreaks among PWID in Europe North America and Israel, that had been previously identified, were contacted early May 2020. Out of 17 sites invited to participate, 13 accepted. Semi-structured qualitative site reports were prepared covering data from March to May 2020, analyzed/coded and confirmed with a structured questionnaire, in which all sites explicitly responded to all 103 issues reported in the qualitative reports. Opioid maintenance treatment, needle/syringe programs and antiretroviral treatment /hepatitis C treatment continued, but with important reductions and operational changes. Increases in overdoses, widespread difficulties with food and hygiene needs, disruptions in drug supply, and increased homelessness were reported. Service programs rapidly reformed long established, and politically entrenched, restrictive service delivery policies. Future epidemic control measures should include mitigation of negative side-effects on service provision and socio-economic determinants in PWID.

RESUMEN: La prevención del VIH/VHC entre las personas que se inyectan drogas (PWID) es de vital importancia para la salud pública. Nuestro objetivo fue evaluar el impacto de COVID-19 y las medidas de respuesta asociadas en los servicios de prevención del VIH/VHC y el estado socioeconómico de las PWID en sitios de alto riesgo de VIH. Se contactó con sitios con brotes recientes (2011­2019) de VIH entre PWID en Europa, América del Norte e Israel, que habían sido previamente identificados, a principios de mayo de 2020. De los 17 sitios invitados a participar, 13 aceptaron. Se prepararon informes cualitativos semiestructurados del sitio que cubrían los datos de marzo a mayo de 2020, analizados/codificados y confirmados con un cuestionario estructurado, en el que todos los sitios respondieron explícitamente a los 103 asuntos reportados en los informes cualitativos. El tratamiento de mantenimiento con opiáceos, los programas de agujas/jeringas y el tratamiento antirretroviral/tratamiento de la hepatitis C continuaron, pero con importantes reducciones y cambios operativos. Se reportaron aumentos en las sobredosis, dificultades generalizadas con las necesidades alimentarias y de higiene, interrupciones en el suministro de medicamentos y aumento de personas sin hogar. Los programas de servicios reformaron rápidamente las políticas restrictivas de prestación de servicios, establecidas desde hace mucho tiempo y políticamente arraigadas. Las futuras medidas de control de epidemias deben incluir la mitigación de los efectos secundarios negativos en la prestación de servicios y los determinantes socioeconómicos en las PWID.

Decreasing surface albedo signifies a growing importance of clouds for Greenland Ice Sheet meltwater production.

Clouds regulate the Greenland Ice Sheet's surface energy balance through the competing effects of shortwave radiation shading and longwave radiation trapping. However, the relative importance of these effects within Greenland's narrow ablation zone, where nearly all meltwater runoff is produced, remains poorly quantified. Here we use machine learning to merge MODIS, CloudSat, and CALIPSO satellite observations to produce a high-resolution cloud radiative effect product. For the period 2003-2020, we find that a 1% change in cloudiness has little effect (±0.16 W m-2) on summer net radiative fluxes in the ablation zone because the warming and cooling effects of clouds compensate. However, by 2100 (SSP5-8.5 scenario), radiative fluxes in the ablation zone will become more than twice as sensitive (±0.39 W m-2) to changes in cloudiness due to reduced surface albedo. Accurate representation of clouds will therefore become increasingly important for forecasting the Greenland Ice Sheet's contribution to global sea-level rise.

Boldness moderates cognitive performance under acute threat: Evidence from a task-switching paradigm involving cueing for shock.

Understanding factors that influence behavioral performance in high-pressure contexts is relevant to critical occupations such as first responders, military personnel, and frontline medical workers. A recent study by Yancey et al. (2019) demonstrated an association between boldness, a biobehavioral trait reflecting social dominance and fearlessness, and enhanced task-switching performance during threat of shock relative to a no-shock (safe) condition. This study used a sustained threat manipulation in which cues signaling possible shock were present throughout blocks of multiple task trials. Here, we extended this work by evaluating the relationship between boldness and task-switching performance under acute threat of shock conditions, in which cues signaling possible shock occurred during individual task trials, intermingled with safe trials. Participants (N = 79) completed a task-switching procedure involving acute threat of shock in which unwarned noise probes were presented to elicit blink-startle responses. Boldness was associated with better switching performance under threat versus safe conditions, with high-bold participants who exhibited low startle potentiation during threat showing the best performance. These findings provide additional evidence that dispositional boldness is a meaningful individual difference characteristic related to effective performance in high-pressure situations and have implications for personnel selection and assignment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Assessing the Association Between Pre-operative Feeding and the Development of Oral Feeding Skills in Infants with Single Ventricle Heart Disease: An Analysis of the NPC-QIC Dataset.

Pre-operative feeding may improve long-term feeding outcomes in single ventricle patients, including weaning from supplemental tube feedings in infancy. This study examines the association between pre-operative enteral feeding and subsequent long-term feeding outcomes while also assessing the counterbalancing risk of necrotizing enterocolitis (NEC). Secondary analysis of the National Pediatric Cardiology Quality Improvement Collaborative database was performed. The association between pre-operative feeding practice and achieving all oral feeds through the first year of life was examined using a multivariable regression model. Similarly, the association between pre-operative oral feeding and NEC was also assessed. Of 944 patients with 1-year feeding outcomes available, 58% were fed preoperatively (41.3% exclusively oral) and 12.3% were not fed per institutional approach. At hospital discharge after Stage 1 palliation, 57% required a feeding tube, while 39% required a feeding tube at their first birthday. In infants who were orally fed, the odds ratio to achieving tube-free feeding at 1 year was not significantly increased (1.3, confidence interval 0.8-2.0). Of 1740 infants with pre-operative feeding and Stage 1 there was no statistically significant difference in NEC among patients who were preoperatively fed versus those that were not fed per institutional approach (p = 0.2). Pre-operative feeding of infants with single ventricle heart disease was not associated with early achievement of tube-free feeding in the first year of life. However, pre-operative oral feeding was also not associated with increased risk of NEC, suggesting that it can be safely offered among appropriate patients.

Predicting Antarctic Net Snow Accumulation at the Kilometer Scale and Its Impact on Observed Height Changes.

Sub-grid-scale processes occurring at or near the surface of an ice sheet have a potentially large impact on local and integrated net accumulation of snow via redistribution and sublimation. Given observational complexity, they are either ignored or parameterized over large-length scales. Here, we train random forest (RF) models to predict variability in net accumulation over the Antarctic Ice Sheet using atmospheric variables and topographic characteristics as predictors at 1 km resolution. Observations of net snow accumulation from both in situ and airborne radar data provide the input observable targets needed to train the RF models. We find that local net accumulation deviates by as much as 172% of the atmospheric model mean. The correlation in space between the predicted net accumulation variability and satellite-derived surface-height change indicates that surface processes operate differently through time, driven largely by the seasonal anomalies in snow accumulation.

The Role of PERK in Understanding Development of Neurodegenerative Diseases.

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein's role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.

Discovering the landscape of protein modifications.

Protein modifications modulate nearly every aspect of cell biology in organisms, ranging from Archaea to Eukaryotes. The earliest evidence of covalent protein modifications was found in the early 20th century by studying the amino acid composition of proteins by chemical hydrolysis. These discoveries challenged what defined a canonical amino acid. The advent and rapid adoption of mass-spectrometry-based proteomics in the latter part of the 20th century enabled a veritable explosion in the number of known protein modifications, with more than 500 discrete modifications counted today. Now, new computational tools in data science, machine learning, and artificial intelligence are poised to allow researchers to make significant progress in discovering new protein modifications and determining their function. In this review, we take an opportunity to revisit the historical discovery of key post-translational modifications, quantify the current landscape of covalent protein adducts, and assess the role that new computational tools will play in the future of this field.

Response of tertiary addictions services to opioid dependence during the COVID-19 pandemic.

The emergence of the COVID-19 pandemic has presented the addiction services with an unprecedented set of challenges. Opioid users are particularly vulnerable because of their high level of pre-existing health problems and lifestyle factors. In order to minimise their risks to self and to others in the current Covid-19 crisis, addiction services sought to urgently identify vulnerable individuals, and induct them into opioid substitution treatment (OST) promptly. Additionally, several guidelines were created and regularly updated by the health and safety executive (HSE) for any healthcare staff working with opioid users. These include guidance documents, to facilitate prompt induction of patients onto the OST programme, the prescribing of naloxone to all patients at risk of overdose, eConsultation, medication management for those in self-isolation, and the delivery of injecting equipment. The guidance documents and resources will provide a template for a new way of working for the sector during these challenging times and into the future.

Evaluation of the cognitive benefits of intrathecal baclofen pump implantation in people with intractable multiple sclerosis related spasticity.

BACKGROUND: Spasticity is a common problematic symptom in Multiple Sclerosis with over one third of patients failing first line therapies. Intrathecal baclofen is a safe and efficacious option for treatment resistant spasticity. Anecdotally patients report improved concentration/cognitive performance when switching to intrathecal baclofen (ITB) from systemic medications. AIM: To explore whether subjects who proceed with ITB pump implantation for spasticity management and reduce oral anti-spasticity agents will have improved cognitive function. METHODS: Subjects were admitted for trial of ITB via lumbar puncture and subsequent pump implantation. Spasticity and cognitive measures before ITB trial and 3 months post implant were recorded. Paired t-test or Wilcoxon Signed Ranks test was used for within subject change and effect sizes (Cohen's dz) were calculated. Subgroup analysis of those on ≥2, or ≤ 1 spasticity medications at baseline was performed. RESULTS: 27 subjects with MS completed per protocol. Mean age 46 years [26 - 56], disease duration 15 years [6 - 26], RRMS = 3, SPMS = 17 and PPMS=7. The majority were on multiple spasticity medications. Spasticity scores significantly improved post pump implant. Mean ITB dose at 3 months was 143 mcg / day and 19 discontinued all other treatments for spasticity. There was no deterioration on any cognitive or mood measure. An improvement of moderate effect size was found in Backwards Digit Span (d=0.41, p=0.059) and HADS - anxiety (d=0.37, p=0.097). Fatigue Severity Scale score decreased substantially (d=0.81, p=0.005). Small improvements in Symbol Digit Modalities Test score (d=0.24) and Sustained Attention to Response Task response time (d=0.23) were non-significant. Performance on other measures did not change. Effect sizes were larger in subgroup on ≥2 oral spasticity medications at baseline, compared to the group on ≤1 medication (SDMT, d=0.42 vs d=0.07; Backwards digit span 0.45 vs 0.28; HADS-anxiety 0.39 vs 0.32; HADS-depression d=0.32 vs 0.05 and FSS, d= 1.14 vs 0.42). CONCLUSIONS: In a pilot study exploring the impact of ITB on cognition, spasticity scores improved universally and beneficial effects on some measures of fatigue, anxiety, auditory attention and verbal working memory were found. Improvement of speed of processing in those withdrawing higher doses of oral medication was also demonstrated suggesting that switching to ITB has added cognitive and psychological benefits for people with MS.

Evaluation of the impact of intrathecal baclofen on the walking ability of people with Multiple Sclerosis related spasticity.

BACKGROUND: Spasticity is a frequent and disabling symptom in people with Multiple Sclerosis (MS). Intrathecal baclofen (ITB) is an effective but infrequently used treatment in ambulant people. OBJECTIVE: To evaluate the impact of ITB on ambulation in people with moderate to severe MS related spasticity. METHODS: Data was collected prospectively regarding spasticity and ambulation at baseline, after ITB trial via lumbar puncture, 3 months and annually thereafter. RESULTS: 30 subjects; Mean age 47.9 (26-64), 67% female, mean EDSS 6.5 [6.5-7.5]. Reduction in mean Ashworth score (pre 1.44: post 0.98, p<0.001) and Penn spasm score (pre 3: post 1; p<0.001) was shown. 20 people (67%) proceeded with implantation; lower limb MRC power was predictive of proceeding to pump (OR 2.98; 95% CI 1.01 - 8.7; p <0.05). In those proceeding to implantation there was no difference in 10mTW at 1 year (ANOVA (F(3,24) = 2.6, p=0.13). Currently, 15 (75%) remain ambulatory (mean 3.75 years, range 1-9). After implant, 17 (85%) discontinued all oral anti-spasticity treatments conferring other benefits. CONCLUSION: Ambulation in people with MS can be preserved for several years whilst effectively treating spasticity with ITB with careful patient selection; ITB should not be considered a last resort.

Observations of Buried Lake Drainage on the Antarctic Ice Sheet.

Between 1992 and 2017, the Antarctic Ice Sheet (AIS) lost ice equivalent to 7.6 ± 3.9 mm of sea level rise. AIS mass loss is mitigated by ice shelves that provide a buttress by regulating ice flow from tributary glaciers. However, ice-shelf stability is threatened by meltwater ponding, which may initiate, or reactivate preexisting, fractures, currently poorly understood processes. Here, through ground penetrating radar (GPR) analysis over a buried lake in the grounding zone of an East Antarctic ice shelf, we present the first field observations of a lake drainage event in Antarctica via vertical fractures. Concurrent with the lake drainage event, we observe a decrease in surface elevation and an increase in Sentinel-1 backscatter. Finally, we suggest that fractures that are initiated or reactivated by lake drainage events in a grounding zone will propagate with ice flow onto the ice shelf itself, where they may have implications for its stability.

Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes.

Glutamylation, introduced by tubulin tyrosine ligase-like (TTLL) enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases post-translationally add glutamates to internal glutamates in tubulin carboxy-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize in initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this enzyme an elongase. We show that TTLL4 is exclusively an initiase and, through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines post-translationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules.

Author Correction: Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Studies of Thioamide Effects on Serine Protease Activity Enable Two-Site Stabilization of Cancer Imaging Peptides.

Thioamide substitutions in peptides can be used as fluorescence quenchers in protease sensors and as stabilizing modifications of hormone analogs. To guide these applications in the context of serine proteases, we here examine the cleavage of several model substrates, scanning a thioamide between the P3 and P3' positions, and identify perturbing positions for thioamide substitution. While all serine proteases tested were affected by P1 thioamidation, certain proteases were also significantly affected by other thioamide positions. We demonstrate how these findings can be applied by harnessing the combined P3/P1 effect of a single thioamide on kallikrein proteolysis to protect two key positions in a neuropeptide Y-based imaging probe, increasing its serum half-life to >24 h while maintaining potency for binding to Y1 receptor expressing cells. Such stabilized peptide probes could find application in imaging cell populations in animal models or even in clinical applications such as fluorescence-guided surgery.

Effect of integrating HIV and addiction care for non-engaging HIV-infected opiate-dependent patients.

BACKGROUND: HIV-positive substance dependent patients contribute disproportionally to HIV morbidity and mortality as a result of poor compliance with their HIV treatment. For HIV-positive opiate-dependent patients integrating HIV and addiction care improves HIV morbidity but the effect on addiction morbidity is not known. AIMS: This study aims to establish if integrating HIV and addiction care has a significant effect on addiction and HIV morbidity for non-engaging HIV-positive opiate-dependent patients. METHODS: Patients attending the National Drug Treatment Centre who had disengaged from their HIV treatment in St James's Hospital were recruited to receive HIV care integrated into their methadone maintenance programme. Outcome was investigated in terms of urine toxicology (opiates, cocaine, cannabis and amphetamines); adherence to methadone; proportion receiving directly observed antiretroviral therapy; proportion HIV virally suppressed; and the CD4 cell count. RESULTS: No significant change in substance use or methadone adherence was demonstrated in the 19 recruited participants. There was a significant increase in the proportion receiving directly observed antiretroviral therapy, and in the CD4 cell count. CONCLUSION: Integration of HIV and addiction care optimises the physical health of non-engaging HIV-positive opiate-dependent patients with no substantial effect on their methadone maintenance programme.

Health-related quality of life of HIV-infected intravenous drug users.

To investigate health-related quality of life in HIV-infected intravenous drug users registered but not engaged in HIV outpatient care (missing ≥2 outpatient appointments over 1 year or non-attendance for ≥6 months) we conducted a cross-sectional study to examine health-related quality of life of HIV-infected intravenous drug users registered for care at an inner city HIV unit. EQ-5D, SF-36, SF-6D, mood disorder, clinical and substance misuse data were collected. Mean scores and preference derived utility scores were calculated. Statistical relationships between health-related quality of life and other variables were explored using univariate and multivariate analysis. Fifty-five patients were recruited, 64% were males. The mean anxiety value was 11.44 (anxious) and mean depression score was 9.3 (borderline depressed). The mean EQ-5D utility was 0.45 (95% CI 0.35, 0.55) and mean SF-6D utility was 0.52 (95% CI 0.48, 0.55). There was no statistical relationship between HIV indices, substance misuse and EQ-5D and SF-6D utility. Anxiety and depression were significantly correlated with EQ-5D and SF-6D utility values on univariate and multivariate analysis. Health-related quality of life was reduced in this HIV-infected intravenous drug user population. Whilst hepatitis C co-infection and substance misuse did not affect health-related quality of life, anxiety and depression had a significant impact on it.

Use of the Alcohol Use Disorders Identification Test (AUDIT) to determine the prevalence of alcohol misuse among HIV-infected individuals.

The aim of the paper is to evaluate alcohol misuse among an inner city adult HIV clinic population with AUDIT (Alcohol Use Disorders Identification Test). A cross-sectional HIV outpatient clinic analysis between 28 February 2011 and 11 March 2011 was carried out. AUDIT, demographic and clinical data were collected. Univariate analysis was performed to look for the associations between variables. Backward stepwise multivariate analyses were performed on significant variables from the univariate analysis to assess for predictors of alcohol dependence. In total, 111 patients were included (60% uptake of clinic attendees); 66% were men and 26% were hepatitis C virus (HCV) co-infected. The median AUDIT score was 5 (within normal range). Thirty-four 'AUDIT positive' cases were identified: five (4.5%) indicated consumption of hazardous levels of alcohol; 21 (19%) indicated harmful levels of alcohol; and eight (7%) were likely alcohol dependent. Younger age (<40 years old) was significantly associated with AUDIT positivity (P = 0.006). On multivariate analysis younger age (P = 0.045, odds ratio 13.8) and lower level of education (P = 0.006, odds ratio 6.7) were predictive of scores indicative of alcohol dependence (AUDIT ≥20). In conclusion, younger age and lower educational levels were associated with scores consistent with alcohol dependence. AUDIT was well tolerated and easy to administer in this outpatient HIV clinic population.