Constrained TACC3 peptidomimetics for a non-canonical protein-protein interface elucidate allosteric communication in Aurora-A kinase.

Peptidomimetic design for non-canonical interfaces is less well established than for α-helix and β-strand mediated protein-protein interactions. Using the TACC3/Aurora-A kinase interaction as a model, we developed a series of constrained TACC3 peptide variants with 10-fold increased binding potencies ( ) towards Aurora-A in comparison to the parent peptide. High-affinity is achieved in part by restricting the accessible conformational ensemble of the peptide leading to a more favourable entropy of binding.

Discovery of Trypanosoma brucei inhibitors enabled by a unified synthesis of diverse sulfonyl fluorides.

Sets of electrophilic probes are generally prepared using a narrow toolkit of robust reactions, which tends to limit both their structural and functional diversity. A unified synthesis of skeletally-diverse sulfonyl fluorides was developed that relied upon photoredox-catalysed dehydrogenative couplings between hetaryl sulfonyl fluorides and hydrogen donor building blocks. A set of 32 diverse probes was prepared, and then screened against Trypanosoma brucei.

Hepatocyte Growth Factor Delivery to Injured Cervical Spinal Cord Using an Engineered Biomaterial Protects Respiratory Neural Circuitry and Preserves Functional Diaphragm Innervation.

A major portion of spinal cord injury (SCI) cases occur in the cervical region, where essential components of the respiratory neural circuitry are located. Phrenic motor neurons (PhMNs) housed at cervical spinal cord level C3-C5 directly innervate the diaphragm, and SCI-induced damage to these cells severely impairs respiratory function. In this study, we tested a biomaterial-based approach aimed at preserving this critical phrenic motor circuitry after cervical SCI by locally delivering hepatocyte growth factor (HGF).

Family caregivers of service members in United States Department of Defense health care report impairment in longitudinal health outcomes.

Objective: To examine elevated symptoms on health-related quality of life (HRQOL) measures over 2 years in caregivers of service members with traumatic brain injury (TBI). To compare outcomes to caregivers of veterans.

Method: Caregivers ( = 315) were classified into two groups: (a) service member caregiver group ( = 55) and (b) veteran caregiver group ( = 260).

Low resilience is associated with worse health-related quality of life in caregivers of service members and veterans with traumatic brain injury: a longitudinal study.

Purpose: To examine [a] the association of caregiver health-related quality of life (HRQOL) and service member/veteran (SMV) neurobehavioral outcomes with caregiver resilience; [b] longitudinal change in resilience at the group and individual level; and [c] the magnitude of change at the individual level.

Methods: Caregivers (N = 232) of SMVs with traumatic brain injury completed a resilience measure, and 18 caregiver HRQOL and SMV neurobehavioral outcome measures at a baseline evaluation and follow-up evaluation three years later. Caregivers were divided into two resilience groups at baseline and follow-up: [1] Low Resilience (≤ 45 T, baseline n = 99, follow-up n = 93) and [2] High Resilience (> 45 T, baseline n = 133, follow-up n = 139).

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region.

Activation of fluoride anion as nucleophile in water with data-guided surfactant selection.

A principal component was developed for 91 commonly accessible surfactants for use in surfactant-enabled organic reactions in water, an important approach for sustainable chemical processes. This map was built using 22 experimental and theoretical descriptors relevant to the physicochemical nature of these surfactant-enabled reactions, and advanced principal component analysis algorithms. It is comprised of all classes of surfactants, cationic, anionic, zwitterionic and neutral surfactants, including designer surfactants.

Identity Theft, Deep Brain Stimulation, and the Primacy of Post-trial Obligations.

Patient narratives from two investigational deep brain stimulation trials for traumatic brain injury and obsessive-compulsive disorder reveal that injury and illness rob individuals of personal identity and that neuromodulation can restore it. The early success of these interventions makes a compelling case for continued post-trial access to these technologies. Given the centrality of personal identity to respect for persons, a failure to provide continued access can be understood to represent a metaphorical identity theft.

Timing of treatment for opioid use disorder among birthing people.

Background: The number of pregnant women with opioid use disorder (OUD) has increased over time. Although effective treatment options exist, little is known about the extent to which women receive treatment during pregnancy and at what stage of pregnancy care is initiated.

Methods: Using a national private health insurance claims database, we identified women aged 13-49 who gave birth in 2006-2019 and had an OUD or nonfatal opioid overdose (NFOO) diagnosis during the year prior to or at delivery.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

Unlabelled: High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region.

EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood.

Brain injury, medical progress, and the disability paradox: Towards an Americans with Abilities Act.

It is helpful to think about the needs of patients with moderate to severe brain injury through the lens of disability law. However, there are limitations to current disability law that contribute to ongoing segregation and marginalization of individuals with severe brain injury. Indeed, one of the paradoxes of American jurisprudence is that more clear constitutional protections accrue to those who have definitively immutable conditions.

Longitudinal health outcomes in caregivers of military members with traumatic brain injury.

Purpose/objective: To examine longitudinal change in health-related quality of life (HRQOL) in caregivers of service members/veterans with traumatic brain injury and factors associated with clinically elevated symptoms.

Research Method/design: Caregivers ( = 220) completed nine HRQOL outcome measures and 10 risk factor measures at a baseline evaluation and follow-up evaluation 3 years later. Caregiver's responses on the nine HRQOL outcome measures were classified into four clinical change categories based on the presence/absence of clinically elevated -scores (≥ 60 T) at baseline and follow-up: (a) Persistent (baseline ≥ 60T + follow-up ≥ 60 T), (b) Developed (baseline < 60 T + follow-up ≥ 60 T), (c) Improved (baseline ≥ 60 T + follow-up < 60 T), and (d) Asymptomatic (baseline < 60 T + follow-up < 60 T).

The Scholarly and Pedagogical Benefits of the Legal Laboratory: Lessons from the Consortium for the Advanced Study of Brain Injury at Yale Law School.

In our article, we share the lessons we have learned after creating and running a successful legal laboratory over the past seven years at Yale Law School. Our legal laboratory, which focuses on the intersection of law and severe brain injury, represents a unique pedagogical model for legal academia, and is closely influenced by the biomedical laboratory.

Longitudinal health-related quality of life in military caregivers no longer providing care.

Purpose/objective: To examine health-related quality of life (HRQOL) in caregivers when providing care and no longer providing care to service members/veterans with traumatic brain injury.

Research Method/design: Participants included 466 caregivers enrolled in a 15-year longitudinal study. During an annual follow-up evaluation, a subsample of caregivers self-identified as no longer providing care and were retained in the study as a No Longer Caregiving group ( = 48).

Inhibition of Aurora-A/N-Myc Protein-Protein Interaction Using Peptidomimetics: Understanding the Role of Peptide Cyclization.

Using N-Myc as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface.

Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury.

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype.

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation Trial for Traumatic Brain Injury: Part II.

This is the second paper in a two-part series describing subject and family perspectives from the CENTURY-S (CENtral Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain InjURY-Safety) first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury (msTBI). To participate, subjects were independently assessed to formally establish decision-making capacity to provide voluntary informed consent. Here, we report on post-operative interviews conducted after a successful trial of thalamic stimulation.

Health outcomes in caregivers of service members and veterans with traumatic brain injury enrolled in the U.S. Veterans Affairs Caregiver Support Program.

To explore health outcomes in caregivers of service members and veterans (SMV) with traumatic brain injury (TBI) enrolled in two programs within the U.S. Department of Veterans Affairs (VA) Caregiver Support Program (CSP) (General and Comprehensive Programs) and those not enrolled.

Chemical biology tools for protein labelling: insights into cell-cell communication.

Multicellular organisms require carefully orchestrated communication between and within cell types and tissues, and many unicellular organisms also sense their context and environment, sometimes coordinating their responses. This review highlights contributions from chemical biology in discovering and probing mechanisms of cell-cell communication. We focus on chemical tools for labelling proteins in a cellular context and how these can be applied to decipher the target receptor of a signalling molecule, label a receptor of interest in situ to understand its biology, provide a read-out of protein activity or interactions in downstream signalling pathways, or discover protein-protein interactions across cell-cell interfaces.