Second harmonic generation microscopy of electromechanical reshaping on corneal collagen.

Refractive errors remain a global health concern, as a large proportion of the world's population is myopic. Current ablative approaches are costly, not without risks, and not all patients are candidates for these procedures. Electromechanical reshaping (EMR) has been explored as a viable cost-effective modality to directly shape tissues, including cartilage. In this study, stromal collagen structure and fibril orientation was examined before and after EMR with second-harmonic generation microscopy (SHG), a nonlinear multiphoton imaging method that has previously been used to study native corneal collagen with high spatial resolution. EMR, using a milled metal contact lens and potentiostat, was performed on the corneas of five extracted rabbit globes. SHG was performed using a confocal microscopy system and all images underwent collagen fibril orientation analysis. The collagen SHG signal in controls is uniform and is similarly seen in samples treated with pulsed potential, while continuous EMR specimens have reduced, nonhomogeneous signal. Collagen fibril orientation in native tissue demonstrates a broad distribution with suggestion of another peak evolving, while with EMR treated eyes a bimodal characteristic becomes readily evident. Pulsed EMR may be a means to correct refractive errors, as when comparing its SHG signal to negative control, preservation of collagen structures with little to no damage is observed. From collagen fiber orientation analysis, it can be inferred that simple DC application alters the structure of collagen. Future studies will involve histological assessment of these layers and multi-modal imaging analysis of dosimetry.

Location of medial collateral ligament tears: introduction to a magnetic resonance imaging-based classification.

PURPOSE: Despite established tear grade classifications, there is currently no radiological classification for sMCL tear locations. This study aims to establish a magnetic resonance imaging (MRI) tear location classification system for sMCL tears, to enhance understanding and guide treatment decisions by categorizing tear types. METHODS: A retrospective search in a single institution's MRI database identified patients with acute, Grade III sMCL tears (< 30 days between injury and MRI) from January to December 2022. Non-acute and partial tears were excluded, and three observers assessed tear types based on the proposed sMCL MRI tear location system: type I (proximal 25%), Ib (proximal femoral bony avulsion), II (midsubstance, 25-75%), III (distal 25%), IIIb (distal tibial bony avulsion), IIIs (Stener-like lesion). The interclass correlation coefficient (ICC) was used to assess interrater and intrarater reliability for continuous data; Fleiss and Cohen's kappa assessed interrater and intrarater reliability for categorical data. RESULTS: MRI scans of thirty patients with diagnosed sMCL injuries (53% female, mean age 37 ± 13 years, range 16-68 years) were included based on inclusion/exclusion criteria. Interrater reliability was excellent (ICC: 0.968, 95% CI, 0.933-0.985), and intrarater reliability was excellent (ICC: 0.938, 95% CI: 0.874-0.970 & 0.900, 95% CI, 0.789-0.952). Type I injuries were most common (60%), followed by type III (33.3%), type II (3.3%), type Ib (3.3%), type IIIb (0.0%), and type IIIs (0.0%). CONCLUSION: The presented MRI-based sMCL tear location classification provides a reproducible system for grading high-grade sMCL injuries. We propose that this framework will significantly unify tear location understanding and support more informed treatment decisions.

Arteriovenous fistula aneurysmorrhaphy is associated with improved patency and decreased vascular access abandonment.

BACKGROUND: Upper extremity hemodialysis arteriovenous fistulas (AVFs) can become aneurysmal over time due to repeated cannulation and/or outflow steno-occlusive disease. The optimal surgical management of aneurysmal AVFs (aneurysmorrhaphy vs interposition graft) has remained unclear. METHODS: We performed a retrospective review in which current procedural terminology codes were used to screen for patients who had undergone surgical treatment of aneurysmal AVFs between 2016 and 2021 at a single hospital system. The patients were included after a review of the operative reports. The cases were divided by surgical procedure (aneurysmorrhaphy vs interposition graft placement). The patients who had undergone primary AVF ligation or other types of repair were excluded. The primary outcomes were primary assisted and secondary patency, and the secondary outcome was dialysis access abandonment. Multivariable Cox proportional hazards regression was used to test the association between the type of AVF aneurysm repair and the primary and secondary outcomes. RESULTS: From 2016 to 2021, 6951 patients had undergone 16,190 dialysis access procedures. Of these procedures, 381 (2.4%) were related to surgical treatment of an aneurysmal AVF. We excluded 58 primary AVF ligation cases and 20 cases involving other types of repair, leaving 303 cases for analysis. These were divided into two groups: aneurysmorrhaphy (n = 123; 41%) and interposition graft (n = 180; 59%). No differences were found between the groups in male gender (68% vs 63%), hypertension (98% vs 98%), or central stenosis (14% vs 22%). The patients who had undergone aneurysmorrhaphy were younger (median age, 54 years vs 59 years); had had a lower rate of diabetes (41% vs 59%), coronary artery disease (41% vs 58%), and congestive heart failure (41% vs 55%); and were less likely to have undergone upper arm access (72% vs 92%). The median follow-up was 11.1 months (interquartile range, 3.6-25.2 months). No differences were found in the incidence of 30-day wound complications (1% vs 3%) or surgical site infections (4% vs 6%). On multivariable Cox regression, interposition graft placement was associated with the loss of primary assisted patency (adjusted hazard ratio [aHR], 2.42; 95% confidence interval [CI], 1.18-4.95), loss of secondary patency (aHR, 3.10; 95% CI, 1.21-7.94), and abandonment of dialysis access (aHR, 3.07; 95% CI, 1.61-5.87; P < .05 for all) at 2 years. CONCLUSIONS: AVF aneurysmorrhaphy was associated with improved primary assisted and secondary patency and decreased abandonment of dialysis access. We suggest using aneurysmorrhaphy when AVF aneurysms are indicated for repair. However, individual factors such as patient comorbidities, AVF anatomy, remaining dialysis access options, and patient preference should be considered when planning the surgical approach.

Cortical thickness is related to cognitive-motor automaticity and attention allocation in individuals with Alzheimer's disease: a regions of interest study.

Alzheimer's disease (AD) is characterized by a distinct pattern of cortical thinning and resultant changes in cognition and function. These result in prominent deficits in cognitive-motor automaticity. The relationship between AD-related cortical thinning and decreased automaticity is not well-understood. We aimed to investigate the relationship between cortical thickness regions-of-interest (ROI) and automaticity and attention allocation in AD using hypothesis-driven and exploratory approaches. We performed an ROI analysis of 46 patients with AD. Data regarding MR images, demographic characteristics, cognitive-motor dual task performance, and cognition were extracted from medical records. Cortical thickness was calculated from MR T1 images using FreeSurfer. Data from the dual task assessment was used to calculate the combined dual task effect (cDTE), a measure of cognitive-motor automaticity, and the modified attention allocation index (mAAI). Four hierarchical multiple linear regression models were conducted regressing cDTE and mAAI separately on (1) hypothesis-generated ROIs and (2) exploratory ROIs. For cDTE, cortical thicknesses explained 20.5% (p = 0.014) and 25.9% (p = 0.002) variability in automaticity in the hypothesized ROI and exploratory models, respectively. The dorsal lateral prefrontal cortex (DLPFC) (ß = - 0.479, p = 0.018) and superior parietal cortex (SPC) (ß = 0.467, p = 0.003), and were predictors of automaticity. For mAAI, cortical thicknesses explained 20.7% (p = 0.025) and 28.3% (p = 0.003) variability in attention allocation in the hypothesized ROI and exploratory models, respectively. Thinning of SPC and fusiform gyrus were associated with motor prioritization (ß = - 0.405, p = 0.013 and ß = - 0.632, p = 0.004, respectively), whereas thinning of the DLPFC was associated with cognitive prioritization (ß = 0.523, p = 0.022). Cortical thinning in AD was related to cognitive-motor automaticity and task prioritization, particularly in the DLPFC and SPC. This suggests that these regions may play a primary role in automaticity and attentional strategy during dual-tasking.

Persisting Effects in Daphnia magna Following an Acute Exposure to Flowback and Produced Waters from the Montney Formation.

Hydraulic fracturing extracts oil and gas through the injection of water and proppants into subterranean formations. These injected fluids mix with the host rock formation and return to the surface as a complex wastewater containing salts, metals, and organic compounds, termed flowback and produced water (FPW). Previous research indicates that FPW is toxic to Daphnia magna (D. magna), impairing reproduction, molting, and maturation time; however, recovery from FPW has not been extensively studied. Species unable to recover have drastic impacts on populations on the ecological scale; thus, this study sought to understand if recovery from an acute 48 h FPW exposure was possible in the freshwater invertebrate, D. magna by using a combination of physiological and molecular analyses. FPW (0.75%) reduced reproduction by 30% and survivorship to 32% compared to controls. System-level quantitative proteomic analyses demonstrate extensive perturbation of metabolism and protein transport in both 0.25 and 0.75% FPW treatments after a 48 h FPW exposure. Collectively, our data indicate that D. magna are unable to recover from acute 48 h exposures to ≥0.25% FPW, as evidence of toxicity persists for at least 19 days post-exposure. This study highlights the importance of considering persisting effects following FPW remediation when modeling potential spill scenarios.

Nucleus reuniens inactivation does not impair consolidation or reconsolidation of fear extinction.

Recent data reveal that the thalamic nucleus reuniens (RE) has a critical role in the extinction of conditioned fear. Muscimol (MUS) infusions into the RE impair within-session extinction of conditioned freezing and result in poor long-term extinction memories in rats. Although this suggests that RE inactivation impairs extinction learning, it is also possible that it is involved in the consolidation of extinction memories. To examine this possibility, we examined the effects of RE inactivation on the consolidation and reconsolidation of fear extinction in male and female rats. Twenty-four hours after auditory fear conditioning, rats underwent an extinction procedure (45 CS-alone trials) in a novel context and were infused with saline (SAL) or MUS within minutes of the final extinction trial. Twenty-four hours later, conditioned freezing to the extinguished CS was assessed in the extinction context. Postextinction inactivation of the RE did not affect extinction retrieval. In a second experiment, rats underwent extinction training and, 24 h later, were presented with a single CS to reactivate the extinction memory; rats were infused with SAL or MUS immediately after the reactivation session. Pharmacological inactivation of the RE did not affect conditioned freezing measured in a drug-free retrieval test the following day. Importantly, we found in a subsequent test that MUS infusions immediately before retrieval testing increased conditioned freezing and impaired extinction retrieval, as we have previously reported. These results indicate that although RE inactivation impairs the expression of extinction, it does not impair either the consolidation or reconsolidation of extinction memories. We conclude that the RE may have a critical role in suppressing context-inappropriate fear memories in the extinction context.

Contour-enhanced attention CNN for CT-based COVID-19 segmentation.

Accurate detection of COVID-19 is one of the challenging research topics in today's healthcare sector to control the coronavirus pandemic. Automatic data-powered insights for COVID-19 localization from medical imaging modality like chest CT scan tremendously augment clinical care assistance. In this research, a Contour-aware Attention Decoder CNN has been proposed to precisely segment COVID-19 infected tissues in a very effective way. It introduces a novel attention scheme to extract boundary, shape cues from CT contours and leverage these features in refining the infected areas. For every decoded pixel, the attention module harvests contextual information in its spatial neighborhood from the contour feature maps. As a result of incorporating such rich structural details into decoding via dense attention, the CNN is able to capture even intricate morphological details. The decoder is also augmented with a Cross Context Attention Fusion Upsampling to robustly reconstruct deep semantic features back to high-resolution segmentation map. It employs a novel pixel-precise attention model that draws relevant encoder features to aid in effective upsampling. The proposed CNN was evaluated on 3D scans from MosMedData and Jun Ma benchmarked datasets. It achieved state-of-the-art performance with a high dice similarity coefficient of 85.43% and a recall of 88.10%.

CT-based severity assessment for COVID-19 using weakly supervised non-local CNN.

Evaluating patient criticality is the foremost step in administering appropriate COVID-19 treatment protocols. Learning an Artificial Intelligence (AI) model from clinical data for automatic risk-stratification enables accelerated response to patients displaying critical indicators. Chest CT manifestations including ground-glass opacities and consolidations are a reliable indicator for prognostic studies and show variability with patient condition. To this end, we propose a novel attention framework to estimate COVID-19 severity as a regression score from a weakly annotated CT scan dataset. It takes a non-locality approach that correlates features across different parts and spatial scales of the 3D scan. An explicit guidance mechanism from limited infection labeling drives attention refinement and feature modulation. The resulting encoded representation is further enriched through cross-channel attention. The attention model also infuses global contextual awareness into the deep voxel features by querying the base CT scan to mine relevant features. Consequently, it learns to effectively localize its focus region and chisel out the infection precisely. Experimental validation on the MosMed dataset shows that the proposed architecture has significant potential in augmenting existing methods as it achieved a 0.84 R-squared score and 0.133 mean absolute difference.

Locus Coeruleus Norepinephrine Drives Stress-Induced Increases in Basolateral Amygdala Firing and Impairs Extinction Learning.

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.

Ventral hippocampus mediates the context-dependence of two-way signaled avoidance in male rats.

Considerable work indicates that instrumental responding is context-dependent, but the neural mechanisms underlying this phenomenon are poorly understood. Given the important role for the hippocampal formation in contextual processing, we hypothesized that reversible inactivation of the hippocampus would impair the context-dependence of active avoidance. To test this hypothesis, we used a two-way signaled active avoidance (SAA) task that requires rats to shuttle across a divided chamber during a tone CS in order to avoid a footshock US. After training, avoidance responding was assessed in an extinction test in both the training context and a novel context in a counterbalanced order. Rats performed significantly more avoidance responses in the training context than in the novel context, demonstrating the context-dependence of shuttle avoidance behavior. To examine the role of the hippocampus in the context-dependence of SAA, we reversibly inactivated either the dorsal (DH) or ventral hippocampus (VH) prior to testing. Inactivation of the VH eliminated the context-dependence of SAA and elevated avoidance responding in the novel context to levels similar to that expressed in the training context. In contrast, DH inactivation had no effect on avoidance in either context, and neither manipulation affected freezing behavior. Therefore, the integrity of the VH, but not DH, is required for the expression of the context-dependence of avoidance behavior.

Assessment of groundwater from an industrial coastal area of south India for human health risk from consumption and irrigation suitability.

We assessed the groundwater quality in an industrial area (Tiruchendur Taluk) of Tamil Nadu state in coastal south India for human health risk from drinking as well as irrigation suitability by using the drinking water quality index (DWQI), irrigation factors (sodium adsorption ratio, sodium percentage, residual sodium carbonate and permeability index) and health hazard valuation (THQI- by consuming NO3- and F-). About 57% of the samples represented Ca2+-Mg2+-Cl--SO42- facies and the anthropological unhygienic inputs elevated the salinity. Our results indicated that all the samples are unsuitable for drinking (DWQI up to 1063) and almost half of them are also unsuitable for irrigation due to sodium risk. Total hazard quotient index (THQI; HQ nitrate and HQ fluoride) suggested the order of health risk as children > women > men with about 64%, 70% and 79% of the samples posing non-carcinogenic risks for men, women and children, respectively. Different mitigation measures and sustainable development should be enforced to minimize the health issues from contamination caused by industries, fertilizers in agro-fields and natural processes and reduce the sodium dominance in groundwater. The spatial distribution maps of this study could also be helpful in organization of proper treatment plans to provide safe and hygienic groundwater to the community.

Outcomes of Microneurolysis of Hourglass Constrictions in Chronic Neuralgic Amyotrophy.

PURPOSE: Wide variability in the recovery of patients affected by neuralgic amyotrophy (NA) is recognized, with up to 30% experiencing residual motor deficits. Using magnetic resonance imaging and ultrasound (US), we identified hourglass constrictions (HGCs) in all affected nerves of patients with chronic motor paralysis from NA. We hypothesized that chronic NA patients undergoing microsurgical epineurolysis and perineurolysis of constrictions would experience greater recovery compared with patients managed nonsurgically. METHODS: We treated 24 patients with chronic motor palsy from NA and HGCs identified on magnetic resonance imaging and US either with microsurgical epineurolysis and perineurolysis of HGCs (11 of 24) or nonsurgically (13 of 24). Muscle strength (both groups) and electrodiagnostic testing (EDX) (operative group) was performed before and after surgery. Preoperative EDX confirmed muscle denervation in the distribution of affected nerve(s). All patients met criteria for microneurolysis: 12 months without improvement since onset or failure of clinical and EDX improvement after 6 months documented by 3 successive examinations, each at least 6 weeks apart. RESULTS: Mean time from onset to surgery was 12.5 ± 4.0 months. Average time to most recent post-onset follow-up occurred at 27.3 months (range, 18-42 months; 15 nerves). Average time to latest follow-up among nonsurgical patients was 33.6 months (range, 18-108 months; 16 nerves). Constrictions involved individual fascicular groups (FCs) of the median nerve and the suprascapular, axillary and radial nerves proper (HGCs). Nine of 11 operative patients experienced clinical recovery compared with 3 of 13 nonsurgical patients. EMG revealed significant motor unit recovery from axonal regeneration in the operative group. CONCLUSIONS: Microsurgical epineurolysis and perineurolysis of FCs and HGCs was associated with significantly improved clinical and nerve regeneration at an average follow-up of 14.8 months compared with nonsurgical management. We recommend microneurolysis of HGCs and FCs as a treatment option for patients with chronic NA who have failed to improve with nonsurgical treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Learning distinctive filters for COVID-19 detection from chest X-ray using shuffled residual CNN.

COVID-19 is a deadly viral infection that has brought a significant threat to human lives. Automatic diagnosis of COVID-19 from medical imaging enables precise medication, helps to control community outbreak, and reinforces coronavirus testing methods in place. While there exist several challenges in manually inferring traces of this viral infection from X-ray, Convolutional Neural Network (CNN) can mine data patterns that capture subtle distinctions between infected and normal X-rays. To enable automated learning of such latent features, a custom CNN architecture has been proposed in this research. It learns unique convolutional filter patterns for each kind of pneumonia. This is achieved by restricting certain filters in a convolutional layer to maximally respond only to a particular class of pneumonia/COVID-19. The CNN architecture integrates different convolution types to aid better context for learning robust features and strengthen gradient flow between layers. The proposed work also visualizes regions of saliency on the X-ray that have had the most influence on CNN's prediction outcome. To the best of our knowledge, this is the first attempt in deep learning to learn custom filters within a single convolutional layer for identifying specific pneumonia classes. Experimental results demonstrate that the proposed work has significant potential in augmenting current testing methods for COVID-19. It achieves an F1-score of 97.20% and an accuracy of 99.80% on the COVID-19 X-ray set.

Unexpected entanglement dynamics in semidilute blends of supercoiled and ring DNA.

Blends of polymers of different topologies, such as ring and supercoiled, naturally occur in biology and often exhibit emergent viscoelastic properties coveted in industry. However, due to their complexity, along with the difficulty of producing polymers of different topologies, the dynamics of topological polymer blends remains poorly understood. We address this void by using both passive and active microrheology to characterize the linear and nonlinear rheological properties of blends of relaxed circular and supercoiled DNA. We characterize the dynamics as we vary the concentration from below the overlap concentration c* to above (0.5c* to 2c*). Surprisingly, despite working at the dilute-semidilute crossover, entanglement dynamics, such as elastic plateaus and multiple relaxation modes, emerge. Finally, blends exhibit an unexpected sustained elastic response to nonlinear strains not previously observed even in well-entangled linear polymer solutions.

Teaching vs learning: Impact of deliberate practice and formative feedback on developing point of care ultrasound skills.

PURPOSE: The study investigators hypothesized that Point of Care Ultrasound (POCUS) training through bolus didactic and workshop experiences may be sufficient for trainees to learn the cognitive aspects, while an extended period of exposure with formative feedback is responsible for developing the psychomotor skills critical for POCUS. METHODS: The investigators studied trainees over the course of an academic year. They compared trainees' performance on written (cognitive) and observed image acquisition (psychomotor) exams at baseline and at each subsequent quarter, using a stepped-wedge design. They performed linear regression analysis to determine which variables contributed to knowledge and psychomotor skill development. RESULTS: Twenty-six trainees met the study requirements and participated in the POCUS curriculum. Participating in a POCUS rotation was consistently associated with an increase in psychomotor scores. There was no consistent variable to predict an increase in trainee's score on written knowledge assessments. CONCLUSIONS: Extended exposure to POCUS over a 4-week rotation with direct and indirect formative feedback can explain difference in scores on psychomotor skills assessments. Trainees scored similarly on the written assessment with or without a POCUS rotation. Training through didactic and workshop experiences may be sufficient to learn the cognitive aspects, but not psychomotor skills required for POCUS.

Nucleus Reuniens Is Required for Encoding and Retrieving Precise, Hippocampal-Dependent Contextual Fear Memories in Rats.

The nucleus reuniens (RE) is a ventral midline thalamic nucleus that interconnects the medial prefrontal cortex (mPFC) and hippocampus (HPC). Considerable data indicate that HPC-mPFC circuits are involved in contextual and spatial memory; however, it is not clear whether the RE mediates the acquisition or retrieval of these memories. To examine this question, we inactivated the RE with muscimol before either the acquisition or retrieval of pavlovian fear conditioning in rats; freezing served as the index of fear. We found that RE inactivation before conditioning impaired the acquisition of contextual freezing, whereas inactivation of the RE before retrieval testing increased the generalization of freezing to a novel context; inactivation of the RE did not affect either the acquisition or expression of auditory fear conditioning. Interestingly, contextual conditioning impairments were absent when retrieval testing was also conducted after RE inactivation. Contextual memories acquired under RE inactivation were hippocampal independent, insofar as contextual freezing in rats conditioned under RE inactivation was insensitive to intrahippocampal infusions of the NMDA receptor antagonist aminophosphonovalerate. Together, these data reveal that the RE supports hippocampal-dependent encoding of precise contextual memories that allow discrimination of dangerous contexts from safe contexts. When the RE is inactive, however, alternate neural systems acquire an impoverished contextual memory that is expressed only when the RE is off-line.SIGNIFICANCE STATEMENT The midline thalamic nucleus reuniens (RE) coordinates communication between the hippocampus and medial prefrontal cortex, brain areas that are critical for contextual and spatial memory. Here we show that temporary pharmacological inactivation of RE impairs the acquisition and precision of contextual fear memories after pavlovian fear conditioning in rats. However, inactivating the RE before retrieval testing restored contextual memory in rats conditioned after RE inactivation. Critically, we show that imprecise contextual memories acquired under RE inactivation are learned independently of the hippocampus. These data reveal that the RE is required for hippocampal-dependent encoding of precise contextual memories to support the discrimination of safe and dangerous contexts.

Multivariate group-level analysis for task fMRI data with canonical correlation analysis.

Task-based functional Magnetic Resonance Imaging (fMRI) has been widely used to determine population-based brain activations for cognitive tasks. Popular group-level analysis in fMRI is based on the general linear model and constitutes a univariate method. However, univariate methods are known to suffer from low sensitivity for a given specificity because the spatial covariance structure at each voxel is not taken entirely into account. In this study, a spatially constrained local multivariate model is introduced for group-level analysis to improve sensitivity at a given specificity for activation detection. The proposed model is formulated in terms of a multivariate constrained optimization problem based on the maximum log likelihood method and solved efficiently with numerical optimization techniques. Both simulated data mimicking real fMRI time series at multiple noise fractions and real fMRI episodic memory data have been used to evaluate the performance of the proposed method. For simulated data, the area under the receiver operating characteristic curves in detecting group activations increases for the subject and group level multivariate method by 20%, as compared to the univariate method. Results from real fMRI data indicate a significant increase in group-level activation detection, particularly in hippocampus, para-hippocampal area and nearby medial temporal lobe regions with the proposed method.

Understanding white matter structural connectivity differences between cognitively impaired and nonimpaired active professional fighters.

Long-term traumatic brain injury due to repeated head impacts (RHI) has been shown to be a risk factor for neurodegenerative disorders, characterized by a loss in cognitive performance. Establishing the correlation between changes in the white matter (WM) structural connectivity measures and neuropsychological test scores might help to identify the neural correlates of the scores that are used in daily clinical setting to investigate deficits due to repeated head blows. Hence, in this study, we utilized high angular diffusion MRI (dMRI) of 69 cognitively impaired and 70 nonimpaired active professional fighters from the Professional Fighters Brain Health Study, and constructed structural connectomes to understand: (a) whether there is a difference in the topological WM organization between cognitively impaired and nonimpaired active professional fighters, and (b) whether graph-theoretical measures exhibit correlations with neuropsychological scores in these groups. A dMRI derived structural connectome was constructed for every participant using brain regions defined in AAL atlas as nodes, and the product of fiber number and average fractional anisotropy of the tracts connecting the nodes as edges. Our study identified a topological WM reorganization due to RHI in fighters prone to cognitive decline that was correlated with neuropsychological scores. Furthermore, graph-theoretical measures were correlated differentially with neuropsychological scores between groups. We also found differentiated WM connectivity involving regions of hippocampus, precuneus, and insula within our cohort of cognitively impaired fighters suggesting that there is a discernible WM topological reorganization in fighters prone to cognitive decline.

Synergistic Interactions Between DNA and Actin Trigger Emergent Viscoelastic Behavior.

Composites of flexible and rigid polymers are ubiquitous in biology and industry alike, yet the physical principles determining their mechanical properties are far from understood. Here, we couple force spectroscopy with large-scale Brownian dynamics simulations to elucidate the unique viscoelastic properties of custom-engineered blends of entangled flexible DNA molecules and semiflexible actin filaments. We show that composites exhibit enhanced stress stiffening and prolonged mechanomemory compared to systems of actin or DNA alone, and that these nonlinear features display a surprising nonmonotonic dependence on the fraction of actin in the composite. Simulations reveal that these counterintuitive results arise from synergistic microscale interactions between the two biopolymers. Namely, DNA entropically drives actin filaments to form bundles that stiffen the network but reduce the entanglement density, while a uniform well-connected actin network is required to reinforce the DNA network against yielding and flow. The competition between bundling and connectivity triggers an unexpected stress response that leads equal mass DNA-actin composites to exhibit the most pronounced stress stiffening and the most long-lived entanglements.

MS2 Lysis of Escherichia coli Depends on Host Chaperone DnaJ.

The L protein of the single-stranded RNA phage MS2 causes lysis of Escherichia coli without inducing bacteriolytic activity or inhibiting net peptidoglycan (PG) synthesis. To find host genes required for L-mediated lysis, spontaneous Ill (insensitivity to Llysis) mutants were selected as survivors of L expression and shown to have a missense change of the highly conserved proline (P330Q) in the C-terminal domain of DnaJ. In the dnaJP330Q mutant host, L-mediated lysis is completely blocked at 30°C without affecting the intracellular levels of L. At higher temperatures (37°C and 42°C), both lysis and L accumulation are delayed. The lysis block at 30°C in the dnaJP330Q mutant was recessive and could be suppressed by Lovercomes dnaJ (Lodj ) alleles selected for restoration of lysis. All three Lodj alleles lack the highly basic N-terminal half of the lysis protein and cause lysis ∼20 min earlier than full-length L. DnaJ was found to form a complex with full-length L. This complex was abrogated by the P330Q mutation and was absent with the Lodj truncations. These results suggest that, in the absence of interaction with DnaJ, the N-terminal domain of L interferes with its ability to bind to its unknown target. The lysis retardation and DnaJ chaperone dependency conferred by the nonessential, highly basic N-terminal domain of L resembles the SlyD chaperone dependency conferred by the highly basic C-terminal domain of the E lysis protein of ϕX174, suggesting a common theme where single-gene lysis can be modulated by host factors influenced by physiological conditions.IMPORTANCE Small single-stranded nucleic acid lytic phages (Microviridae and Leviviridae) lyse their host by expressing a single "protein antibiotic." The protein antibiotics from two out of three prototypic small lytic viruses have been shown to inhibit two different steps in the conserved PG biosynthesis pathway. However, the molecular basis of lysis caused by L, the lysis protein of the third prototypic virus, MS2, is unknown. The significance of our research lies in the identification of DnaJ as a chaperone in the MS2 L lysis pathway and the identification of the minimal lytic domain of MS2 L. Additionally, our research highlights the importance of the highly conserved P330 residue in the C-terminal domain of DnaJ for specific protein interactions.