Reclaiming Agency in Care Decisions and Barriers From the Perspectives of Individuals With Acquired Brain Injury and Their Family Members.

BACKGROUND: The ability to self-advocate or have a say in one's care is integral to personalised care after acquired brain injury (ABI). This study aimed to understand what constitutes self-advocacy and associated barriers and facilitators throughout hospital transitions and into the community. METHOD: Qualitative methodology was employed with semistructured interviews conducted with 12 people with ABI and 13 family members. Interviews were conducted at predischarge (in-person or via telephone) and 4 months postdischarge (via telephone) from the brain injury rehabilitation unit of a tertiary hospital. Data were thematically analysed using a hybrid deductive-inductive approach. RESULTS: Self-advocacy reflects the process of reclaiming agency or people's efforts to exert influence over care decisions after ABI. Agency varies along a continuum, often beginning with impaired processing of the self or environment (loss of agency) before individuals start to understand and question their care (emerging agency) and ultimately plan and direct their ongoing and future care (striving for agency). This process may vary across individuals and contexts. Barriers to self-advocacy for individuals with ABI include neurocognitive deficits that limit capacity and desire for control over decisions, unfamiliar and highly structured environments and lack of family support. Facilitators include neurocognitive recovery, growing desire to self-advocate and scaffolded support from family and clinicians. CONCLUSION: Self-advocacy after ABI entails a process of reclaiming agency whereby individuals seek to understand, question and direct their ongoing care. This is facilitated by neurocognitive recovery, growing capacity and desire and scaffolded supports. Research evaluating approaches for embedding self-advocacy skills early in brain injury rehabilitation is recommended. PATIENT OR PUBLIC CONTRIBUTION: Two caregivers with lived experience of supporting a family member with ABI were involved in the design and conduct of this study and contributed to and provided feedback on the manuscript.

CoCoNuTs are a diverse subclass of Type IV restriction systems predicted to target RNA.

A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote coiled-coil nuclease tandems (CoCoNuTs) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with three distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.

All organisms, from animals to bacteria, are subject to genetic parasites, such as viruses and transposons. Genetic parasites are pieces of nucleic acids (DNA or RNA) that can use a cell's machinery to copy themselves at the expense of their hosts. This often leads to the host's demise, so organisms evolved many types of defense mechanisms. One of the most ancient and common forms of defense against viruses and transposons is the targeted restriction of nucleic acids, that is, deployment of host enzymes that can destroy or restrict nucleic acids containing specific sequence motifs or modifications. In bacteria, many of the restriction enzymes targeting parasitic genetic elements are formed by fusions of proteins from the so-called McrBC systems with a protein domain called EVE. EVE and other functionally similar domains are a part of proteins that recognize and bind modified bases in nucleic acids. Enzymes can use the ability of these specificity domains to bind modified bases to detect non-host nucleic acids. Bell et al. conducted a comprehensive computational search for McrBC systems and discovered a large and highly diverse branch of this family with unusual characteristic structural and functional domains. These features include regions that form long alpha-helices (coils) that coil with other alpha-helices (known as coiled-coils), as well as several distinct enzymatic domains that break down nucleic acids (known as nucleases). They call these systems CoCoNuTs (coiled-coiled nuclease tandems). All CoCoNuTs contain domains, including EVE-like ones, which are predicted to interact with components of the RNA-based systems responsible for producing proteins in the cell (translation), suggesting that the CoCoNuTs have an important impact on protein abundance and RNA metabolism. Bell et al.'s findings will be of interest to scientists working on prokaryotic immunity and virulence. Furthermore, similarities between CoCoNuTs and components of eukaryotic RNA-degrading systems suggest evolutionary connections between this diverse family of bacterial predicted RNA restriction systems and RNA regulatory pathways of eukaryotes. Further deciphering the mechanisms of CoCoNuTs could shed light on how certain pathways of RNA metabolism and regulation evolved, and how they may contribute to advances in biotechnology.

Feasibility of a physiotherapist-supervised walking program with telephone coaching to increase physical activity following acquired brain injury.

Background Physical activity has health benefits for adults with acquired brain injury, but it is a challenge to increase physical activity during inpatient rehabilitation. The objectives of this pilot study were to determine whether a physiotherapy-supervised inpatient walking program was feasible and able to improve physical activity and sedentary behaviour in the short and medium term. Methods Adults with acquired brain injury receiving inpatient rehabilitation undertook twice-weekly supervised walks plus behavioural therapy for 4 weeks. Feasibility was measured via recruitment, participation and drop out rates, adverse events and intervention delivery costs. Physical activity and sedentary behaviour were measured with an activPAL. Assessments were conducted at baseline, post-intervention and 3-6 months post-intervention. Results The program was safe to deliver (no adverse events), recruitment rate was 55% (16/29) and the participation rate for eligible individuals was high (14/19, 74%). However, the program had a high drop out rate (7/16, 44%) and physical activity and sedentary behaviour did not significantly change during the 4-week intervention. Costs were AU$427.71/participant. Physical activity and sedentary behaviour did improve 3-6 months after the intervention (vs baseline, on average: +3913 steps per day, 95% CI: 671, 7156). Conclusion This pilot study demonstrated a supervised physiotherapy walking program is safe and feasible to recruit in an inpatient setting. However, drop out during the study was high and behaviour change did not occur. More work is required to boost physical activity during sub-acute rehabilitation for acquired brain injury.

CoCoNuTs: A diverse subclass of Type IV restriction systems predicted to target RNA.

A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote CoCoNuTs (coiled-coil nuclease tandems) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with 3 distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.

Cocaine Use Prediction With Tensor-Based Machine Learning on Multimodal MRI Connectome Data.

This letter considers the use of machine learning algorithms for predicting cocaine use based on magnetic resonance imaging (MRI) connectomic data. The study used functional MRI (fMRI) and diffusion MRI (dMRI) data collected from 275 individuals, which was then parcellated into 246 regions of interest (ROIs) using the Brainnetome atlas. After data preprocessing, the data sets were transformed into tensor form. We developed a tensor-based unsupervised machine learning algorithm to reduce the size of the data tensor from 275 (individuals) × 2 (fMRI and dMRI) × 246 (ROIs) × 246 (ROIs) to 275 (individuals) × 2 (fMRI and dMRI) × 6 (clusters) × 6 (clusters). This was achieved by applying the high-order Lloyd algorithm to group the ROI data into six clusters. Features were extracted from the reduced tensor and combined with demographic features (age, gender, race, and HIV status). The resulting data set was used to train a Catboost model using subsampling and nested cross-validation techniques, which achieved a prediction accuracy of 0.857 for identifying cocaine users. The model was also compared with other models, and the feature importance of the model was presented. Overall, this study highlights the potential for using tensor-based machine learning algorithms to predict cocaine use based on MRI connectomic data and presents a promising approach for identifying individuals at risk of substance abuse.

Meniscus Allograft Transplantation Augmented With Autologous Bone Marrow Aspirate Concentrate.

Meniscus allograft transplantation (MAT) has been shown to be a feasible surgical option for younger patients, below 50 years of age who have meniscal insufficiency and have failed conservative treatment measures. In this technical note, we describe a procedure of harvesting and injecting bone marrow aspirate concentrate in a meniscus allograft during a MAT procedure, which may allow for longer lasting transplants and improve patient outcomes. In this technical note, bone marrow aspirate concentrate is harvested arthroscopically from the intercondylar notch at the surgical site, which prevents additional donor site morbidity, as seen with harvesting from other locations, such as the iliac crest. This also reduces operating time, since harvesting from the iliac crest requires different patient positioning and usually additional anesthesia. The authors of this surgical technique believe that biological augmentation during MATs will assist surgeons in maximizing graft survivorship and, ultimately, lead to better patient outcomes.

Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.

Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.

Cocaine use is associated with cerebral white matter hyperintensities in HIV disease.

BACKGROUND: White matter hyperintensities (WMH), a marker of cerebral small vessel disease and predictor of cognitive decline, are observed at higher rates in persons with HIV (PWH). The use of cocaine, a potent central nervous system stimulant, is disproportionately common in PWH and may contribute to WMH. METHODS: The sample included of 110 PWH on antiretroviral therapy. Fluid-attenuated inversion recovery (FLAIR) and T1-weighted anatomical MRI scans were collected, along with neuropsychological testing. FLAIR images were processed using the Lesion Segmentation Toolbox. A hierarchical regression model was run to investigate predictors of WMH burden [block 1: demographics; block 2: cerebrovascular disease (CVD) risk; block 3: lesion burden]. RESULTS: The sample was 20% female and 79% African American with a mean age of 45.37. All participants had persistent HIV viral suppression, and the median CD4+ T-cell count was 750. Nearly a third (29%) currently used cocaine regularly, with an average of 23.75 (SD = 20.95) days in the past 90. In the hierarchical linear regression model, cocaine use was a significant predictor of WMH burden (ß = .28). WMH burden was significantly correlated with poorer cognitive function (r = -0.27). Finally, higher WMH burden was significantly associated with increased serum concentrations of interferon-γ-inducible protein 10 (IP-10) but lower concentrations of myeloperoxidase (MPO); however, these markers did not differ by COC status. CONCLUSIONS: WMH burden is associated with poorer cognitive performance in PWH. Cocaine use and CVD risk independently contribute to WMH, and addressing these conditions as part of HIV care may mitigate brain injury underlying neurocognitive impairment.

The Individualized Prediction of Neurocognitive Function in People Living with HIV Based on Clinical and Multimodal Connectome Data.

Neurocognitive impairment continues to be common comorbidity for people living with HIV (PLWH). Given the chronic nature of HIV disease, identifying reliable biomarkers of these impairments is essential to advance our understanding of the underlying neural foundation and facilitate screening and diagnosis in clinical care. While neuroimaging provides immense potential for such biomarkers, to date, investigations in PLWH have been mostly limited to either univariate mass techniques or a single neuroimaging modality. In the present study, connectome-based predictive modeling (CPM) was proposed to predict individual differences of cognitive functioning in PLWH, using resting-state functional connectivity (FC), white matter structural connectivity (SC), and clinical relevant measures. We also adopted an efficient feature selection approach to identify the most predictive features, which achieved an optimal prediction accuracy of r = 0.61 in the discovery dataset (n = 102) and r = 0.45 in an independent validation HIV cohort (n = 88). Two brain templates and nine distinct prediction models were also tested for better modeling generalizability. Results show that combining multimodal FC and SC features enabled higher prediction accuracy of cognitive scores in PLWH, while adding clinical and demographic metrics may further improve the prediction by introducing complementary information, which may help better evaluate the individual-level cognitive performance in PLWH.

Cortico-striatal networking deficits associated with advanced HIV disease and cocaine use.

Cocaine use is disproportionately prevalent in people with HIV (PWH) and is known to potentiate HIV neuropathogenesis. As both HIV and cocaine have well-documented cortico-striatal effects, PWH who use cocaine and have a history of immunosuppression may exhibit greater FC deficits compared to PWH without these conditions. However, research investigating the legacy effects of HIV immunosuppression (i.e., a history of AIDS) on cortico-striatal functional connectivity (FC) in adults with and without cocaine use is sparse. Resting-state functional magnetic resonance imaging (fMRI) and neuropsychological assessment data from 273 adults were analyzed to examine FC in relation to HIV disease: HIV-negative (n = 104), HIV-positive with nadir CD4 ≥ 200 (n = 96), HIV-positive with nadir CD4 < 200 (AIDS; n = 73), and cocaine use (83 COC and 190 NON). Using independent component analysis/dual regression, FC was assessed between the basal ganglia network (BGN) and five cortical networks: dorsal attention network (DAN), default mode network, left executive network, right executive network, and salience network. There were significant interaction effects such that AIDS-related BGN-DAN FC deficits emerged in COC but not in NON participants. Independent of HIV, cocaine effects emerged in FC between the BGN and executive networks. Disruption of BGN-DAN FC in AIDS/COC participants is consistent with cocaine potentiation of neuro-inflammation and may be indicative of legacy HIV immunosuppressive effects. The current study bolsters previous findings linking HIV and cocaine use with cortico-striatal networking deficits. Future research should consider the effects of the duration of HIV immunosuppression and early treatment initiation.

Electronic Assistive Technology to Support Memory Function After Traumatic Brain Injury: A Systematic Review of Efficacy and User Perspectives.

Abstract Rapid technology advances have led to diverse assistive technology (AT) options for use in memory rehabilitation after traumatic brain injury (TBI). This systematic review aimed to evaluate the efficacy of electronic AT for supporting phases of memory in daily life after TBI. A secondary aim was to examine user perspectives on the utility of AT and factors influencing uptake or use. A systematic search of PsycINFO, MEDLINE, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Excerpta Medica database (Embase), Scopus, and Cochrane Library was conducted from database inception to June 13, 2022, to identify eligible studies. Methodological quality was assessed by two independent reviewers. Nineteen eligible articles involving a total of 311 participants included four randomized controlled trials (RCTs; Class I), five single-case experimental designs (Class II), and 10 pre-post group (n > 10) or single-case studies without experimental control (Class III). Three Class I studies, two Class II studies and eight Class III studies supported the efficacy of AT for supporting memory functioning. Treatment fidelity was not examined in any study. There was the most empirical support for the efficacy of AT for facilitating retrieval and execution phases of memory (i.e., supported by 6/9 studies) with external support to encode memory intentions or pre-programmed reminders. Further controlled studies are needed to determine whether outcomes vary according to individuals' level of independence with use (e.g., self-initiated vs. pre-programmed reminders) and to examine user characteristics and design features influencing uptake and effectiveness. Greater involvement of end-users with brain injury in the design and evaluation of AT features is also recommended to enhance usability and uptake in daily life.

Additive cortical gray matter deficits in people living with HIV who use cocaine.

Cocaine use, which is disproportionately common in people living with HIV (PWH), is known to have neurotoxic effects that may exacerbate HIV neuropathogenesis. While both cocaine use and HIV disease are independently associated with deficits in gray matter (GM) volume, the additive effect of cocaine use to HIV disease on GM volume has not been explored. Here, we investigated subcortical and cortical brain volume differences between four groups of individuals with and without HIV disease and/or cocaine use. Participants also completed a comprehensive neuropsychological testing battery, and HIV disease characteristics were recorded. Within subcortical regions, cocaine use was independently associated with higher volume in the dorsal striatum and pallidum, while HIV disease was associated with lower volume in the nucleus accumbens and thalamus. For cortical regions, there was an additive effect of cocaine use on HIV disease in parietal and occipital lobe volume with PWH who used cocaine displaying the lowest GM volume. Within regions that differed between groups, higher neurocognitive function was positively associated with thalamic, nucleus accumbens, dorsal striatum, and occipital lobe volume. For regions that showed a significant main effect of HIV disease, lower nadir CD4 + T cell count was associated with lower nucleus accumbens and occipital lobe volume. Lower current CD4 + T cell count was associated with lower occipital lobe volume. These results suggest that PWH who use cocaine are at greater risk for cortical atrophy than cocaine use or HIV disease alone.

Use and cost of Medicare Benefits Schedule and Pharmaceutical Benefits Scheme services following inpatient rehabilitation for acquired disability in Australia.

Objectives This study explored publicly funded health system and patient expenditure in the post-acute phase following discharge from inpatient acquired brain injury (ABI) or spinal cord injury (SCI) rehabilitation. The secondary aim was to explore sociodemographic and injury characteristics associated with high costs. Methods This was a prospective cohort study. 153 patients (ABI: n = 85; SCI: n = 68) who consented to the use of their Medicare data were recruited between March 2017 and March 2018, at the point of discharge from ABI or SCI specialist rehabilitation units. The main outcome measure involved linkage of the Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data for the 12 months following discharge from rehabilitation. Bayesian penalised regression was used to determine characteristics associated with high costs. Results The median number of MBS items used in the 12 months after discharge was 33 (IQR: 21-52). General practitioners and allied health services were accessed by 100% and 41% of the cohort, respectively. The median MBS system cost (in Australian dollars) was $2006 (IQR: $162-$3090). Almost half (46%) of the participants had no MBS patient expenditure. The median PBS system cost was $541 (IQR: $62-$1574). For people with ABI, having a traumatic injury or one comorbidity was associated with lower PBS system costs by on average $119 and $134, respectively. We also found that hospitalisation in ABI was associated with higher PBS system costs, by on average $669. Conclusion There was evidence of high and variable MBS and PBS costs, raising concerns about financial hardship. Future research should focus on identifying any unmet service and prescription needs in the post-acute rehabilitation phase for these populations.

Neuroimaging and immunological features of neurocognitive function related to substance use in people with HIV.

This study sought to identify neuroimaging and immunological factors associated with substance use and that contribute to neurocognitive impairment (NCI) in people with HIV (PWH). We performed cross-sectional immunological phenotyping, neuroimaging, and neurocognitive testing on virally suppressed PWH in four substance groups: cocaine only users (COC), marijuana only users (MJ), dual users (Dual), and Non-users. Participants completed substance use assessments, multimodal MRI brain scan, neuropsychological testing, and blood and CSF sampling. We employed a two-stage analysis of 305 possible biomarkers of cognitive function associated with substance use. Feature reduction (Kruskal Wallis p-value < 0.05) identified 53 biomarkers associated with substance use (22 MRI and 31 immunological) for model inclusion along with clinical and demographic variables. We employed eXtreme Gradient Boosting (XGBoost) with these markers to predict cognitive function (global T-score). SHapley Additive exPlanations (SHAP) values were calculated to rank features for impact on model output and NCI. Participants were 110 PWH with sustained HIV viral suppression (33 MJ, 12 COC, 22 Dual, and 43 Non-users). The ten highest ranking biomarkers for predicting global T-score were 4 neuroimaging biomarkers including functional connectivity, gray matter volume, and white matter integrity; 5 soluble biomarkers (plasma glycine, alanine, lyso-phosphatidylcholine (lysoPC) aC17.0, hydroxy-sphingomyelin (SM.OH) C14.1, and phosphatidylcholinediacyl (PC aa) C28.1); and 1 clinical variable (nadir CD4 count). The results of our machine learning model suggest that substance use may indirectly contribute to NCI in PWH through both metabolomic and neuropathological mechanisms.

Effectiveness of an Accelerated Rehabilitation Protocol After Tibial Tubercle Osteotomy.

Background: Patients with recurrent patellar dislocations with trochlear dysplasia are commonly treated surgically with a tibial tubercle osteotomy (TTO). Recovery and rehabilitation processes are often nonoperative out of concern for fixation failure or fracture. A more accelerated rehabilitation protocol allowing for early weightbearing and quadriceps strengthening may help to improve patient outcomes as long as complications are not increased. Purpose: To evaluate the safety and effectiveness of an accelerated weightbearing and early strengthening postoperative rehabilitation program for patients who undergo TTO. Study Design: Case series; Level of evidence, 4. Methods: Included were patients who underwent unilateral/staged bilateral TTO performed by a single surgeon between August 2013 and February 2018 with ≥6 months of follow-up. The surgical indication was primarily for patients with recurrent patellar instability. In all cases, a diagnostic arthroscopy was performed to evaluate the cartilage surfaces and document patellar tracking. The TTO was performed using a freehand technique and two 3.5-mm fully threaded screws for fixation. Patients underwent an accelerated postoperative rehabilitation program that allowed for weightbearing and lower extremity strengthening starting at 4 weeks. Objective and subjective outcome measures included any postoperative complications, knee range of motion, and patient-reported outcome scores (Kujala Anterior Knee Pain Scale [AKPS] and Knee injury and Osteoarthritis Outcome Score composite [(KOOS5]). Results: A total of 51 knees in 50 patients (38 female, 12 male) with a mean age of 31.24 ± 12.57 years were included in the final analysis. Compared with preoperative values, postoperative maximum knee flexion was significantly improved (117.67° ± 32.65° vs 131.12° ± 9.02°, respectively; P = .022). Postoperative complications included 6 patients with arthrofibrosis requiring manipulation under anesthesia, 4 with removal of symptomatic hardware, 1 tibial fracture (due to a fall), and 1 conversion to patellofemoral arthroplasty. The mean postoperative AKPS and KOOS5 scores were 72.98 ± 21.51 and 75.05 ± 16.02, respectively. Conclusion: Accelerated postoperative rehabilitation in TTO patients was an effective means of treatment with good subjective and objective outcomes and complication rates lower than traditional rehabilitation protocols.

Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress.

Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage.

Strengthened and posterior-shifted structural rich-club organization in people who use cocaine.

BACKGROUND: People with cocaine use disorder (CUD) often have abnormal cognitive function and brain structure. Cognition is supported by brain networks that typically have characteristics like rich-club organization, which is a group of regions that are highly connected across the brain and to each other, and small worldness, which is a balance between local and long-distance connections. However, it is unknown whether there are abnormalities in structural brain network connectivity of CUD. METHODS: Using diffusion-weighted imaging, we measured structural connectivity in 37 people with CUD and 38 age-matched controls. We identified differences in rich-club organization and whether such differences related to small worldness and behavior. We also tested whether rich-club reorganization was associated with caudate and putamen structural connectivity due to the relevance of the dopamine system to cocaine use. RESULTS: People with CUD had a higher normalized rich-club coefficient than controls, more edges connecting rich-club nodes to each other and to non-rich-club nodes, and fewer edges connecting non-rich-club nodes. Rich-club nodes were shifted posterior and lateral. Rich-club reorganization was related to lower clustered connectivity around individual nodes found in CUD, to increased impulsivity, and to a decrease in caudate connectivity. CONCLUSIONS: These findings are consistent with previous work showing increased rich-club connectivity in conditions associated with a hypofunctional dopamine system. The posterior shift in rich-club nodes in CUD suggests that the structural connectivity of posterior regions may be more impacted than previously recognized in models based on brain function and morphology.

Chromatin Reorganization during Myoblast Differentiation Involves the Caspase-Dependent Removal of SATB2.

The induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that the removal of the special AT-rich binding protein 2 (SATB2), a nuclear protein known to bind matrix attachment regions, is a key event in initiating myogenic differentiation. The deletion of myoblast SATB2 in vitro initiates chromatin remodeling and accelerates differentiation, which is dependent on the caspase 7-mediated cleavage of SATB2. A genome-wide analysis indicates that SATB2 binding within chromatin loops and near anchor points influences both loop and sub-TAD domain formation. Consequently, the chromatin changes that occur with the removal of SATB2 lead to the derepression of differentiation-inducing factors while also limiting the expression of genes that inhibit this cell fate change. Taken together, this study demonstrates that the temporal control of the SATB2 protein is critical in shaping the chromatin environment and coordinating the myogenic differentiation program.

Principal component analysis denoising improves sensitivity of MR diffusion to detect white matter injury in neuroHIV.

BACKGROUND AND PURPOSE: Diffusion-weighted imaging is able to capture important information about cerebral white matter (WM) structure. However, diffusion data can suffer from MRI and biological noise that degrades the quality of the images and makes finding important features difficult. We investigated how effectively local and nonlocal denoising increased the sensitivity to detect differences in cerebral WM in neuroHIV. METHODS: We utilized principal component analysis (PCA) denoising to detect WM differences using fractional anisotropy. Local and nonlocal PCA denoising paradigms were implemented that varied in search area and number of components. We examined different-sized WM tracts that consistently show differences between people living with Human Immunodeficiency Virus (HIV) (PWH) and HIV-negative individuals (corpus callosum, forceps minor, and right uncinate fasciculus), and size-matched tracts not typically associated with HIV-related differences (spinothalamic, right medial lemniscus, and left occipitopontine). We first conducted a full sample comparison of WM differences between groups, and then randomly reduced the sample to the point where we still found differences in WM. RESULTS: Nonlocal PCA denoising allowed us to detect differences after a sample reduction of 35% in the forceps minor, 17% in the right uncinate fasciculus, and 6% in the corpus callosum. CONCLUSIONS: PCA denoising had a beneficial effect on detecting significant differences in PWH after sample size reduction. The smaller forceps minor tract and right uncinate fasciculus showed greater sensitivity to PCA denoising than the larger corpus callosum. These results show the importance of identifying the most effective PCA denoising strategy when investigating WM in PWH.