The neuroanatomical basis behind acupuncture practice is still poorly understood. Here, we used intersectional genetic strategy to ablate NPY+ noradrenergic neurons and/or adrenal chromaffin cells. ...Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low-intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY+ adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality.
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•Intersectional genetic manipulation of NPY+ sympathetic cells•Electroacupuncture stimulation (ES) drives distinct sympathetic pathways•ES operates in somatotopy- and intensity-dependent manners•NPY+ noradrenergic neurons bidirectionally modulate systemic inflammation
Liu et al. reveals a neuroanatomical basis for acupuncture practice, showing that electroacupuncture stimulation can drive distinct autonomic pathways and modulate systemic inflammation in somatotopy-, stimulation-intensity-, and disease-state-dependent manners.
As core units of organ tissues, cells of various types play their harmonious rhythms to maintain the homeostasis of the human body. It is essential to identify the characteristics of cells in human ...organs and their regulatory networks for understanding the biological mechanisms related to health and disease. However, a systematic and comprehensive single-cell transcriptional profile across multiple organs of a normal human adult is missing.
We perform single-cell transcriptomes of 84,363 cells derived from 15 tissue organs of one adult donor and generate an adult human cell atlas. The adult human cell atlas depicts 252 subtypes of cells, including major cell types such as T, B, myeloid, epithelial, and stromal cells, as well as novel COCH
fibroblasts and FibSmo cells, each of which is distinguished by multiple marker genes and transcriptional profiles. These collectively contribute to the heterogeneity of major human organs. Moreover, T cell and B cell receptor repertoire comparisons and trajectory analyses reveal direct clonal sharing of T and B cells with various developmental states among different tissues. Furthermore, novel cell markers, transcription factors, and ligand-receptor pairs are identified with potential functional regulations in maintaining the homeostasis of human cells among tissues.
The adult human cell atlas reveals the inter- and intra-organ heterogeneity of cell characteristics and provides a useful resource in uncovering key events during the development of human diseases in the context of the heterogeneity of cells and organs.
Efficient conversion of carbon dioxide (CO
) into value-added products is essential for clean energy research. Design of stable, selective, and powerful electrocatalysts for CO
reduction reaction (CO
...RR) is highly desirable yet largely unmet. In this work, a series of metalloporphyrin-tetrathiafulvalene based covalent organic frameworks (M-TTCOFs) are designed. Tetrathiafulvalene, serving as electron donator or carrier, can construct an oriented electron transmission pathway with metalloporphyrin. Thus-obtained M-TTCOFs can serve as electrocatalysts with high FE
(91.3%, -0.7 V) and possess high cycling stability (>40 h). In addition, after exfoliation, the FE
value of Co-TTCOF nanosheets (~5 nm) is higher than 90% in a wide potential range from -0.6 to -0.9 V and the maximum FE
can reach up to almost 100% (99.7%, -0.8 V). The electrocatalytic CO
RR mechanisms are discussed and revealed by density functional theory calculations. This work paves a new way in exploring porous crystalline materials in electrocatalytic CO
RR.
Computation-in-memory (CIM) is a promising candidate to improve the energy efficiency of multiply-and-accumulate (MAC) operations of artificial intelligence (AI) chips. This work presents an static ...random access memory (SRAM) CIM unit-macro using: 1) compact-rule compatible twin-8T (T8T) cells for weighted CIM MAC operations to reduce area overhead and vulnerability to process variation; 2) an even-odd dual-channel (EODC) input mapping scheme to extend input bandwidth; 3) a two's complement weight mapping (C2WM) scheme to enable MAC operations using positive and negative weights within a cell array in order to reduce area overhead and computational latency; and 4) a configurable global-local reference voltage generation (CGLRVG) scheme for kernels of various sizes and bit precision. A 64 × 60 b T8T unit-macro with 1-, 2-, 4-b inputs, 1-, 2-, 5-b weights, and up to 7-b MAC-value (MACV) outputs was fabricated as a test chip using a foundry 55-nm process. The proposed SRAM-CIM unit-macro achieved access times of 5 ns and energy efficiency of 37.5-45.36 TOPS/W under 5-b MACV output.
Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Several proteins including α-synuclein trigger the activation ...of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD.
There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein.
We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels.
Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.
Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought ...an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
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•Human ACE2 knockin mice were generated by using CRISPR/Cas9 technology•SARS-CoV-2 leads to robust replication in lung, trachea, and brain•SARS-CoV-2 causes interstitial pneumonia and elevated cytokine in aged hACE2 mice•High dose of SARS-CoV-2 can establish infection via intragastric route in hACE2 mice
The COVID-19 pandemic has brought an urgent need for small animal models. Here, Sun et al. established an ACE2 humanized mouse by CRISPR/Cas9 knockin technology. These hACE2 mice are susceptible to SARS-CoV-2 infection upon intranasal inoculation, and the resulting pulmonary infection and pathological changes resemble those observed in COVID-19 patients.
Alzheimer's disease (AD), as the most common cause of dementia, brings huge economic burden for patients and social health care systems, which motivates researchers to study multiple protective ...factors, among which physical activity and exercise have been proven to be both effective and economically feasible.
A systematic literature search was performed for eligible studies published up to November 1st 2018 on three international databases (PubMed, Cochrane Library, and Embase) and two Chinese databases (Wanfang Data, China National Knowledge Infrastructure). All analyses were conducted using Stata 14.0. Due to heterogeneity between studies, a random-effects model was used for this meta-analysis. Meta-analysis was used to explore if physical activity and exercise can exert positive effects on cognition of elderly with AD and subgroup analyses were conducted to find out if there are dose-response effects.
A total of 13 randomized controlled trials were included with a sample size of 673 subjects diagnosed with AD. Intervention groups showed a statistically significant improvement in cognition of included subjects measured by the MMSE score (SMD = 1.12 CI:0.66~1.59) compared to the control groups. Subgroup analyses showed different amounts of physical activity and exercise can generate different effects.
As one of few meta-analyses comparing different quantities of physical activity and exercise interventions for AD in details, our study suggests that physical activity and exercise can improve cognition of older adults with AD. While the concomitant effects on cognition functions of high frequency interventions was not greater than that of low frequency interventions, the threshold remains to be settled. However, more RCTs with rigorous study design are needed to support our findings.
Previous SRAM-based computing-in-memory (SRAM-CIM) macros suffer small read margins for high-precision operations, large cell array area overhead, and limited compatibility with many input and weight ...configurations. This work presents a 1-to-8-bit configurable SRAM CIM unit-macro using: 1) a hybrid structure combining 6T-SRAM based in-memory binary product-sum (PS) operations with digital near-memory-computing multibit PS accumulation to increase read accuracy and reduce area overhead; 2) column-based place-value-grouped weight mapping and a serial-bit input (SBIN) mapping scheme to facilitate reconfiguration and increase array efficiency under various input and weight configurations; 3) a self-reference multilevel reader (SRMLR) to reduce read-out energy and achieve a sensing margin 2<inline-formula> <tex-math notation="LaTeX">\times </tex-math></inline-formula> that of the mid-point reference scheme; and 4) an input-aware bitline voltage compensation scheme to ensure successful read operations across various input-weight patterns. A 4-Kb configurable 6T-SRAM CIM unit-macro was fabricated using a 55-nm CMOS process with foundry 6T-SRAM cells. The resulting macro achieved access times of 3.5 ns per cycle (pipeline) and energy efficiency of 0.6-40.2 TOPS/W under binary to 8-b input/8-b weight precision.
To conquer the bottleneck of sluggish kinetics in cathodic oxygen reduction reaction (ORR) of metal‐air batteries, catalysts with dual‐active centers have stood out. Here, a “pre‐division metal ...clusters” strategy is firstly conceived to fabricate a N,S‐dual doped honeycomb‐like carbon matrix inlaid with CoN4 sites and wrapped Co2P nanoclusters as dual‐active centers (Co2P/CoN4@NSC‐500). A crystalline {CoII2} coordination cluster divided by periphery second organic layers is well‐designed to realize delocalized dispersion before calcination. The optimal Co2P/CoN4@NSC‐500 executes excellent 4e− ORR activity surpassing the benchmark Pt/C. Theoretical calculation results reveal that the CoN4 sites and Co2P nanoclusters can synergistically quicken the formation of *OOH on Co sites. The rechargeable Zn‐air battery (ZAB) assembled by Co2P/CoN4@NSC‐500 delivers ultralong cycling stability over 1742 hours (3484 cycles) under 5 mA cm−2 and can light up a 2.4 V LED bulb for ≈264 hours, evidencing the promising practical application potentials in portable devices.
A “pre‐division metal clusters” strategy is first conceived to fabricate dual‐active center catalysts (Co2P/CoN4@NSC‐500) with dispersed CoN4 and Co2P sites. The optimal catalyst executes superior ORR activity and was applied in ultralong Zn‐air batteries surpassing the benchmark 20 % Pt/C. Theoretical calculations demonstrate that the dual‐active sites synergistically quicken the formation of the *OOH intermediate, greatly boosting the performance.
Background
Minimally invasive radical hysterectomy has been reported to increase the risk of cancer relapse and death compared with open surgery in women with early‐stage cervical cancer. The use of ...a uterine manipulator is considered one of the risk factors.
Objectives
To investigate whether women with early‐stage cervical cancer treated with minimally invasive radical hysterectomy without using uterine manipulator have oncological outcomes similar to those of open surgery.
Search strategy
Searches were performed in MEDLINE, Embase and CENTRAL from their inception until 31 March 2022.
Selection criteria
Inclusion criteria were: (1) randomised controlled trials or observational cohort studies published in English, (2) studies comparing minimally invasive radical hysterectomy without using a uterine manipulator with open radical hysterectomy in women with early‐stage cervical cancer, and (3) studies comparing survival outcomes.
Data collection and analysis
Two authors independently conducted data extraction and assessed study quality. We calculated the hazard ratios (HR) and the 95% confidence intervals (CI) using the inverse variance approach for survival outcome.
Main results
Six observational studies with 2150 women were included. The minimally invasive surgery group had a significantly higher risk of cancer relapse compared with open surgery group (HR 1.55, 95% CI 1.15–2.10).
Conclusions
Minimally invasive radical hysterectomy without using a uterine manipulator resulted in an inferior recurrence‐free survival compared with open radical hysterectomy in the treatment of women with early‐stage cervical cancer.
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