Generation of rat forebrain tissues in mice.

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.

DRG afferents that mediate physiologic and pathologic mechanosensation from the distal colon.

The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.

Parallel ascending spinal pathways for affective touch and pain.

The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain1-4. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that  express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.

PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation.

Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is a central protein in necroptosis, but posttranslational processes that regulate RIP3 activity and stability remain poorly understood. Here, we identify pellino E3 ubiquitin protein ligase 1 (PELI1) as an E3 ligase that targets RIP3 for proteasome-dependent degradation. Phosphorylation of RIP3 on T182 leads to interaction with the forkhead-associated (FHA) domain of PELI1 and PELI1-mediated K48-linked polyubiquitylation of RIP3 on K363. This same phosphorylation event is also important for RIP3 kinase activity; thus, PELI1 preferentially targets kinase-active RIP3 for degradation. PELI1-mediated RIP3 degradation effectively prevents cell death triggered by RIP3 hyperactivation. Importantly, upregulated RIP3 expression in keratinocytes from toxic epidermal necrolysis (TEN) patients is correlated with low expression of PELI1, suggesting that loss of PELI1 may play a role in the pathogenesis of TEN. We propose that PELI1 may function to control inadvertent activation of RIP3, thus preventing aberrant cell death and maintaining cellular homeostasis.

Minimizing Global Buffer Access in a Deep Learning Accelerator Using a Local Register File with a Rearranged Computational Sequence.

We propose a method for minimizing global buffer access within a deep learning accelerator for convolution operations by maximizing the data reuse through a local register file, thereby substituting the local register file access for the power-hungry global buffer access. To fully exploit the merits of data reuse, this study proposes a rearrangement of the computational sequence in a deep learning accelerator. Once input data are read from the global buffer, repeatedly reading the same data is performed only through the local register file, saving significant power consumption. Furthermore, different from prior works that equip local register files in each computation unit, the proposed method enables sharing a local register file along the column of the 2D computation array, saving resources and controlling overhead. The proposed accelerator is implemented on an off-the-shelf field-programmable gate array to verify the functionality and resource utilization. Then, the performance improvement of the proposed method is demonstrated relative to popular deep learning accelerators. Our evaluation indicates that the proposed deep learning accelerator reduces the number of global-buffer accesses to nearly 86.8%, consequently saving up to 72.3% of the power consumption for the input data memory access with a minor increase in resource usage compared to a conventional deep learning accelerator.

Suppression of Osteoarthritis progression by post-natal Induction of Nkx3.2.

Osteoarthritis (OA) is an incurable joint disease affecting 240 million elderly population, and major unmet medical needs exist for better therapeutic options for OA. During skeletal development, Nkx3.2 has been shown to promote chondrocyte differentiation and survival, but to suppress cartilage hypertrophy and blood vessel invasion. Here we show that Nkx3.2 plays a key role in osteoarthritis (OA) pathogenesis. Marked reduction of Nkx3.2 expression was observed in three different murine OA models. Consistent with these findings, analyses of surgery-induced and age-driven OA models revealed that cartilage-specific post-natal induction of Nkx3.2 can suppress OA progression in mice. These results suggest that Nkx3.2 may serve as a promising target for OA drug development.

COVID-19 cases in US counties: roles of racial/ethnic density and residential segregation.

OBJECTIVE: To investigate how racial/ethnic density and residential segregation shape the uneven burden of COVID-19 in US counties and whether (if yes, how) residential segregation moderates the association between racial/ethnic density and infections. DESIGN: We first merge various risk factors from federal agencies (e.g. Census Bureau and Centers for Disease Control and Prevention) with COVID-19 cases as of June 13th in contiguous US counties (N = 3,042). We then apply negative binomial regression to the county-level dataset to test three interrelated research hypotheses and the moderating role of residential segregation is presented with a figure. RESULTS: Several key results are obtained. (1) Counties with high racial/ethnic density of minority groups experience more confirmed cases than those with low levels of density. (2) High levels of residential segregation between whites and non-whites increase the number of COVID-19 infections in a county, net of other risk factors. (3) The relationship between racial/ethnic density and COVID-19 infections is enhanced with the increase in residential segregation between whites and non-whites in a county. CONCLUSIONS: The pre-existing social structure like residential segregation may facilitate the spread of COVID-19 and aggravate racial/ethnic health disparities in infections. Minorities are disproportionately affected by the novel coronavirus and focusing on pre-existing social structures and discrimination in housing market may narrow the uneven burden across racial/ethnic groups.

Duration of Vasodilatory Action After Intra-arterial Infusions of Calcium Channel Blockers in Animal Model of Cerebral Vasospasm.

BACKGROUND: In medically refractory vasospasm, invasive intervention may be required. A commonly used approach is intra-arterial (IA) drug infusion. Although calcium channel blockers (CCBs) have been widely applied in this setting, studies comparing their efficacies and durations of action have been few. This study was performed to compare attributes of three CCBs (nicardipine, nimodipine, and verapamil), focusing on duration of the vasodilatory action based on angiography. METHODS: Vasospasm was produced in New Zealand white rabbits (N = 22) through experimentally induced subarachnoid hemorrhage and confirmed in each via conventional angiography, grouping them by IA-infused drug. After chemoangioplasty, angiography was performed hourly for 5 h to compare dilated and vasospastic arterial diameters. Drug efficacy, duration of action, and changes in mean arterial pressure (relative to baseline) were analyzed by group. RESULTS: Effective vasodilation was evident in all three groups immediately after IA drug infusion. The vasodilative effects of nimodipine and nicardipine peaked at 1 h and were sustained at 2 h, returning to initial vasospastic states at 3 h. In verapamil recipients, effects were more transient by comparison, entirely dissipating at 1 h. Only the nicardipine group showed a significant 3-h period of lowered blood pressure. CONCLUSIONS: Although nimodipine and nicardipine proved longer acting than verapamil in terms of vasodilation, their effects were not sustained beyond 2 h after IA infusion. Further study is required to confirm the vasodilatory duration of IA CCB based on perfusion status, and an effort should be made to find new alternative to extend the duration.

A Novel Procedure of Enhancing the Throughput of a Mode-2 Sidelink Based on Partial Sensing.

Partial sensing is used to reduce the power consumption of pedestrian user equipment (P-UE) that operates in the signal environment of a mode-2 sidelink. However, because the data trans-mission is allowed only for the window duration of each corresponding P-UE, the throughput of the P-UE decreases by the ratio between the width of the window and the entire data period. This paper presents a novel method for enhancing the throughput of the P-UE that operates with partial sensing in the mode-2 sidelink. The proposed technique employs an additional UE, denoted the roadside unit (RSU), to collect the sensing results from each P-UE that operates with partial sensing. The proposed RSU sequentially aligns all of the partial sensing windows, such that the combination of each partial sensing window can eventually provide an almost complete sensing result. In this study, extensive computer simulations were performed. The results reveal that the proposed method enhances the throughput of each P-UE operating with partial sensing almost to that of full sensing without increasing the required power consumption.

Deep-Learning-Based Wi-Fi Indoor Positioning System Using Continuous CSI of Trajectories.

In a Wi-Fi indoor positioning system (IPS), the performance of the IPS depends on the channel state information (CSI), which is often limited due to the multipath fading effect, especially in indoor environments involving multiple non-line-of-sight propagation paths. In this paper, we propose a novel IPS utilizing trajectory CSI observed from predetermined trajectories instead of the CSI collected at each stationary location; thus, the proposed method enables all the CSI along each route to be continuously encountered in the observation. Further, by using a generative adversarial network (GAN), which helps enlarge the training dataset, the cost of trajectory CSI collection can be significantly reduced. To fully exploit the trajectory CSI's spatial and temporal information, the proposed IPS employs a deep learning network of a one-dimensional convolutional neural network-long short-term memory (1DCNN-LSTM). The proposed IPS was hardware-implemented, where digital signal processors and a universal software radio peripheral were used as a modem and radio frequency transceiver, respectively, for both access point and mobile device of Wi-Fi. We verified that the proposed IPS based on the trajectory CSI far outperforms the state-of-the-art IPS based on the CSI collected from stationary locations through extensive experimental tests and computer simulations.

Comparison of Posterior Cruciate-Retaining and High-Flexion Cruciate-Retaining Total Knee Arthroplasty Design.

BACKGROUND: High-flexion prostheses have been developed to achieve deep flexion after total knee arthroplasty. The purpose of this study is to compare standard NexGen (CR, cruciate-retaining) and high-flexion NexGen (CR-flex) total knee prostheses in terms of range of motion, clinical and radiologic outcomes, rates of complications, and survivorship in long-term follow-up. METHODS: From January 2000 to December 2008, 423 consecutive knees underwent total knee arthroplasty using standard CR or CR-flex prostheses. Fifty-three patients were lost to follow-up or declined to participate and 54 died, leaving 290 knees. The minimum duration of follow-up was 8 years (mean 10.1 years). Physical examination and knee scoring of patients were assessed preoperatively, at 6 months and 1 year after surgery, and annually thereafter. Supine anteroposterior and lateral radiographs and standing anteroposterior hip-to-ankle radiographs were obtained preoperatively and at each follow-up. RESULTS: Mean postoperative range of motions in the standard CR group and the CR-flex group were similar, showing no significant difference between the 2 groups (P = .853). At the time of the final follow-up, mean total Hospital for Special Surgery scores were similar between the 2 groups (P = .118). Mean Knee Society pain (P = .325) and function scores (P = .659) were also comparable between the 2 groups. Western Ontario and McMaster Universities Osteoarthritis Index score showed no intergroup difference either (P = .586). The mean hip-knee-ankle angle at the final follow-up was approximately the same (P = .940). Mean coronal angles of femoral and tibial component at final follow-up were also similar (P = .211 and P = .764, respectively). The prevalence of the radiolucent line was 0.6% in the standard CR group and 0.9% in the CR-flex group. Estimated survival rate according to Kaplan-Meier survival analysis was 97.2% in the standard CR group and 95.6% in the CR-flex group at mean follow-up of 10.1 years. CONCLUSION: This study suggests that excellent clinical and radiographic outcomes could be achieved with both standard and high-flexion CR total knee designs. High-flexion CR prosthesis did not show any advantages over the standard design.

Is arachnoid cyst a static disease? A case report and literature review.

INTRODUCTION: The increasing use of intracranial imaging has led to more frequent diagnoses of arachnoid cysts (ACs). Although ACs are a frequent finding on neuroimaging in children, the prevalence and natural history of these cysts are not well defined. Most ACs may persist and remain asymptomatic throughout life and not require treatment. However, there have been some case reports of ACs that have become larger or smaller over time and, in rare cases, have even spontaneously resolved. It is the authors' practice to recommend serial neuroimaging in patients with asymptomatic sylvian ACs and not offer surgery to patients without symptoms, even in those with a relatively large cyst. CASE REPORT: The present article describes a case involving a 6-year-old boy with a large, asymptomatic AC in the left Sylvian fissure involving the temporo-frontal region, which resolved spontaneously during the 2-year follow-up period after initial diagnosis without any surgical intervention. Currently, at the 7-year follow-up, the patient has remained neurologically intact, attends school, and is symptom-free. CONCLUSION: Clinicians should be mindful of the possibility of spontaneous regression when encountering patients with asymptomatic and/or incidentally diagnosed sylvian ACs.

Sensory Neurons Arouse C. elegans Locomotion via Both Glutamate and Neuropeptide Release.

C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states.

Differential investments and opportunities: How do neighborhood conditions moderate the relationship between perceived housing discrimination and social capital?

Though the adverse consequences of perceived housing discrimination have been documented, little is known about whether such experience undermines one's social capital in a neighborhood and even less is about whether and how this relationship is altered by neighborhood features. We proposed a framework that simultaneously considers within-individual and between-neighborhood processes. We applied multilevel structural equation models to data from Philadelphia (n = 9987) and found that (a) perceived housing discrimination was negatively associated with one's social capital even after other confounders were considered, (b) this negative association could be partly explained by the proliferated daily stress and anxiety mechanisms, (c) differential exposures to neighborhood social disadvantage accounted for the variation in social capital across neighborhoods, and (d) the adverse association between perceived housing discrimination and social capital could be attenuated by neighborhood stability. The findings suggested that appropriate interventions should buffer the negative association of perceived housing discrimination with social capital.

Glucose deprivation triggers protein kinase C-dependent ß-catenin proteasomal degradation.

Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation-induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of ß-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas ß-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3ß was unable to abolish the glucose deprivation-mediated ß-catenin degradation or up-regulation of LC3-II protein levels, which suggested GSK3ß-independent protein degradation. Intriguingly, the inhibition of PKCα using a pharmacological inhibitor and transfection of siRNA for PKCα was observed to effectively block glucose deprivation-induced ß-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3ß-independent protein degradation of ß-catenin, leading to autophagy.

RABA members act in distinct steps of subcellular trafficking of the FLAGELLIN SENSING2 receptor.

Cell surface proteins play critical roles in the perception of environmental stimuli at the plasma membrane (PM) and ensuing signal transduction. Intracellular localization of such proteins must be strictly regulated, which requires elaborate integration of exocytic and endocytic trafficking pathways. Subcellular localization of Arabidopsis thaliana FLAGELLIN SENSING2 (FLS2), a receptor that recognizes bacterial flagellin, also depends on membrane trafficking. However, our understanding about the mechanisms involved is still limited. In this study, we visualized ligand-induced endocytosis of FLS2 using green fluorescent protein (GFP)-tagged FLS2 expressed in Nicotiana benthamiana. Upon treatment with the flg22 peptide, internalized FLS2-GFP from the PM was transported to a compartment with properties intermediate between the trans-Golgi network (TGN) and the multivesicular endosome. This compartment gradually discarded the TGN characteristics as it continued along the trafficking pathway. We further found that FLS2 endocytosis involves distinct RABA/RAB11 subgroups at different steps. Moreover, we demonstrated that transport of de novo-synthesized FLS2 to the PM also involves a distinct RABA/RAB11 subgroup. Our results demonstrate the complex regulatory system for properly localizing FLS2 and functional differentiation in RABA members in endo- and exocytosis.

Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability.

During endochondral ossification, a process that accounts for the majority of bone formation in vertebrates, hypertrophic chondrocytes display a greater susceptibility to apoptosis when compared to proliferating chondrocytes. However, the molecular mechanisms underlying this phenomenon remain unclear. Nkx3.2, a member of the NK class of homeoproteins, is initially expressed in chondrogenic precursor cells, and later, during cartilage maturation, its expression is restricted to proliferating chondrocytes. Here, we show that the nuclear factor kappa B (NF-kappaB) pathway is required for chondrocyte viability and that Nkx3.2 supports chondrocyte survival by constitutively activating RelA. Although signal-dependent NF-kappaB activation has been intensively studied, ligand-independent NF-kappaB activation is poorly understood. The data presented here support a novel ligand-independent mechanism of NF-kappaB activation, whereby Nkx3.2 recruits the RelA-IkappaBalpha heteromeric complex into the nucleus by direct protein-protein interactions and activates RelA through proteasome-dependent IkappaBalpha degradation in the nucleus. Furthermore, we demonstrate that stage-specific NF-kappaB activation, mediated by Nkx3.2, regulates chondrocyte viability during cartilage maturation.

Gender Differences in the Protective Role of Grandparenting in Dementia Risk.

OBJECTIVES: This study provides one of the first national longitudinal studies of the association between caring for grandchildren (i.e., grandparenting) and the risk of dementia in the United States, with a focus on gender-specific variations. METHODS: We estimated discrete-time event history models, drawing upon data from the Health and Retirement Study (2000-2016). The analytic sample included 10,217 community-dwelling White and Black grandparents aged 52 years and older at baseline. RESULTS: Noncoresident grandparenting was associated with a lower risk of dementia for both women and men compared to grandparents who did not take care of grandchildren. However, the cognitive advantage showed different patterns based on gender and the combination of care intensity and family structure. Grandmothers had a lower risk of dementia than noncaregiving grandmothers when providing a light level of noncoresident grandparenting, whereas grandfathers who provided intensive noncoresident grandparenting had a reduced risk of dementia compared to their noncaregiving counterparts. Grandparenting experiences within multigenerational households and skipped-generation households were not associated with dementia risk. DISCUSSION: Intergenerational caregiving plays a pivotal role in shaping cognitive health during later life; however, the impact is nuanced, depending on factors such as gender, care intensity, and family structure.

Neighborhood Features and Cognitive Function: Moderating Roles of Individual Socioeconomic Status.

INTRODUCTION: There is an interest in exploring the associations between neighborhood characteristics and individual cognitive function; however, little is known about whether these relationships can be modified by individual socioeconomic status, such as educational attainment and income. METHODS: Drawing from the 2010-2018 Health and Retirement Study, this study analyzed 10,621 older respondents (aged 65+) with a total of 33,931 person-waves. These respondents did not have dementia in 2010 and stayed in the same neighborhood throughout the study period. Cognitive function was measured with a 27-point indicator biennially, and neighborhood characteristics (i.e., walkability, concentrated disadvantage, and social isolation) were assessed in 2010. All analyses were performed in 2023. RESULTS: Cognitive function is positively associated with neighborhood walkability and negatively related to concentrated disadvantage, suggesting that exposures to these neighborhood characteristics have long-lasting impacts on cognitive function. Furthermore, individual socioeconomic status modifies the relationship between neighborhood characteristics and cognitive function. Compared with those graduating from college, respondents without a bachelor's degree consistently have lower cognitive function but the educational gap in cognitive function narrows with increases in walkability (b= -0.152, SE=0.092), and widens when neighborhood concentrated disadvantage (b=0.212, SE=0.070) or social isolation (b=0.315, SE=0.125) rises. The income gap in cognitive function shrinks with increases in walkability (b= -0.063, SE=0.027). CONCLUSIONS: The moderating role of socioeconomic status indicates that low-socioeconomic status older adults who also live in disadvantaged neighborhoods face a higher risk of poor cognitive function. Low-education and low-income aging adults may have the most to gain from investments to improve neighborhood characteristics.

Enhancing the Evaluation System of Training Hospitals for Neurosurgical Residency Training and Education in South Korea : Striving for Balanced Participation and Differentiation.

The Korean Neurosurgical Society, with its 62 years of history, has witnessed substantial growth in the field of neurosurgery, producing over 3,400 neurosurgeons, establishing 12 divisions and 9 regional branches, and advancing in clinical management, diagnostic methods and academic research. Despite these developments, the regulations governing neurosurgical training and evaluation methods for training hospitals have remained largely unchanged, necessitating comprehensive revisions in response to evolving medical environments. To provide balanced participation opportunities for neurosurgery residents, the Korean Neurosurgical Society formed the Training Status Investigation Standard Change Task Force (TF Team) under the Training Education Committee. This paper presents the TF Team's findings and proposals for revising training status investigation standards and evaluation criteria. Through the processes including a lot of team meetings, workshops, education programs, official communications with 12 division societies, benchmarking from other societies and analysis of encrypted data from the past 5 years for neurosurgical training hospitals, the TF Team created a revised training status investigation proposal, supplemented main surgery criteria. And we applied this revised proposal to the training status investigation data collected from training hospitals in 2022 for simulation. We reduced the score for main surgeries to 10 points, introduced core competency surgery standards, allocating 5 points each for brain core competency surgery and spine and peripheral core competency surgery, for a total of 10 points. We also adjusted the major surgery score to 13 points, expanding the total surgery index score to 33 points. We introduced additional definitions for main surgeries in the areas of spine, pediatrics, and functional surgery. The equipment score was reduced from 17 points to 9 points. We specified minimum requirements for resident allocation eligibility, and if a hospital meets all of these criteria, they become eligible to apply for resident allocation. We introduced a new bonus point system for hospitals performing mechanical thrombectomy or stenting and peripheral nerve. The proposed revisions aim to improve the training and education of neurosurgical residents and overall neurosurgical care in Korea by creating a balanced and differentiated evaluation system for training hospitals. Further monitoring, communication, and adjustments are crucial for successful implementation.