Expanded Naloxone Distribution by Opioid Overdose Prevention Programs to High-Need Populations and Neighborhoods in New York City.

From 2014 to 2017, the drug overdose death rate per 100,000 in New York City (NYC) increased by 81%, with 57% of overdoses in 2017 involving the opioid fentanyl. In response, overdose education and naloxone dispensing (OEND) efforts were expanded in NYC, informed by neighborhood-level and population-level opioid overdose fatality rates. We describe the demographic and geographical distribution of naloxone by NYC opioid overdose prevention programs (OOPPs; the primary distributor of naloxone to laypersons in NYC) as OEND was expanded in NYC.

"New Normal:" Opportunities and Challenges Faced by Syringe Service Programs Following the Effects of the COVID-19 Pandemic.

Syringe services programs (SSPs) provide critical evidence-based public health services that decrease harms from drug use for people who use drugs (PWUD). Many SSPs have experienced significant and evolving COVID-19-related disruptions. We aimed to characterize the impacts of COVID-19 on SSP operations in the United States approximately two years into the pandemic.

Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival.

Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation.

Nonvesicular lipid transfer drives myelin growth in the central nervous system.

Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive.

Improving racial/ethnic health equity and naloxone access among people at risk for opioid overdose: A simulation modeling analysis of community-based naloxone distribution strategies in Massachusetts, United States.

Background And Aims: During the COVID-19 pandemic, there was a surge in opioid overdose deaths (OODs) in Massachusetts, USA, particularly among Black and Hispanic/Latinx populations. Despite the increasing racial and ethnic disparities in OODs, there was no compensatory increase in naloxone distributed to these groups. We aimed to evaluate two community-based naloxone expansion strategies, with the objective of identifying approaches that could mitigate mortality and racial and ethnic disparities in OODs.

A ubiquitin-specific, proximity-based labeling approach for the identification of ubiquitin ligase substrates.

Over 600 E3 ligases in humans execute ubiquitination of specific target proteins in a spatiotemporal manner to elicit desired signaling effects. Here, we developed a ubiquitin-specific proximity-based labeling method to selectively biotinylate substrates of a given ubiquitin ligase. By fusing the biotin ligase BirA and an Avi-tag variant to the candidate E3 ligase and ubiquitin, respectively, we were able to specifically enrich bona fide substrates of a ligase using a one-step streptavidin pulldown under denaturing conditions.

NEXT: description, rationale, and evaluation of a novel internet-based mail-delivered syringe service program.

Background: Despite proven health benefits, harm reduction services provided through in-person syringe services programs (SSPs) and pharmacies are largely unavailable to most people who inject drugs (PWID). Internet-based mail-delivered harm reduction services could overcome barriers to in-person SSPs. This manuscript describes Needle Exchange Technology (NEXT) Harm Reduction, the first formal internet-based mail delivery SSP in the US.

Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH.

Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane.

Economic Evaluations of Establishing Opioid Overdose Prevention Centers in 12 North American Cities: A Systematic Review.

Objectives: Overdose prevention centers (OPCs) provide a safe place where people can consume preobtained drugs under supervision so that a life-saving medical response can be provided quickly in the event of an overdose. OPCs are programs that are established in Canada and have recently become legally sanctioned in only a few United States jurisdictions.

Methods: We conducted a systematic review that summarizes and identifies gaps of economic evidence on establishing OPCs in North America to guide future expansion of OPCs.

High Interest in Injectable Opioid Agonist Treatment With Hydromorphone Among Urban Syringe Service Program Participants.

Background: Injectable opioid agonist treatment with hydromorphone (iOAT-H) is effective for persons who inject drugs (PWID) with opioid use disorder (OUD) but remains unavailable in the United States. Our objective was to determine interest in iOAT-H among syringe services program (SSP) participants.

Methods: We recruited PWID with OUD from SSPs in New York City.

Atg8 family proteins, LIR/AIM motifs and other interaction modes.

The Atg8 family of ubiquitin-like proteins play pivotal roles in autophagy and other processes involving vesicle fusion and transport where the lysosome/vacuole is the end station. Nuclear roles of Atg8 proteins are also emerging. Here, we review the structural and functional features of Atg8 family proteins and their protein-protein interaction modes in model organisms such as yeast, and to humans.

NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.

NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges.

The COP9 signalosome reduces neuroinflammation and attenuates ischemic neuronal stress in organotypic brain slice culture model.

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a deNEDDylase controlling ubiquitination activity of cullin-RING-E3 ligases (CRLs) and thus the levels of key cellular proteins. While the CSN and its catalytic subunit CSN5 have been extensively studied in cancer, its role in inflammatory and neurological diseases is less understood. Following verification that CSN5 is expressed in mouse and human brain, here we studied the role of the CSN in neuroinflammation and ischemic neuronal damage employing models of relevant brain-resident cell types, an ex vivo organotypic brain slice culture model, and the CRL NEDDylation state-modifying drugs MLN4924 and CSN5i-3, which mimic and inhibit, respectively, CSN5 deNEDDylase activity.

Similar additive effects of doxorubicin in combination with photon or proton irradiation in soft tissue sarcoma models.

High-precision radiotherapy with proton beams is frequently used in the management of aggressive soft tissue sarcoma (STS) and is often combined with doxorubicin (Dox), the first-line chemotherapy for STS. However, current treatment approaches continue to result in high local recurrence rates often occurring within the treatment field. This strongly indicates the need of optimized treatment protocols taking the vast heterogeneity of STS into account, thereby fostering personalized treatment approaches.

Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy.

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms.

C9orf72 protein quality control by UBR5-mediated heterotypic ubiquitin chains.

Hexanucleotide repeat expansions within C9orf72 are a frequent cause of amyotrophic lateral sclerosis and frontotemporal dementia. Haploinsufficiency leading to reduced C9orf72 protein contributes to disease pathogenesis. C9orf72 binds SMCR8 to form a robust complex that regulates small GTPases, lysosomal integrity, and autophagy.

Comprehensive investigation of lateral dose profile and output factor measurements in small proton fields from different delivery techniques.

Background And Purpose: As a part of the commissioning and quality assurance in proton beam therapy, lateral dose profiles and output factors have to be acquired. Such measurements can be performed with point detectors and are especially challenging in small fields or steep lateral penumbra regions as the detector's volume effect may lead to perturbations. To address this issue, this work aims to quantify and correct for such perturbations of six point detectors in small proton fields created via three different delivery techniques.

Spatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2.

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2). While TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport, it remains elusive how exactly TECPR2 is involved in autophagy and secretion and what downstream sequels arise from defective TECPR2 due to its involvement in these processes. To address these questions, we determine molecular consequences of TECPR2 deficiency along the secretory pathway.

The effects of COVID-19 on New York State's Drug User Health Hubs and syringe service programs: a qualitative study.

Background: Syringe service programs (SSPs) deliver critical harm reduction services to people who inject drugs (PWID). Some SSPs in New York State received enhanced funding to provide additional services to combat opioid overdose fatalities. These SSPs, known as Drug User Health Hubs, provide buprenorphine for the treatment of opioid use disorder and other health-related services in addition to their syringe services.

Optimization of proton pencil beam positioning in collimated fields.

Background: The addition of static or dynamic collimator systems to the pencil beam scanning delivery technique increases the number of options for lateral field shaping. The collimator shape needs to be optimized together with the intensity modulation of spots.

Purpose: To minimize the proton field's lateral penumbra by investigating the fundamental relations between spot and collimating aperture edge position.

Validating a double Gaussian source model for small proton fields in a commercial Monte-Carlo dose calculation engine.

Purpose: The primary fluence of a proton pencil beam exiting the accelerator is enveloped by a region of secondaries, commonly called "spray". Although small in magnitude, this spray may affect dose distributions in pencil beam scanning mode e.g.