Gα13 restricts nutrient driven proliferation in mucosal germinal centers.

Germinal centers (GCs) that form in mucosal sites are exposed to gut-derived factors that have the potential to influence homeostasis independent of antigen receptor-driven selective processes. The G-protein Gα13 confines B cells to the GC and limits the development of GC-derived lymphoma. We discovered that Gα13-deficiency fuels the GC reaction via increased mTORC1 signaling and Myc protein expression specifically in the mesenteric lymph node (mLN). The competitive advantage of Gα13-deficient GC B cells (GCBs) in mLN was not dependent on T cell help or gut microbiota. Instead, Gα13-deficient GCBs were selectively dependent on dietary nutrients likely due to greater access to gut lymphatics. Specifically, we found that diet-derived glutamine supported proliferation and Myc expression in Gα13-deficient GCBs in the mLN. Thus, GC confinement limits the effects of dietary glutamine on GC dynamics in mucosal tissues. Gα13 pathway mutations coopt these processes to promote the gut tropism of aggressive lymphoma.

Dual circuits originating from the ventral hippocampus independently facilitate affective empathy.

Affective empathy enables social mammals to learn and transfer emotion to conspecifics, but an understanding of the neural circuitry and genetics underlying affective empathy is still very limited. Here, using the naive observational fear between cagemates as a paradigm similar to human affective empathy and chemo/optogenetic neuroactivity manipulation in mouse brain, we investigate the roles of multiple brain regions in mouse affective empathy. Remarkably, two neural circuits originating from the ventral hippocampus, previously unknown to function in empathy, are revealed to regulate naive observational fear. One is from ventral hippocampal pyramidal neurons to lateral septum GABAergic neurons, and the other is from ventral hippocampus pyramidal neurons to nucleus accumbens dopamine-receptor-expressing neurons. Furthermore, we identify the naive observational-fear-encoding neurons in the ventral hippocampus. Our findings highlight the potentially diverse regulatory pathways of empathy in social animals, shedding light on the mechanisms underlying empathy circuity and its disorders.

The application of functional imaging in visual field defects: a brief review.

Visual field defects (VFDs) represent a prevalent complication stemming from neurological and ophthalmic conditions. A range of factors, including tumors, brain surgery, glaucoma, and other disorders, can induce varying degrees of VFDs, significantly impacting patients' quality of life. Over recent decades, functional imaging has emerged as a pivotal field, employing imaging technology to illustrate functional changes within tissues and organs. As functional imaging continues to advance, its integration into various clinical aspects of VFDs has substantially enhanced the diagnostic, therapeutic, and management capabilities of healthcare professionals. Notably, prominent imaging techniques such as DTI, OCT, and MRI have garnered widespread adoption, yet they possess unique applications and considerations. This comprehensive review aims to meticulously examine the application and evolution of functional imaging in the context of VFDs. Our objective is to furnish neurologists and ophthalmologists with a systematic and comprehensive comprehension of this critical subject matter.

Neuroligin 2 governs synaptic morphology and function through RACK1-cofilin signaling in Drosophila.

Neuroligins are transmembrane cell adhesion proteins well-known for their genetic links to autism spectrum disorders. Neuroligins can function by regulating the actin cytoskeleton, however the factors and mechanisms involved are still largely unknown. Here, using the Drosophila neuromuscular junction as a model, we reveal that F-Actin assembly at the Drosophila NMJ is controlled through Cofilin signaling mediated by an interaction between DNlg2 and RACK1, factors not previously known to work together. The deletion of DNlg2 displays disrupted RACK1-Cofilin signaling pathway with diminished actin cytoskeleton proteo-stasis at the terminal of the NMJ, aberrant NMJ structure, reduced synaptic transmission, and abnormal locomotion at the third-instar larval stage. Overexpression of wildtype and activated Cofilin in muscles are sufficient to rescue the morphological and physiological defects in dnlg2 mutants, while inactivated Cofilin is not. Since the DNlg2 paralog DNlg1 is known to regulate F-actin assembly mainly via a specific interaction with WAVE complex, our present work suggests that the orchestration of F-actin by Neuroligins is a diverse and complex process critical for neural connectivity.

A new AAV tool for highly preferentially targeting hippocampal CA2.

Mice hippocampus contains three prominent subregions, CA1, CA3 and DG and is well regarded as an essential multiple task processor for learning, memory and cognition based on tremendous studies on these three subregions. The narrow region sandwiched between CA1 and CA3 called CA2 has been neglected for a long time. But it raises great attentions recently since this region manifests the indispensable role in social memory. Its unique physical position connecting CA1 and CA3 suggests the potential novel functions besides social memory regulation. But the CA2 is too small to be accurately targeted. A flexible AAV tool capable of accurately and efficiently targeting this region is highly demanded. To fill this gap, we generate an AAV expressing Cre driven by the mini Map3k15 promoter, AAV/M1-Cre, which can be easily utilized to help tracing and manipulating CA2 pyramidal neurons. However, M1-Cre labeled a small percentage of M1+RGS14- neurons that do not colocalize with any RGS14+/STEP+/PEP4+/Amigo2+ pyramidal neurons. They are proved to be the mixture of normal CA2 pyramidal neurons, CA3-like neurons in CA2-CA3 mixed border, some CA2 interneurons and rarely few CA1-like neurons, which are probably the ones projecting to the revealed CA2 downstream targets, VMH, STHY and PMV in WT mice injecting this AAV/M1-Cre virus but not in Amigo2-Cre mice. Though it is still challenging to get a pure CA2 tracking and manipulation system, this tool provides a new, more flexible and extended strategy for in-depth CA2 functional study in the future.

Bibliometric Analysis of Post-Stroke Pain Research Published from 2012 to 2021.

Background and Purpose: Pain is one of the most common symptoms in patients after stroke. It is a distressing experience that affects patients' quality of life, and it is highly prevalent in clinical practice. The pathogenesis mechanisms of PSP are not so clear, and there is currently a lack of effective medical treatments, hence it is necessary to establish a sufficient understanding of this disease. Limited number of studies have applied bibliometric methods to systematically analyze studies on post-stroke pain. This study aimed to systematically analyze scientific studies conducted worldwide on post-stroke pain from 2012 to 2021 to evaluate global trends in this field using a bibliometric analysis. Methods: Publications related to post-stroke pain from 2012 to 2021 were obtained from the Web of Science Core Collection database. Bibliometrics Biblioshiny R-package software was used to analyze the relationship of publication year with country, institution, journals, authors, and keywords and to generate variant visual maps to show annual publications, most relevant countries, authors, sources, keywords, and top-cited articles. Results: In this study, 5484 papers met the inclusion criteria. The annual growth rate of publications was 5.13%. The USA had the highest number of publications (1381, 25.2%) and citations (36,395), and the University of Toronto had the highest number of papers (156, 2.8%). "Stroke", "management", "pain", "risk", "prevalence", "ischemic stroke", "risk factors", "disease", "diagnosis" and "therapy" are the top 10 keywords. Conclusion: The global research interest regarding PSP has maintained growing over the past ten years. Both central post stroke pain and hemiplegic shoulder pain are the hottest research subjects. Further investigations are needed in order to reveal the mystery of the pathophysiologic mechanisms of CPSP, and high-quality well-designed trials of potential treatments of CPSP and HSP are also needed.

Aberrant expansion of spontaneous splenic germinal centers induced by hallmark genetic lesions of aggressive lymphoma.

Unique molecular vulnerabilities have been identified in the aggressive MCD/C5 genetic subclass of diffuse large B-cell lymphoma (DLBCL). However, the premalignant cell-of-origin exhibiting MCD-like dependencies remains elusive. In this study, we examined animals carrying up to 4 hallmark genetic lesions found in MCD consisting of gain-of-function mutations in Myd88 and Cd79b, loss of Prdm1, and overexpression of BCL2. We discovered that expression of combinations of these alleles in vivo promoted a cell-intrinsic accumulation of B cells in spontaneous splenic germinal centers (GCs). As with MCD, these premalignant B cells were enriched for B-cell receptors (BCRs) with evidence of self-reactivity, displayed a de novo dependence on Tlr9, and were more sensitive to inhibition of Bruton's tyrosine kinase. Mutant spontaneous splenic GC B cells (GCB) showed increased proliferation and IRF4 expression. Mice carrying all 4 genetic lesions showed a >50-fold expansion of spontaneous splenic GCs exhibiting aberrant histologic features with a dark zone immunophenotype and went on to develop DLBCL in the spleen with age. Thus, by combining multiple hallmark genetic alterations associated with MCD, our study identifies aberrant spontaneous splenic GCBs as a likely cell-of-origin for this aggressive genetic subtype of lymphoma.

Traditional Chinese Mind-Body Exercise Baduanjin Modulate Gray Matter and Cognitive Function in Older Adults with Mild Cognitive Impairment: A Brain Imaging Study.

BACKGROUND: Previous studies found traditional Chinese mind-body exercise Baduanjin could modulate cognition of community older adults. OBJECTIVE: This study aims to investigate the effect of 6 months of Baduanjin exercise on brain structure and cognitive function in older adults with mild cognitive impairment (MCI). METHODS: The MCI older adults were randomly assigned into either Baduanjin training, brisk walking training or usual physical activity control group. Magnetic Resonance Imaging (MRI), Montreal Cognitive Assessment (MoCA) and Wechsler Memory Scale-Chinese Revised (WMS-CR) were applied to measure gray matter volume (GMV), global cognitive ability and memory at baseline and end of intervention. RESULTS: Compared to usual physical activity, Baduanjin exercise significantly improved MoCA, WMS-CR scores, WMS-MQ, and mental control and comprehension memory subscores of the WMS-CR; significantly increased the GMV in the temporal gyrus, frontal gyrus, parietal gyrus, medial occipital gyrus, cingulate gyrus and angular gyrus after 6 months of intervention. Compared to brisk walking, Baduanjin significantly improved MoCA scores and picture reproduction subscores of memory, and significantly increased the GMV in the right frontal gyrus, precentral gyrus, occipital gyrus. Furthermore, the increased GMV in the right medial temporal gyrus was significantly associated with improvement in the MoCA scores. CONCLUSION: The present study suggested that regular Baduanjin training could have a positive effect in increasing brain gray matter and improving cognitive function in older adults with MCI.

Investigations on the Respiratory Function in COVID-19 Patients: A Prospective Cohort Study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a global public health crisis. However, whether it can cause respiratory dysfunction or physical and psychological disorders in patients remains unknown. Thus, this study was conducted to investigate the respiratory function, activities of daily living, quality of life, and mental status of patients with COVID-19. Participants and outcomes. Data was collected from the follow-up of eligible patients who attended the fever clinic of three hospitals in Jiangxi Province, from March to May 2020. The outcomes included respiratory muscle function, degree of dyspnea, aerobic capacity, activities of daily living, quality of life, and mental status. RESULTS: A total of 139 patients (72 men and 67 women) were included in this study. The proportions of mild, moderate, severe, and critical cases of COVID-19 were 7.1% (10 cases), 68.3% (95 cases), 20.1% (28 cases), and 4.2% (6 cases), respectively. The rates of abnormal maximal inspiratory pressure were 10.0%, 25.2%, 25.0%, and 16.7%, respectively. There were 50%, 65.3%, 50%, and 66.7% of the patients with abnormal dyspnea in the four clinical classifications, respectively. Patients generally show a decline in quality of life, anxiety, and depression symptoms. CONCLUSIONS: Respiratory dysfunction, decreased quality of life, and psychological disorders were present in each clinical classification of COVID-19. Therefore, it is necessary to carry out respiratory rehabilitation and psychological intervention for COVID-19 patients.

Mind-Body Exercise Modulates Locus Coeruleus and Ventral Tegmental Area Functional Connectivity in Individuals With Mild Cognitive Impairment.

Mild cognitive impairment (MCI) is a common global health problem. Recently, the potential of mind-body intervention for MCI has drawn the interest of investigators. This study aims to comparatively explore the modulation effect of Baduanjin, a popular mind-body exercise, and physical exercise on the cognitive function, as well as the norepinephrine and dopamine systems using the resting state functional connectivity (rsFC) method in patients with MCI. 69 patients were randomized to the Baduanjin, brisk walking, or healthy education control group for 6 months. The Montreal Cognitive Assessment (MoCA) and magnetic resonance imaging (MRI) scans were applied at baseline and at the end of the experiment. Results showed that (1) compared to the brisk walking, the Baduanjin significantly increased MoCA scores; (2) Baduanjin significantly increased the right locus coeruleus (LC) and left ventral tegmental area (VTA) rsFC with the right insula and right amygdala compared to that of the control group; and the right anterior cingulate cortex (ACC) compared to that of the brisk walking group; (3) the increased right LC-right insula rsFC and right LC-right ACC rsFC were significantly associated with the corresponding MoCA score after 6-months of intervention; (4) both exercise groups experienced an increased effective connectivity from the right ACC to the left VTA compared to the control group; and (5) Baduanjin group experienced an increase in gray matter volume in the right ACC compared to the control group. Our results suggest that Baduanjin can significantly modulate intrinsic functional connectivity and the influence of the norepinephrine (LC) and dopamine (VTA) systems. These findings may shed light on the mechanisms of mind-body intervention and aid the development of new treatments for MCI.

Decoding brain encoded by genome.

Human brain is the most complicated living organ in nature. How the human genome encodes the structure and function of brain is a fundamental question to understand the essence of mind. Currently, it is still an unsolved scientific problem requiring the further breakthrough of comprehensive technologies. Here, we summarize the recent advances in brain development/function OMICS studies, and discuss the huge challenges and prospects in understanding how brain is encoded by genome.

Liuzijue is a promising exercise option for rehabilitating discharged COVID-19 patients.

BACKGROUND: Among discharged COVID-19 patients, the health-related quality of life is poor, and patients suffer from significant physical and psychological impairment. This study was designed to investigate the effects of Liuzijue exercise on the rehabilitation of COVID-19 patients. METHODS: Thirty three eligible patients with COVID-19 were enrolled in the study after discharge. All the participants practiced Liuzijue exercise once per day for 20 minutes over 4 weeks. Data were collected at baseline and the end of the intervention. Primary outcomes involved functional capacity and secondary outcomes involved quality of life. RESULTS: The maximal inspiratory pressure (MIP), peak inspiratory flow (PIF), and diaphragm movement in deep breathing (DM-DB) of patients increased significantly after 4 weeks of intervention. The dyspnea was also alleviated and exercise capacity was significantly improved. In terms of quality of life, physical functioning and role-physical scores were significantly increased. Moreover, Liuzijue could significantly alleviate the depression and anxiety status of the patients. CONCLUSION: Liuzijue exercise is a viable alternative home exercise program that produced better functional capacity and quality of life in discharged patients with COVID-19. These findings also showed the necessity of rehabilitation intervention for cured COVID-19 patients.

Compromised counterselection by FAS creates an aggressive subtype of germinal center lymphoma.

Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell-derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh-B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma.

Predictive Value and Correlation of Neuron-Specific Enolase for Prognosis in Patients with Coma: A Systematic Review and Meta-Analysis.

OBJECTIVE: Coma is the most serious disturbance of consciousness, which affects the life quality of patients and increases the burden of their family. Studies to assess the prognostic value of neuron-specific enolase (NSE) in patients with coma have not led to precise, generally accepted prognostic rules. The study aims to assess the correlation between NSE and prognosis of coma and the predictive value of NSE for clinical prognosis. METHODS: A search was conducted using PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and WanFang Data from the establishment time of databases to December 2019. This analysis included patients with coma, regardless of how long the coma was. In total, 26 articles were retrieved and included in the review. RESULTS: The meta-analysis revealed the NSE concentration of patients with coma is significantly higher than that of the control group (standard mean difference = 0.88, 95% confidence interval [CI]: 0.63-1.12, p < 0.05). The pooled sensitivity and specificity of NSE in coma diagnosis was 0.5 (95% CI: 0.39-0.61) and 0.86 (95% CI: 0.71-0.94). CONCLUSIONS: The NSE concentration of patients with poor coma prognosis is significantly higher than that of the control group. The high NSE concentration is not necessarily a poor prognosis for coma, but low NSE concentration indicates a high probability of a good prognosis for coma.

HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy.

Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUGexp) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSALR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.

The Effect of Traditional Chinese Mind-Body Exercise (Baduanjin) and Brisk Walking on the Dorsal Attention Network in Older Adults With Mild Cognitive Impairment.

A growing number of studies have shown that mind-body exercise is beneficial to cognitive function, especially memory, in elderly MCI patients. However, few studies have explored the effect of mind-body exercise on the attention of MCI population. We recruited 69 participants and divided them equally into Baduanjin, brisk walking (BWK) exercise or usual physical activity (UAP) control groups. The two exercise groups performed 60 min of exercise three times per week for 24 weeks. All subjects underwent whole-brain functional MRI and assessment of attentional abilities, including selective, divided, and sustained attention, and processing speed at baseline and after 24 weeks. The results show that: Baduanjin exercise significantly increased the selective attention of MCI patients, and Dorsal attention network (DAN) of Baduanjin exercise group exhibited functional connectivity decreased in right rolandic operculum (ROL. R), right middle temporal gyrus (MTG. R), right supramarginal inferior parietal, angular gyri (IPL. R), right precuneus (PCUN. R), and right fusiform gyrus (FFG. R) regions compared with the other two groups. The BWK exercise group had obviously functional connectivity increased in IPL. R and decreased in the MTG. R region compared to that in the UAP group. But no significant association between the changes of functional connectivity of DAN and the change of attentional ability test was observed. Thus, our data indicated Baduanjin exercise may be a potential beneficial intervention to improve the attention of the elderly with MCI. Further study with more samples is necessary to elucidate its imaging mechanism.

TGFß signaling in germinal center B cells promotes the transition from light zone to dark zone.

B cells in germinal centers (GCs) cycle between light zone (LZ) and dark zone (DZ). The cues in the GC microenvironment that regulate the transition from LZ to DZ have not been well characterized. In Peyer's patches (PPs), transforming growth factor-ß (TGFß) promotes IgA induction in activated B cells that can then differentiate into GC B cells. We show here that TGFß signaling occurs in B cells in GCs and is distinct from signaling that occurs in activated B cells in PPs. Whereas in activated B cells TGFß signaling is required for IgA induction, in the GC it was instead required for the transition from LZ to DZ. In the absence of TGFß signaling, there was an accumulation of LZ GC B cells and reduced antibody affinity maturation likely due to reduced activation of Foxo1. This work identifies TGFß as a microenvironmental cue that is critical for GC homeostasis and function.

Mind-body exercise improves cognitive function and modulates the function and structure of the hippocampus and anterior cingulate cortex in patients with mild cognitive impairment.

Mild cognitive impairment (MCI) is a common neurological disorder. This study aims to investigate the modulation effect of Baduanjin (a popular mind-body exercise) on MCI. 69 patients were randomized to Baduanjin, brisk walking, or an education control group for 24 weeks. The Montreal Cognitive Assessment (MoCA) and Magnetic Resonance Imaging scans were applied at baseline and at the end of the experiment. Compared to the brisk walking and control groups, the Baduanjin group experienced significantly increased MoCA scores. Amplitude of low-frequency fluctuations (ALFF) analysis showed significantly decreased ALFF values in the right hippocampus (classic low-freqency band, 0.01-0.08 Hz) in the Baduanjin group compared to the brisk walking group and increased ALFF values in the bilateral anterior cingulate cortex (ACC, slow-5 band, 0.01-0.027 Hz) in the Baduanjin group compared to the control group. Further, ALFF value changes in the right hippocampus and bilateral ACC were significantly associated with corresponding MoCA score changes across all groups. We also found increased gray matter volume in the Baduanjin group in the right hippocampus compared to the brisk walking group and in the bilateral ACC compared to the control group. In addition, there was an increased resting state functional connectivity between the hippocampus and right angular gyrus in the Baduanjin group compared to the control group. Our results demonstrate the potential of Baduanjin for the treatment of MCI.

Neurexin-Neuroligin 1 regulates synaptic morphology and functions via the WAVE regulatory complex in Drosophila neuromuscular junction.

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.

Alterations in resting-state functional connectivity of the default mode network in amnestic mild cognitive impairment: an fMRI study.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is characterized by cognitive functional decline, especially in memory. Resting-state functional magnetic resonance imaging (fMRI) has been widely used in neuroimaging studies that explore alterations between patients and normal individuals to elucidate the pathological mechanisms of different diseases. The current study was performed to investigate alterations in the functional connectivity of the default mode network (DMN) in aMCI patients compared to healthy elderly controls, as well as further define the association between neurological alterations and memory function. METHODS: Twenty-five aMCI patients and 25 healthy individuals were recruited and underwent both fMRI and neuropsychological examinations. fMRI data was analyzed by independent component analysis. RESULTS: Compared to healthy individuals, aMCI patients exhibited a significant increase in functional connectivity between the DMN and right-middle and right-superior frontal gyri, left-middle occipital gyrus, and left-middle temporal gyrus, but reduced functional connectivity between the DMN and left-middle and left-inferior frontal gyri and left insula. These alterations were found to be associated with reduced memory function. CONCLUSIONS: aMCI patients exhibited abnormal functional connectivity between the DMN and certain brain regions which is associated with changes in memory function associated with aMCI.