Nuclear ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program.

Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFß stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFß-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.

Uncovering the hidden effects of repetitive subconcussive head impact exposure: A mega-analytic approach characterizing seasonal brain microstructural changes in contact and collision sports athletes.

Repetitive subconcussive head impacts (RSHI) are believed to induce sub-clinical brain injuries, potentially resulting in cumulative, long-term brain alterations. This study explores patterns of longitudinal brain white matter changes across sports with RSHI-exposure. A systematic literature search identified 22 datasets with longitudinal diffusion magnetic resonance imaging data. Four datasets were centrally pooled to perform uniform quality control and data preprocessing. A total of 131 non-concussed active athletes (American football, rugby, ice hockey; mean age: 20.06 ± 2.06 years) with baseline and post-season data were included. Nonparametric permutation inference (one-sample t tests, one-sided) was applied to analyze the difference maps of multiple diffusion parameters. The analyses revealed widespread lateralized patterns of sports-season-related increases and decreases in mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) across spatially distinct white matter regions. Increases were shown across one MD-cluster (3195 voxels; mean change: 2.34%), one AD-cluster (5740 voxels; mean change: 1.75%), and three RD-clusters (817 total voxels; mean change: 3.11 to 4.70%). Decreases were shown across two MD-clusters (1637 total voxels; mean change: -1.43 to -1.48%), two RD-clusters (1240 total voxels; mean change: -1.92 to -1.93%), and one AD-cluster (724 voxels; mean change: -1.28%). The resulting pattern implies the presence of strain-induced injuries in central and brainstem regions, with comparatively milder physical exercise-induced effects across frontal and superior regions of the left hemisphere, which need further investigation. This article highlights key considerations that need to be addressed in future work to enhance our understanding of the nature of observed white matter changes, improve the comparability of findings across studies, and promote data pooling initiatives to allow more detailed investigations (e.g., exploring sex- and sport-specific effects).

Psychometric Properties of the Arabic Version of the Pain Resilience Scale among Lebanese Adults with Chronic Musculoskeletal Pain.

Background: The Pain Resilience Scale (PRS), which measures behavioral perseverance and the ability to regulate emotions and cognition despite ongoing pain, lacks an Arabic version. Objectives: This study aimed to translate, culturally adapt, and validate an Arabic version of the Pain Resilience Scale (PRS-A) among Lebanese adults. Methods: Phase 1 involved translation and cross-cultural adaptation of the PRS into Arabic. Phase 2 examined the reliability and validity of the PRS-A. A convenience sample of 154 Lebanese adults with chronic musculoskeletal pain completed the PRS-A and self-report measures of pain catastrophizing, pain self-efficacy, pain intensity and interference, depression and anxiety, and quality of life. Results: The PRS-A yielded a two-factor structure with factor 1 representing "cognitive/affective positivity" and factor 2 representing "behavioral perseverance," accounting for 41.93% and 15.15% of the variance in pain resilience, respectively. Total PRS-A score (M = 33.20 and SD = 9.90) showed significant correlations with pain catastrophizing (M = 27.65, SD = 13.03, and r = -0.52), pain self-efficacy (median = 9.00, IQR = 4, and rho = 0.61), pain intensity (M = 4.50, SD = 2.25, and r = -0.28), pain interference (M = 4.30, SD = 2.89, and r = -0.56), physical (M = 34.95, SD = 9.52, and r = 0.34) and mental (M = 40.08, SD = 12.49, and r = 0.58) health functioning, anxiety (median = 7.00, IQR = 7, and rho = -0.57), and depression (median = 4.00, IQR = 6, and rho = -0.58). PRS-A subscale was also significantly related to all measures except pain intensity, which was correlated with cognitive/affective positivity (r = -0.33) but not behavioral perseverance (r = -0.09). Cronbach's alpha for the PRS-A was 0.87. Conclusion: The PRS-A demonstrated validity and acceptable reliability among Arab-speaking individuals with chronic musculoskeletal pain, suggesting its potential utility for assessing pain resilience within this population.

Gun-free zones and active shootings in the United States: a matched case-control study.

Background: Most Americans believe that gun-free zones make locations more vulnerable to violent crimes, particularly active shootings. However, there is no empirical evidence regarding the impact of gun-free zones on protecting locations from violence. The objective of this study was to estimate the association between gun-free zones and active shootings. Methods: We used a pair-matched case-control study where cases were all US establishments where active shootings occurred between 2014 and 2020, and controls were randomly selected US establishments where active shootings could have but did not occur, pair-matched by establishment type, year, and county. Gun-free status of included establishments was determined via local laws, company policy, news reporting, Google Maps and posted signage, and calling establishments. Findings: Of 150 active shooting cases, 72 (48.0%) were determined to have occurred in a gun-free zone. Of 150 controls where no active shooting occurred, 92 (61.3%) were determined to be gun-free. After accounting for matched pairs, the conditional odds of an active shooting in gun-free establishments were 0.38 times those in non-gun-free establishments, with a 95% confidence interval of 0.19-0.73 (p-value = 0.0038). Several robustness analyses affirmed these findings. Interpretation: It is unlikely that gun-free zones attract active shooters; gun-free zones may be protective against active shootings. This study challenges the proposition of repealing gun-free zones based on safety concerns. Funding: This work was funded in part by the National Collaborative on Gun Violence Research and the Arnold Foundation.

Clinical characteristics and outcomes of adult alveolar rhabdomyosarcoma patients on first-line systemic therapies: A single-institution cohort.

Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.

Shirtsleeves to shirtsleeves in three research generations. A project on the science of science and the exceedingly rare circumstances that sustain research legacies from a mentor to mentee and to theirs: A case study on firearm research.

Background: In the 50 years since public health firearm research began, the decades have witnessed several pioneering investigators, followed by NRA backlash and a CDC funding moratorium, then increasing firearm mortality punctuated by mass shootings, and finally an unprecedented release of funding dedicated for research and to support trainees. Motivated by my own efforts to stay productive in firearm research, by the shirtsleeves-to-shirtsleeves cautionary lesson that wealth - for us this a researcher's funding, infrastructure, and capacity - amassed by one generation will soon diminish, and by my worry that we are not adequately dedicated to growing new investigators, I set out to document researcher lineages in this field. Methods: I created a multigenerational lineage map to find authors using "gun" or "firearm" in the title/abstract as a way to find peer-reviewed publications on firearms as a public health issue. I designated the first author as Gen1 if the manuscript was sole authored or the senior author had never been first author on a firearm publication. I plotted each Gen1 author at the year of their first first-authored publication, and pointed from them to subsequent "first-time first-author investigators" (Gen2) for whom they were senior author, and so on for a Gen2 serving as senior author for a Gen3, and so on in that lineage. Results: Gen1 authors numbered 91 by 2023, the first being Rushforth in 1974.3 Rushforth, 14 years later, produced the first and his only Gen2 author, Paulson,4 who produced no Gen3 authors. The field had produced 6 Gen2 authors when the first Gen3 author appeared in 1993, who produced the first Gen4 author in 1998, 14 years after Kraus5 that initiated that lineage in 1984. To date, only 5 lineages have produced a Gen4 author and among those only one lineage, from Schwab in 2002,6 has produced a Gen5. Twenty-four Gen3 authors have emerged. Only 35% of Gen2 authors produced a Gen3. Conclusion: I hope this motivates years-long strategies to help trainees become established, informed by modeling quantitative and qualitative data to identify characteristics underlying the investigator network related to productivity and shortcomings alike. Without dedication to understand the science of science, shirtsleeves-to-shirtsleeves in three generations may be the fate of firearm research.

Ecological roles and importance of sharks in the Anthropocene Ocean.

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.

Complications and Learning Curve Associated with an Imageless Burr-Based (CORI) Robotic-Assisted Total Knee Arthroplasty System: Results from First 500 Cases.

Background: The use of robotic-assisted total knee arthroplasty (RA-TKA) is gaining traction. There is evidence to suggest that RA-TKA can help to optimize the precision and accuracy of implant positioning and that there may be protective effects on surrounding bony and soft tissues. Yet, there are important differences between the various RA-TKA systems currently on the market. One such newly introduced RA-TKA system uses imageless technology and performs bony cuts with the use of a burr-based device. The learning curve and complications unique to this system have yet to be assessed. Methods: We evaluated 500 consecutive RA-TKA cases using a newly developed burr-based and imageless system which were done by a single surgeon between the months of October 2021 and February 2023. Operative times were recorded and compared to the previous 150 conventional TKA cases allowing for the learning curve to be calculated using the CUSUM method. Intraoperative and postoperative complications were categorically profiled. Results: The learning curve of this RA-TKA system was found to be 6 cases. Intraoperative complications included unintended bony over resection (n = 3), soft tissue injury (n = 2), and robotic system hardware (n = 2) or software (n = 2) malfunction. Postoperative complications consisted of superficial pin site infection (n = 1) and periprosthetic fracture near the pin sites (n = 1). There were no identified cases of prosthetic joint infection, instability events, or wound complications. Conclusions: The learning curve and the complication profile of a newly introduced imageless and burr-based RA-TKA system were described. This information serves to guide surgeons in adopting this technology and can counsel them regarding the potential pitfalls and challenges associated with its integration into practice. The work sheds light on the complexity and learning curve of the recently released imageless burr-based RA-TKA system. This important information is intended to help surgeons accept this cutting-edge technology by providing advice on any errors and difficulties that can occur when integrating it into clinical practice. This information can help surgeons navigate the complexities of integrating this new burr-based robotic technology into knee replacement procedures, enabling them to make well-informed decisions and receive guidance.

Coarse-Grained Simulation of mRNA-Loaded Lipid Nanoparticle Self-Assembly.

Ionizable lipid-containing lipid nanoparticles (LNPs) have enabled the delivery of RNA for a range of therapeutic applications. In order to optimize safe, targeted, and effective LNP-based RNA delivery platforms, an understanding of the role of composition and pH in their structural properties and self-assembly is crucial, yet there have been few computational studies of such phenomena. Here we present a coarse-grained model of ionizable lipid and mRNA-containing LNPs. Our model allows access to the large length- and time-scales necessary for LNP self-assembly and is mapped and parametrized with reference to all-atom structures and simulations of the corresponding components at compositions typical of LNPs used for mRNA delivery. Our simulations reveal insights into the dynamics of self-assembly of such mRNA-encapsulating LNPs, as well as the subsequent pH change-driven LNP morphology and release of mRNA.

CS-PHOC: weekly census counts of Southern Ocean phocids at Cape Shirreff, Livingston Island.

Rapid climatic warming of the Antarctic Peninsula is driving regional population declines and distribution shifts of predators and prey. Affected species include Antarctic ice seals and the southern elephant seal, all of which rely on the peninsula region for critical stages of their life cycle. However, data collection is difficult in this remote region, and therefore long-term time series with which to identify and investigate population trends in these species are rare. We present the Cape Shirreff Phocid Census (CS-PHOC) dataset: weekly counts of phocids (crabeater, leopard, southern elephant, and Weddell seals) hauled out at Cape Shirreff, Livingston Island, during most austral summers since 1997. Data from these censuses were cleaned and aggregated, resulting in robust and comparable count data from 284 censuses across 23 field seasons. The CS-PHOC dataset, which is publicly available through the SCAR Biodiversity Portal, will be updated yearly to provide important information about Southern Ocean phocids in the Antarctic Peninsula.

A simplified protocol for deriving sterile, infectious murine Heligmosomoides polygyrus bakeri larvae.

Gastrointestinal helminth infection occurs within a diverse microbiome, complicating the interpretation of whether effects are caused by the parasite versus the microbial community. Here, we present a protocol for deriving sterile larvae of the murine helminth, Heligmosomoides polygyrus bakeri (H. polygyrus), providing experimental control of the microbiome. We describe steps for sterilizing with a bleach solution and developing into infectious larvae using E. coli. We then detail procedures for removing bacterial contaminants before harvesting to ensure the generation of germ-free larvae.

Image-Derived Skeletal Muscle Activation Metric Map: a Forearm Study Using Ultra-Fast Ultrasound Imaging and High-Density Electromyography.

OBJECTIVE: Quantification of the skeletal muscle response can help better understand the fundamentals of the musculoskeletal system and can serve as a diagnostic measure or recovery assessment tool during rehabilitation for neurological injuries. Surface electromyography (EMG) is commonly used to measure muscle activity, but it is limited to detecting myoelectric signals without anatomy associated information. In this study, we proposed to use ultra-fast ultrasound imaging and introduced a new image analysis methodology to quantify a muscle's spatialtemporal mechanical response. METHODS: The methodology is based on analyzing the spatial-temporal change of the impulsive kinetic energy during the period of muscle contraction. The analysis can derive an anatomy-registered muscle activation metric map that localizes regions of muscle activation. To demonstrate this, we intentionally evoked regional muscle responses in five participants without disabilities by electrically stimulating the median nerve and individual forearm muscle groups, respectively. Both ultrasound images and high-density EMG (HD-EMG) data were recorded and processed. RESULTS: We presented the ultrasound image-derived activation localization from five participants and compared the results with HD-EMG measurements. CONCLUSION: The comparison indicates a good resemblance for describing muscle recruitment pattern. SIGNIFICANCE: The proposed methodology can potentially become an alternative or complementary approach to surface EMG for the study of skeletal muscle activation and for diagnosis and prognosis in clinical settings.

Improving Ocean Management Using Insights from Space.

Advancements in space-based ocean observation and computational data processing techniques have demonstrated transformative value for managing living resources, biodiversity, and ecosystems of the ocean. We synthesize advancements in leveraging satellite-derived insights to better understand and manage fishing, an emerging revolution of marine industrialization, ocean hazards, sea surface dynamics, benthic ecosystems, wildlife via electronic tracking, and direct observations of ocean megafauna. We consider how diverse space-based data sources can be better coupled to modernize and improve ocean management. We also highlight examples of how data from space can be developed into tools that can aid marine decision-makers managing subjects from whales to algae. Thoughtful and prospective engagement with such technologies from those inside and outside the marine remote sensing community is, however, essential to ensure that these tools meet their full potential to strengthen the effectiveness of ocean management.

Association between e-scooter temporal usage patterns with injuries resulting in admission to a level one trauma center.

BACKGROUND: As e-scooters have become common modes of transportations in urban environments, riding e-scooters has become a common mechanism of injury. This study examines the relationship between when riders are using these devices (i.e. day of week, and time of the day) and injury incidence based on data from a large U.S. city. METHODS: This study is a retrospective cohort study of patients in the trauma registry at a level one trauma center. Registry data were combined with a publicly available dataset of all e-scooter trips that occurred during the study period. Frequency of injuries and trips were analyzed using ANOVA. Poisson regressions were conducted to calculate incidence rate ratios associated with injury incidence by day of the week and time of day. RESULTS: A total of 194 injured e-scooter patients were admitted to the trauma center during the study period. Patients were injured most often on Fridays (21%) and most often presented between 18:00-23:59 (38%). E-Scooter riders in general, most often rode on Saturdays (20%) and between 12:00-17:59 (44%). There was no significant relationship between day of week and injury. Riders in the early morning (IRR = 16.7, p < .001 95% CI: 10.5, 26.6), afternoon (IRR = 2.0, p = .01 95% CI: 1.2, 3.4), and evening (IRR = 3.7, p < .001 95% CI: 2.3, 6.2) had significant increased injury incidence compared to morning riders. CONCLUSION: E-Scooter injury incidence varies by the time of day. The time of day in which a person rides an e-scooter can have a significant impact on the likelihood that the person will sustain an injury.

Exertional Heat Stroke Best Practices in U.S. Emergency Medical Services Guidelines.

BACKGROUND: Exertional heat illnesses (EHIs), specifically exertional heat stroke (EHS), are a top cause of nonaccidental death among U.S. laborers. EHS management requires coordination between Emergency Medical Services (EMS) and workplace officials to implement cold water immersion (CWI) and cool first, transport second (CFTS). OBJECTIVE: The purpose of this article was to quantify and identify existing statewide EMS guidelines, determine whether statewide EHS guidelines improved outcomes for EHIs in laborers, and examine the odds of laborer EHS fatalities when best practices are present in EMS statewide guidelines. METHODS: The Paramedic Protocol Provider database and official EMS websites were examined to determine which U.S. states had statewide EMS guidelines and, for those with statewide guidelines, a two-way χ2 analysis with associated odds ratios examined EHI outcomes. Statewide EMS guidelines underwent content analysis by three independent reviewers regarding EHS best practices. Significance was set a priori at p < 0.05. RESULTS: Among 50 states, the District of Columbia, and Puerto Rico, 57.7% (n = 30) had statewide EMS guidelines and 42.3% (n = 22) did not. There was a significant association for EHI outcome for states recommending CWI as a cooling method vs. those that did not (χ21 = 3.336; p = 0.049). The odds of EHS deaths for laborers were 3.0 times higher if CWI was not included in the EMS guidelines. There was a significant association in EHI outcomes for states without CFTS (χ21 = 5.051; p = 0.017). The odds of laborers dying from EHS were 3.7 times higher in states without CFTS. CONCLUSIONS: Laborers are 3.0 and 3.7 times less likely to die from EHS when statewide EMS guidelines include CWI and CFTS, respectively.

Regulation of Rubisco activity by interaction with chloroplast metabolites.

Rubisco activity is highly regulated and frequently limits carbon assimilation in crop plants. In the chloroplast, various metabolites can inhibit or modulate Rubisco activity by binding to its catalytic or allosteric sites, but this regulation is complex and still poorly understood. Using rice Rubisco, we characterised the impact of various chloroplast metabolites which could interact with Rubisco and modulate its activity, including photorespiratory intermediates, carbohydrates, amino acids; as well as specific sugar-phosphates known to inhibit Rubisco activity - CABP (2-carboxy-d-arabinitol 1,5-bisphosphate) and CA1P (2-carboxy-d-arabinitol 1-phosphate) through in vitro enzymatic assays and molecular docking analysis. Most metabolites did not directly affect Rubisco in vitro activity under both saturating and limiting concentrations of Rubisco substrates, CO2 and RuBP (ribulose-1,5-bisphosphate). As expected, Rubisco activity was strongly inhibited in the presence of CABP and CA1P. High physiologically relevant concentrations of the carboxylation product 3-PGA (3-phosphoglyceric acid) decreased Rubisco activity by up to 30%. High concentrations of the photosynthetically derived hexose phosphates fructose 6-phosphate (F6P) and glucose 6-phosphate (G6P) slightly reduced Rubisco activity under limiting CO2 and RuBP concentrations. Biochemical measurements of the apparent Vmax and Km for CO2 and RuBP (at atmospheric O2 concentration) and docking interactions analysis suggest that CABP/CA1P and 3-PGA inhibit Rubisco activity by binding tightly and loosely, respectively, to its catalytic sites (i.e. competing with the substrate RuBP). These findings will aid the design and biochemical modelling of new strategies to improve the regulation of Rubisco activity and enhance the efficiency and sustainability of carbon assimilation in rice.

Impaired pain in mice lacking first-order posterior medial thalamic neurons.

ABSTRACT: The thalamus plays an important role in sensory and motor information processing by mediating communication between the periphery and the cerebral cortex. Alterations in thalamic development have profound consequences on sensory and motor function. In this study, we investigated a mouse model in which thalamic nuclei formation is disrupted because of the absence of Sonic hedgehog (Shh) expression from 2 key signaling centers that are required for embryonic forebrain development. The resulting defects observed in distinct thalamic sensory nuclei in Shh mutant embryos persisted into adulthood prompting us to examine their effect on behavioral responses to somatosensory stimulation. Our findings reveal a role for first-order posterior medial thalamic neurons and their projections to layer 4 of the secondary somatosensory cortex in the transmission of nociceptive information. Together, these results establish a connection between a neurodevelopmental lesion in the thalamus and a modality-specific disruption in pain perception.