Changes in Brain Activity Immediately Post-Exercise Indicate a Role for Central Fatigue in the Volitional Termination of Exercise.

Electroencephalography (EEG) allows for the evaluation of real time changes in brain (electrocortical) activity during exercise. A few studies have examined changes in electrocortical activity using stationary cycling, but the findings have been mixed. Some of these studies have found increases in brain activity following exercise, while others have found decreases in brain activity following exercise. Hence, it is of importance to identify post-exercise changes in brain activity. Sixteen healthy, untrained subjects (8 males; 8 females) participated in the study. All 16 participants performed a graded exercise test (GXT) to volitional exhaustion on an upright cycle ergometer. Continuous EEG recordings were sampled before (PRE) and immediately following (IP) the GXT. Regions of interest were primarily the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and left and right motor cortex (MC). In the DLPFC, a frontal asymmetry index was also identified. There was a statistically significant increase in theta power in the DLPFC, VLPFC, and left and right MC from PRE to IP (all p < 0.05). There was also a shift towards right hemisphere asymmetry at the IP time point in the DLPFC (p < 0.05). Finally, there was an increase in alpha power from PRE to IP in the right MC (p < 0.05). EEG could prove to be an important way to measure the effects of central fatigue on brain activity before and immediately following exercise.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice. CAR-MSCs led to superior T-cell suppression and localization to E-cadherin+ colonic cells, ameliorating the animals' symptoms and survival rates. On antigen-specific stimulation, CAR-MSCs upregulated the expression of immunosuppressive genes and receptors for T-cell inhibition as well as the production of immunosuppressive cytokines while maintaining their stem cell phenotype and safety profile in the animal models. CAR-MSCs may represent a widely applicable therapeutic technology for enhancing immunosuppression.

How old do I look? Aging appearance and experiences of aging among U.S. adults ages 50-80.

Appearance is an indicator of age and life stage, which are linked to socially salient stereotypes and prejudices. Older adults' appearance-related perceptions and behaviors may affect their experiences of aging within broader society, which may in turn influence health. This study examined associations between two measures related to aging appearance-assessment of one's aging appearance relative to same-age peers and investing time or effort to look younger-positive and negative experiences of aging, and health using multivariable regression. Cross-sectional data were from a nationally representative sample of 2006 U.S. adults ages 50-80 (Mage = 63, 52% women, 71% White) who completed Wave 6 of the National Poll on Healthy Aging in 2019. The majority (59%) reported appearing relatively younger than peers, while fewer reported appearing the same age (35%) or older (6%). About a third (35%) reported investing in looking younger. Appearing relatively younger was associated with more positive (p < .001) and less negative experiences of aging (p = .019). Appearing relatively older showed the opposite relationships (p values < .001). Investing in looking younger was associated with more positive and more negative experiences of aging (p values < .001). Few sociodemographic variations were detected. More positive and less negative experiences of aging were associated with better physical and mental health (p values < .001). While aging appearance is often the basis for jokes, it may affect the quality of older adults' experiences of aging and associated health outcomes. Nuanced findings caution against framing youthful biases in aging appearance and investments in looking younger as solely negative (or positive). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Ankle dorsiflexion asymmetry and the relationship with walking performance in people with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neurological disease characterized by demyelination disrupting the central nervous system. Persons with MS may exhibit symptomatic strength asymmetry (SA) that impacts motor gait and ankle mobility. The purpose of the present study was to investigate ankle dorsiflexion SA in people with MS and its relationship to functional performance. RESEARCH QUESTION: Is their a difference in dorsiflexion SA in MS participants compared to healthy individuals and does it impact functional performance? METHODS: 13 MS participants (EDSS 3.5 + 1.8) and 13 age matched NON-MS participants underwent maximal isometric (MVC) dynamometry testing for ankle dorsiflexion in both limbs to determine SA. Participants performed three functional tasks of walking performance. RESULTS: There was a significant intra-limb MVC difference in the MS group, and significantly greater isometric SA (p < 0.007) and isokinetic SA (p < 0.04) in the MS group compared to healthy individuals. The MS group exhibited significant correlations between outcomes of functional walking performance with isokinetic but not isometric SA. There was no significant correlation between disability status and functional task performance. SIGNIFICANCE: Ankle dorsiflexion SA is negatively correlated with functional performance in MS participants. MS disability status was not a predictor of functional task performance, and symptom testing may be appropriate to assess walking ability in persons with MS.

HiTIPS: High-Throughput Image Processing Software for the Study of Nuclear Architecture and Gene Expression.

High-throughput imaging (HTI) generates complex imaging datasets from a large number of experimental perturbations. Commercial HTI software for image analysis workflows does not allow full customization and adoption of new image processing algorithms in the analysis modules. While open-source HTI analysis platforms provide individual modules in the workflow, like nuclei segmentation, spot detection, or cell tracking, they are often limited in integrating novel analysis modules or algorithms. Here, we introduce the High-Throughput Image Processing Software (HiTIPS) to expand the range and customization of existing HTI analysis capabilities. HiTIPS incorporates advanced image processing and machine learning algorithms for automated cell and nuclei segmentation, spot signal detection, nucleus tracking, spot tracking, and quantification of spot signal intensity. Furthermore, HiTIPS features a graphical user interface that is open to integration of new algorithms for existing analysis pipelines and to adding new analysis pipelines through separate plugins. To demonstrate the utility of HiTIPS, we present three examples of image analysis workflows for high-throughput DNA FISH, immunofluorescence (IF), and live-cell imaging of transcription in single cells. Altogether, we demonstrate that HiTIPS is a user-friendly, flexible, and open-source HTI analysis platform for a variety of cell biology applications.

Modulating the Electrochemical Intercalation of Graphene Interfaces with α-RuCl3 as a Solid-State Electron Acceptor.

Intercalation reactions modify the charge density in van der Waals (vdW) materials through coupled electronic-ionic charge accumulation and are susceptible to modulation by interlayer hybridization in vdW heterostructures. Here, we demonstrate that charge transfer between graphene and α-RuCl3, which hole-dopes the graphene, greatly favors the intercalation of lithium ions into graphene-based vdW heterostructures. We systematically tune this effect on Li+ ion intercalation, modulating the intercalation potential, by using varying thicknesses of hexagonal boron nitride (hBN) as spacer layers between graphene and α-RuCl3. Confocal Raman spectroscopy and electronic transport measurements are used to monitor electrochemical intercalation, and density functional theory computations help quantify charge transfer to both α-RuCl3 and graphene upon Li intercalation. This work demonstrates a versatile approach for systematically modulating the electrochemical intercalation behavior of two-dimensional layers akin to electron donating/withdrawing substituent effects used to tune molecular redox potentials.

T-cell phenotype including CD57+ T follicular helper cells in the tumor microenvironment correlate with a poor outcome in follicular lymphoma.

T-lymphocytes are prevalent in the tumor microenvironment of follicular lymphoma (FL). However, the phenotype of T-cells may vary, and the prevalence of certain T-cell subsets may influence tumor biology and patient survival. We therefore analyzed a cohort of 82 FL patients using CyTOF to determine whether specific T-cell phenotypes were associated with distinct tumor microenvironments and patient outcome. We identified four immune subgroups with differing T-cell phenotypes and the prevalence of certain T-cell subsets was associated with patient survival. Patients with increased T cells with early differentiation stage tended to have a significantly better survival than patients with increased T-cells of late differentiation stage. Specifically, CD57+ TFH cells, with a late-stage differentiation phenotype, were significantly more abundant in FL patients who had early disease progression and therefore correlated with an inferior survival. Single cell analysis (CITE-seq) revealed that CD57+ TFH cells exhibited a substantially different transcriptome from CD57- TFH cells with upregulation of inflammatory pathways, evidence of immune exhaustion and susceptibility to apoptosis. Taken together, our results show that different tumor microenvironments among FL patients are associated with variable T-cell phenotypes and an increased prevalence of CD57+ TFH cells is associated with poor patient survival.

Richter Transformation of Chronic Lymphocytic Leukemia-Are We Making Progress?

PURPOSE OF REVIEW: The treatment paradigm of chronic lymphocytic leukemia (CLL) has dramatically changed with the advent of novel targeted agents over the past decade. Richter transformation (RT), or the development of an aggressive lymphoma from a background of CLL, is a well-recognized complication of CLL and carries significantly poor clinical outcomes. Here, we provide an update on current diagnostics, prognostication, and contemporary treatment of RT. RECENT FINDINGS: Several genetic, biologic, and laboratory markers have been proposed as candidate risk factors for the development of RT. Although a diagnosis of RT is typically suspected based on clinical and laboratory findings, tissue biopsy is essential for histopathologic confirmation of diagnosis. The standard of care for RT treatment at this time remains chemoimmunotherapy with the goal of proceeding to allogeneic stem cell transplantation in eligible patients. Several newer treatment modalities are being studied for use in the management of RT, including small molecules, immunotherapy, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy. The management of patients with RT remains a challenge. Ongoing trials show enormous promise for newer classes of therapy in RT, with the hope being that these agents can synergize, and perhaps supersede, the current standard of care in the near future.

Cerebral blood flow dynamics: Is there more to the story at exercise onset?

A monoexponential model characterizing cerebral blood velocity dynamics at the onset of exercise may mask dynamic responses by the cerebrovasculature countering large fluctuations of middle cerebral artery blood velocity (MCAv) and cerebral perfusion pressure (CPP) oscillations. Therefore, the purpose of this study was to determine whether the use of a monoexponential model attributes initial fluctuations of MCAv at the start of exercise as a time delay (TD). Twenty-three adults (10 women, 23.9 ± 3.3 yrs; 23.7 ± 2.4 kg/m2 ) completed 2 min of rest followed by 3 mins of recumbent cycling at 50 W. MCAv, CPP, and Cerebrovascular Conductance index (CVCi), calculated as CVCi = MCAv/MAP × 100 mmHg, were collected, a lowpass filter (0.2 Hz) was applied, and averaged into 3-second bins. MCAv data were then fit to a monoexponential model [ΔMCAv(t) = Amp(1 - e-(t-TD)/τ )]. TD, tau (τ), and mean response time (MRT = TD + τ) were obtained from the model. Subjects exhibited a TD of 20.2 ± 18.1 s. TD was directly correlated with MCAv nadir (MCAvN ), r = -0.560, p = 0.007, which occurred at similar times (16.5 ± 15.3 vs. 20.2 ± 18.1 s, p = 0.967). Regressions indicated CPP as the strongest predictor of MCAvN ( R a 2 $$ {R}_a^2 $$ = 0.36). Fluctuations in MCAv were masked using a monoexponential model. To adequately understand cerebrovascular mechanisms during the transition from rest to exercise, CPP and CVCi must also be analyzed. A concurrent drop in cerebral perfusion pressure and middle cerebral artery blood velocity at the start of exercise forces the cerebrovasculature to respond to maintain cerebral blood flow. The use of a monoexponential model characterizes this initial phase as a time delay and masks this large important response.

Characterization of immune exhaustion and suppression in the tumor microenvironment of splenic marginal zone lymphoma.

The role of the tumor microenvironment (TME) and intratumoral T cells in splenic marginal zone lymphoma (sMZL) is largely unknown. In the present study, we evaluated 36 sMZL spleen specimens by single cell analysis to gain a better understanding of the TME in sMZL. Using mass cytometry (CyTOF), we observed that the TME in sMZL is distinct from that of control non-malignant reactive spleen (rSP). We found that the number of TFH cells varied greatly in sMZL, ICOS+ TFH cells were more abundant in sMZL than rSP, and TFH cells positively correlated with increased numbers of memory B cells. Treg cell analysis revealed that TIGIT+ Treg cells are enriched in sMZL and correlate with suppression of TH17 and TH22 cells. Intratumoral CD8+ T cells were comprised of subsets of short-lived, exhausted and late-stage differentiated cells, thereby functionally impaired. We observed that T-cell exhaustion was present in sMZL and TIM-3 expression on PD-1low cells identified cells with severe immune dysfunction. Gene expression profiling by CITE-seq analysis validated this finding. Taken together, our data suggest that the TME as a whole, and T-cell population specifically, are heterogenous in sMZL and immune exhaustion is one of the major factors impairing T-cell function.

Post-transcriptional polyadenylation site cleavage maintains 3'-end processing upon DNA damage.

The recognition of polyadenylation signals (PAS) in eukaryotic pre-mRNAs is usually coupled to transcription termination, occurring while pre-mRNA is chromatin-bound. However, for some pre-mRNAs, this 3'-end processing occurs post-transcriptionally, i.e., through a co-transcriptional cleavage (CoTC) event downstream of the PAS, leading to chromatin release and subsequent PAS cleavage in the nucleoplasm. While DNA-damaging agents trigger the shutdown of co-transcriptional chromatin-associated 3'-end processing, specific compensatory mechanisms exist to ensure efficient 3'-end processing for certain pre-mRNAs, including those that encode proteins involved in the DNA damage response, such as the tumor suppressor p53. We show that cleavage at the p53 polyadenylation site occurs in part post-transcriptionally following a co-transcriptional cleavage event. Cells with an engineered deletion of the p53 CoTC site exhibit impaired p53 3'-end processing, decreased mRNA and protein levels of p53 and its transcriptional target p21, and altered cell cycle progression upon UV-induced DNA damage. Using a transcriptome-wide analysis of PAS cleavage, we identify additional pre-mRNAs whose PAS cleavage is maintained in response to UV irradiation and occurring post-transcriptionally. These findings indicate that CoTC-type cleavage of pre-mRNAs, followed by PAS cleavage in the nucleoplasm, allows certain pre-mRNAs to escape 3'-end processing inhibition in response to UV-induced DNA damage.

Synthetic analysis of chromatin tracing and live-cell imaging indicates pervasive spatial coupling between genes.

The role of the spatial organization of chromosomes in directing transcription remains an outstanding question in gene regulation. Here, we analyze two recent single-cell imaging methodologies applied across hundreds of genes to systematically analyze the contribution of chromosome conformation to transcriptional regulation. Those methodologies are (1) single-cell chromatin tracing with super-resolution imaging in fixed cells; and (2) high-throughput labeling and imaging of nascent RNA in living cells. Specifically, we determine the contribution of physical distance to the coordination of transcriptional bursts. We find that individual genes adopt a constrained conformation and reposition toward the centroid of the surrounding chromatin upon activation. Leveraging the variability in distance inherent in single-cell imaging, we show that physical distance - but not genomic distance - between genes on individual chromosomes is the major factor driving co-bursting. By combining this analysis with live-cell imaging, we arrive at a corrected transcriptional correlation of [Formula: see text] for genes separated by < 400 nm. We propose that this surprisingly large correlation represents a physical property of human chromosomes and establishes a benchmark for future experimental studies.

Burkitt Lymphoma Presenting as Ileocolic Intussusception in an Adult.

Adult intussusception is rare, highly associated with a malignant lead point, and often requires emergent surgical management. We report the case of a 44-year-old male who presented with generalized abdominal pain and was found to have early ileocolic intussusception secondary to a large ileocecal mass. Biopsies of the mass and an enlarged cardiophrenic lymph node, as well as pleural fluid cytology were all consistent with Burkitt lymphoma (BL). Curiously, the patient's abdominal exam was reassuring, and the intussusception and malignant bowel obstruction resolved over 36 hours with conservative management alone. With a Burkitt lymphoma international prognostic index (BL-IPI) score of 2, the patient proceeded to treatment with combination chemoimmunotherapy and attained a complete response after four cycles. There was no bowel perforation or recurrent intussusception throughout treatment. Thus, this report marks the first reported case of adult BL-associated intussusception to resolve with non-invasive management and establishes a precedent for conservative management in select patients.

Modulation Doping of Single-Layer Semiconductors for Improved Contact at Metal Interfaces.

Single layers of two-dimensional (2D) materials hold the promise for further miniaturization of semiconductor electronic devices. However, the metal-semiconductor contact resistance limits device performance. To mitigate this problem, we propose modulation doping, specifically a doping layer placed on the opposite side of a metal-semiconductor interface. Using first-principles calculations to obtain the band alignment, we show that the Schottky barrier height and, consequently, the contact resistance at the metal-semiconductor interface can be reduced by modulation doping. We demonstrate the feasibility of this approach for a single-layer tungsten diselenide (WSe2) channel and 2D MXene modulation doping layers, interfaced with several different metal contacts. Our results indicate that the Fermi level of the metal can be shifted across the entire band gap. This approach can be straight-forwardly generalized for other 2D semiconductors and a wide variety of doping layers.

Can Clinician-Stabilization with Hand-Held Dynamometry Yield a Reliable Measure of Knee Flexion Torque?

Background: Assessment of knee flexion torque is a relevant clinical measure following various injuries and surgeries to determine progress in rehabilitation and inform decision making. A variety of methods using hand-held dynamometry have been shown to be reliable in obtaining this measure, and typically require a means of external fixation or stabilization. Clinically efficient methods of reliable clinician-stabilization are sparse in the literature. Hypothesis/Purpose: Determine inter and intra-rater reliability of two clinically efficient methods of assessing isometric knee flexion torque using hand-held dynamometry with clinician-stabilization. The hypothesis was that each method would yield good to excellent reliability. Study Design: Cross-Sectional Study. Methods: Twenty healthy individuals were assessed by two clinicians on two separate days. During each session, knee flexion torque was assessed with hand-held dynamometry with two methods: 1) in the seated position with the hip and knee flexed to 90 degrees while the clinician stabilized the dynamometer between the participant's leg and table and 2) in prone with the hip at 0 degrees and knee at 90 degrees while the clinician assumed a stride stance with elbows locked in extension to stabilize the dynamometer on the participant's leg. Inter and intra-rater reliability were determined for each method. Results: ICC values were 0.88-0.94 and 0.77-0.90 for inter and intra-rater reliability respectively with the seated method. The prone method yielded ICC values of 0.84-0.96 and 0.89-0.94 for inter and intra-rater reliability respectively. MDC values ranged from 30-62% with the seated method and 21-40% with the prone method. Conclusion: Inter and intra-rater reliability were good to excellent for assessing knee flexion torque with hand-held dynamometry using both the seated and prone methods with clinically efficient clinician-stabilization approaches. The prone method may be more sensitive to detecting change over time due to lower MDC values. Level of Evidence: 2b.

Disseminated histoplasmosis and hemophagocytic lymphohistiocytosis in a patient receiving TNF-alpha inhibitor therapy.

Histoplasmosis commonly presents as an asymptomatic or self-limited infection in immunocompetent patients, but immunocompromised hosts may present with severe and disseminated disease. Herein, we present a 26-year-old male with history of ulcerative colitis receiving long-term TNF-alpha inhibitor therapy who presented with six months of diarrhea and recently fever and hematochezia. On admission, he was febrile and hypotensive, with initial workup revealing pancytopenia and imaging reporting pulmonary infiltrates, pancolitis, and enlarged mesenteric lymph nodes. Disseminated histoplasmosis was ultimately diagnosed after examination of the colonic biopsy. Bone marrow biopsy was also consistent with the diagnosis of histoplasmosis but also demonstrated hemophagocytic lymphohistiocytosis. The patient was ultimately treated with amphotericin B, intravenous immunoglobulin, etoposide, and corticosteroids.

Antisense transcription from lentiviral gene targeting linked to an integrated stress response in colorectal cancer cells.

Advances in gene therapy research have resulted in the successful development of new therapies for clinical use. Here, we explored a gene targeting approach to deplete ephrinB2 from colorectal cancer cells using an inducible lentiviral vector. EphrinB2, a transmembrane ephrin ligand, promotes colorectal cancer cell growth and viability and predicts poor patient survival when expressed at high levels in colorectal cancer tissues. We discovered that lentiviral vector integration and expression in the host DNA frequently drive divergent host gene transcription, generating antisense reads coupled with splicing events and generation of chimeric vector/host transcripts. Antisense transcription of host DNA was linked to development of an integrated stress response and cell death. Despite recent successes, off-target effects remain a concern in genetic medicine. Our results provide evidence that divergent gene transcription is a previously unrecognized off-target effect of lentiviral vector integration with built-in properties for regulation of gene expression.

Regulating gene expression through control of transcription factor multivalent interactions.

Chong et al. (2022) show how the propensity of transcription factors (TFs) to associate into hubs must be finely regulated for optimal transcription.

A Multi-Systems Approach to Human Movement after ACL Reconstruction: The Musculoskeletal System.

Several negative adaptations to the musculoskeletal system occur following anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR) such as arthrogenic muscle inhibition, decreased lower extremity muscle size, strength, power, as well as alterations to bone and cartilage. These changes have been associated with worse functional outcomes, altered biomechanics, and increased risk for re-injury and post-traumatic osteoarthritis. After ACL injury and subsequent ACLR, examination and evaluation of the musculoskeletal system is paramount to guiding clinical decision making during the rehabilitation and the return to sport process. The lack of access many clinicians have to devices necessary for gold standard assessment of muscle capacities and force profiles is often perceived as a significant barrier to best practices. Fortunately, testing for deficits can be accomplished with methods available to the clinician without access to costly equipment or time-intensive procedures. Interventions to address musculoskeletal system deficits can be implemented with a periodized program. This allows for restoration of physical capacities by adequately developing and emphasizing physical qualities beginning with mobility and movement, and progressing to work capacity and neuromuscular re-education, strength, explosive strength, and elastic or reactive strength. Additional considerations to aid in addressing strength deficits will be discussed such as neuromuscular electrical stimulation, volume and intensity, eccentric training, training to failure, cross-education, and biomechanical considerations. The American Physical Therapy Association adopted a new vision statement in 2013 which supported further development of the profession's identity by promoting the movement system, yet validation of the movement system has remained a challenge. Application of a multi-physiologic systems approach may offer a unique understanding of the musculoskeletal system and its integration with other body systems after ACLR. The purpose of this clinical commentary is to highlight important musculoskeletal system considerations within a multi-physiologic system approach to human movement following ACLR. LEVEL OF EVIDENCE: 5.

Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.