Transcriptome, connectome and neuromodulation of the primate brain.

Single-cell transcriptomic analysis has facilitated cell type identification in the brain and mapping of cell type-specific connectomes, helping to elucidate neural circuits underlying brain functions and to treat brain disorders by neuromodulation. Yet, we lack a consensual definition of neuronal types/subtypes and clear distinction between cause and effect within interconnected networks.

Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma.

The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.

A selective filter for cytoplasmic transport at the axon initial segment.

Distinct molecules are segregated into somatodendritic and axonal compartments of polarized neurons, but mechanisms underlying the development and maintenance of such segregation remain largely unclear. In cultured hippocampal neurons, we observed an ankyrin G- and F-actin-dependent structure that emerged in the cytoplasm of the axon initial segment (AIS) within 2 days after axon/dendrite differentiation, imposing a selective filter for diffusion of macromolecules and transport of vesicular carriers into the axon. Axonal entry was allowed for KIF5-driven carriers of synaptic vesicle protein VAMP2, but not for KIF17-driven carriers of dendrite-targeting NMDA receptor subunit NR2B. Comparisons of transport rates between chimeric forms of KIF17 and KIF5B, with the motor and cargo-binding domains switched, and between KIF5 loaded with VAMP2 versus GluR2 suggest that axonal entry of vesicular carriers depends on the transport efficacy of KIF-cargo complexes. This selective AIS filtering may contribute to preferential trafficking and segregation of cellular components in polarized neurons.

The incidence of Clostridium difficile infection in children with and without inflammatory bowel diseases: A single-center study in Taiwan from 2006 to 2019.

BACKGROUND: The incidence of Clostridium difficile infection (CDI) is increasing around the world, and patients with inflammatory bowel disease (IBD) have a higher risk of obtaining CDI. The data on the incidence rate of CDI in the Asian pediatric IBD population was lacking. METHODS: We retrospectively collected data from a tertiary medical center in Taipei, Taiwan. All patients aged 1-18 years old who visited the outpatient department or were admitted to our hospital between 2006 and 2019 were included. CDI was defined as positive stool C. difficile toxin or C. difficile culture results with appropriate antibiotic use within the range of 7 days prior or 14 days after the result. RESULTS: We compared the average annual incidence of CDI before and after 2013. The average incidence of community-acquired CDI (CA-CDI) increased from 0.063 to 0.564 cases per 1,000 visits, with a rate ratio (RR) of 8.82 (95% CI 5.74-14.38). In patients with IBD, the rate increased from 26.738 to 278.873 cases per 1,000 visits (RR=10.12, 95% CI: 4.57-29.02). The average incidence rate increased from 0.685 to 1.874 cases per 1,000 admissions in pediatric general patients (RR = 2.72, 95% CI 1.82-4.20) and from 14.706 to 62.500 cases per 1,000 admissions in pediatric IBD patients (RR = 3.77, 95% CI 0.71-93.53). CONCLUSIONS: Both CA-CDI and healthcare facility-onset CDI (HO-CDI) were increasing substantially in the pediatric population over the past decade in Taiwan. Compared to the general pediatric population, pediatric IBD patients had a much higher incidence of CDI.

Global enhancement of cortical excitability following coactivation of large neuronal populations.

Correlated activation of cortical neurons often occurs in the brain and repetitive correlated neuronal firing could cause long-term modifications of synaptic efficacy and intrinsic excitability. We found that repetitive optogenetic activation of neuronal populations in the mouse cortex caused enhancement of optogenetically evoked firing of local coactivated neurons as well as distant cortical neurons in both ipsilateral and contralateral hemispheres. This global enhancement of evoked responses required coactivation of a sufficiently large population of neurons either within one cortical area or distributed in several areas. Enhancement of neuronal firing was saturable after repeated episodes of coactivation, diminished by inhibition of N-methyl-d-aspartic acid receptors, and accompanied by elevated excitatory postsynaptic potentials, all consistent with activity-induced synaptic potentiation. Chemogenetic inhibition of neuronal activity of the thalamus decreased the enhancement effect, suggesting thalamic involvement. Thus, correlated excitation of large neuronal populations leads to global enhancement of neuronal excitability.

Opportunities and limitations of genetically modified nonhuman primate models for neuroscience research.

The recently developed new genome-editing technologies, such as the CRISPR/Cas system, have opened the door for generating genetically modified nonhuman primate (NHP) models for basic neuroscience and brain disorders research. The complex circuit formation and experience-dependent refinement of the human brain are very difficult to model in vitro, and thus require use of in vivo whole-animal models. For many neurodevelopmental and psychiatric disorders, abnormal circuit formation and refinement might be at the center of their pathophysiology. Importantly, many of the critical circuits and regional cell populations implicated in higher human cognitive function and in many psychiatric disorders are not present in lower mammalian brains, while these analogous areas are replicated in NHP brains. Indeed, neuropsychiatric disorders represent a tremendous health and economic burden globally. The emerging field of genetically modified NHP models has the potential to transform our study of higher brain function and dramatically facilitate the development of effective treatment for human brain disorders. In this paper, we discuss the importance of developing such models, the infrastructure and training needed to maximize the impact of such models, and ethical standards required for using these models.

Irreducible anteromedial radial head dislocation without fracture caused by transposed biceps tendon in an adult: A case report and literature review.

Irreducible anteromedial radial head dislocation (IARHD) caused by transposed biceps tendon is rare. Delayed diagnosis and surgical failure often occur. A 46-year-old fisherman presented with 10 days history of painful swelling and restricted movement of his right elbow due to strangulation injury by a fishing boat cable. On examination, the images of right elbow reveals in a "semi-extended and pronated" elastic fixation position. Radiography and three-dimensional reconstruction CT reveals an isolated anteromedial radial head dislocation with extreme protonation of the radius and the bicipital tuberosity towards the posterior aspect of the elbow joint, and MRI shows biceps tendon wrapping around the radial neck, similar to umbilical cord wrapping seen in newborns. The Henry approach was applied for the first time to reduce the biceps tendon. The patient achieved a good functional recovery at 26 months, which represents the first reported case of IARHD without fracture caused by biceps tendon in an adult. In treatment of IARHD, attention should be paid to the phenomenon of biceps tendon transposition. Careful clinical examination, comprehensive imaging modalities, and appropriate surgical approach are the keys to successful management.

Investigation of Sulfur Doping in Mn-Co Oxide Nanotubes on Surface-Enhanced Raman Scattering Properties.

Doping engineering is an efficient strategy to manipulate the optoelectronic properties of metal oxides for sensing, catalysis, and energy applications. Herein, we have demonstrated the fabrication of sulfur (S)-doped Mn-Co oxides to regulate their band and surface electronic structures, which is beneficial to enhancing the charge transfer (CT) between the metal oxides and their adsorbed molecules. As expected, significantly enhanced SERS signals are achieved on S-doped Mn-Co oxide nanotubes, and the minimum detection concentration can reach as low as 10-8 M. Furthermore, the change in the electronic structure caused by S-doping provides different microelectric fields to influence the orientation of the interaction between the probe molecules and the substrate. Additionally, the evaluation of the oxidase-like catalytic activity of the substrate proved that, with an increase in the ratio of Co2+/Co3+ content, the number of electrons on the substrate increases, which promotes the CT process and further increases the degree of CT. The nonmetallic doping route in semiconducting metal oxides can provide effective and stable SERS activity; moreover, it provides a new strategy for exploring the relationship between CT in catalysis and SERS performance of semiconductors.

Electrodiffusion phenomena in neuroscience: a neglected companion.

The emerging technological revolution in genetically encoded molecular sensors and super-resolution imaging provides neuroscientists with a pass to the real-time nano-world. On this small scale, however, classical principles of electrophysiology do not always apply. This is in large part because the nanoscopic heterogeneities in ionic concentrations and the local electric fields associated with individual ions and their movement can no longer be ignored. Here, we review basic principles of molecular electrodiffusion in the cellular environment of organized brain tissue. We argue that accurate interpretation of physiological observations on the nanoscale requires a better understanding of the underlying electrodiffusion phenomena.

Growth of non-English-language literature on biodiversity conservation.

English is widely recognized as the language of science, and English-language publications (ELPs) are rapidly increasing. It is often assumed that the number of non-ELPs is decreasing. This assumption contributes to the underuse of non-ELPs in conservation science, practice, and policy, especially at the international level. However, the number of conservation articles published in different languages is poorly documented. Using local and international search systems, we searched for scientific articles on biodiversity conservation published from 1980 to 2018 in English and 15 non-English languages. We compared the growth rate in publications across languages. In 12 of the 15 non-English languages, published conservation articles significantly increased every year over the past 39 years, at a rate similar to English-language articles. The other three languages showed contrasting results, depending on the search system. Since the 1990s, conservation science articles in most languages increased exponentially. The variation in the number of non-English-language articles identified among the search systems differed markedly (e.g., for simplified Chinese, 11,148 articles returned with local search system and 803 with Scopus). Google Scholar and local literature search systems returned the most articles for 11 and 4 non-English languages, respectively. However, the proportion of peer-reviewed conservation articles published in non-English languages was highest in Scopus, followed by Web of Science and local search systems, and lowest in Google Scholar. About 20% of the sampled non-English-language articles provided no title or abstract in English; thus, in theory, they were undiscoverable with English keywords. Possible reasons for this include language barriers and the need to disseminate research in countries where English is not widely spoken. Given the known biases in statistical methods and study characteristics between English- and non-English-language studies, non-English-language articles will continue to play an important role in improving the understanding of biodiversity and its conservation.

RESUMEN: El inglés es reconocido como el idioma de la ciencia y las publicaciones en inglés (PI) cada vez son más. Con frecuencia se asume que el número de publicaciones en idiomas diferentes al inglés está disminuyendo. Esta suposición contribuye al uso reducido de las publicaciones que no están en inglés en las ciencias, prácticas y políticas de la conservación, especialmente a nivel internacional. Sin embargo, el número de artículos de conservación publicados en diferentes idiomas está muy mal documentado. Usamos sistemas de búsqueda locales e internacionales para buscar artículos científicos sobre la conservación de la biodiversidad publicados entre 1980 y 2018 en inglés y en quince idiomas diferentes al inglés. También comparamos la tasa de incremento de publicaciones en los diferentes idiomas. En doce de los quince idiomas diferentes al inglés, los artículos de conservación publicados incrementaron significativamente cada año durante los últimos 39 años, una tasa similar a los artículos en inglés. Los otros tres idiomas mostraron resultados contrastantes según el sistema de búsqueda. Desde la década de 1990, los artículos sobre ciencias de la conservación incrementaron exponencialmente en la mayoría de los idiomas. La variación en el número de artículos identificados en idiomas diferentes al inglés difirió notablemente de acuerdo con los sistemas de búsqueda (p. ej.: en el caso del chino simplificado, obtuvimos 11,148 artículos con el sistema de búsqueda local y 803 con Scopus). Google Scholar y los sistemas locales de búsqueda arrojaron la mayor cantidad de artículos en 11 y 4 idiomas diferentes al inglés, respectivamente. Sin embargo, la proporción de artículos sobre conservación revisados por pares y publicados en idiomas diferentes al inglés fue mayor en Scopus, seguida por Web of Science y los sistemas locales de búsqueda, con la menor proporción en Google Scholar. Aproximadamente el 20% de la muestra de artículos en idiomas diferentes al inglés no contaban con título o con resumen en inglés; por lo tanto, en teoría, eran imposibles de encontrar mediante palabras clave en inglés. Las posibles explicaciones de esto incluyen las barreras del idioma y la necesidad de difundir la investigación en países en los que el inglés no se habla extensamente. Con los sesgos conocidos de los métodos estadísticos y de las características de estudio entre los trabajos en inglés y en otros idiomas, los artículos en idiomas diferentes al inglés seguirán desempeñando un papel importante en el entendimiento de la biodiversidad y su conservación. Incremento de la Literatura sobre la Conservación de la Biodiversidad en Idiomas Diferentes al Inglés.

Frequency and mortality of sepsis and septic shock in China: a systematic review and meta-analysis.

BACKGROUND: Sepsis, a life-threatening organ dysfunction induced by infection, is a major public health problem. This study aimed to evaluate the frequency and mortality of sepsis, severe sepsis, and septic shock in China. METHODS: We Searched MEDLINE, Embase, PubMed, and Cochrane Library from 1 January 1992 to 1 June 2020 for studies that reported on the frequency and mortality of sepsis, severe sepsis, and septic shock conducted in China. Random effects models were performed to estimate the pooled frequency and mortality of sepsis, severe sepsis, and septic shock. RESULTS: Our search yielded 846 results, of which 29 studies were included in this review. The pooled frequency of sepsis was estimated at 33.6% (95% CI 25.9% to 41.3%, I2 = 99.2%; p < 0.001), and the pooled mortality of sepsis, severe sepsis and septic shock were 29.0% (95% CI 25.3%-32.8%, I2 = 92.1%; p = 0), 31.1% (95% CI 25.3% to 36.9%, I2 = 85.8%; p < 0.001) and 37.3% (95% CI 28.6%-46.0%, I2 = 93.5%; p < 0.001). There was significant heterogeneity between studies. With a small number of included studies and the changing definition of sepsis, trends in sepsis frequency and mortality were not sufficient for analysis. Epidemiological data on sepsis in the emergency department (ED) are severely lacking, and more research is urgently needed in this area is urgently needed. CONCLUSIONS: Our findings indicated that the frequency and mortality of sepsis and septic shock in China were much higher than North America and Europe countries. Based on our results, an extremely high incidence and mortality of sepsis and septic shock in China's mainland requires more healthcare budget support. Epidemiological data on sepsis and septic shock in ED are severely lacking, and more research is urgently needed in this area. Trial registration This systematic review was conducted according to the statement of the preferred reporting items for systematic review (PROSPERO CRD42021243325) and the meta-analysis protocols (PRISMA-P).

Emergence of stable striatal D1R and D2R neuronal ensembles with distinct firing sequence during motor learning.

The dorsolateral striatum (DLS) is essential for motor and procedure learning, but the role of DLS spiny projection neurons (SPNs) of direct and indirect pathways, as marked, respectively, by D1 and D2 receptor (D1R and D2R) expression, remains to be clarified. Long-term two-photon calcium imaging of the same neuronal population during mouse learning of a cued lever-pushing task revealed a gradual emergence of distinct D1R and D2R neuronal ensembles that reproducibly fired in a sequential manner, with more D1R and D2R neurons fired during the lever-pushing period and intertrial intervals (ITIs), respectively. This sequential firing pattern was specifically associated with the learned motor behavior, because it changed markedly when the trained mice performed other cued motor tasks. Selective chemogenetic silencing of D1R and D2R neurons impaired the initiation of learned motor action and suppression of erroneous lever pushing during ITIs, respectively. Thus, motor learning involves reorganization of DLS neuronal activity, forming stable D1R and D2R neuronal ensembles that fired sequentially to regulate different aspects of the learned behavior.

Local homogeneity of tonotopic organization in the primary auditory cortex of marmosets.

Marmoset has emerged as a useful nonhuman primate species for studying brain structure and function. Previous studies on the mouse primary auditory cortex (A1) showed that neurons with preferential frequency-tuning responses are mixed within local cortical regions, despite a large-scale tonotopic organization. Here we found that frequency-tuning properties of marmoset A1 neurons are highly uniform within local cortical regions. We first defined the tonotopic map of A1 using intrinsic optical imaging and then used in vivo two-photon calcium imaging of large neuronal populations to examine the tonotopic preference at the single-cell level. We found that tuning preferences of layer 2/3 neurons were highly homogeneous over hundreds of micrometers in both horizontal and vertical directions. Thus, marmoset A1 neurons are distributed in a tonotopic manner at both macro- and microscopic levels. Such organization is likely to be important for the organization of auditory circuits in the primate brain.

Functional organization of intrinsic and feedback presynaptic inputs in the primary visual cortex.

In the primary visual cortex (V1) of many mammalian species, neurons are spatially organized according to their preferred orientation into a highly ordered map. However, whether and how the various presynaptic inputs to V1 neurons are organized relative to the neuronal orientation map remain unclear. To address this issue, we constructed genetically encoded calcium indicators targeting axon boutons in two colors and used them to map the organization of axon boutons of V1 intrinsic and V2-V1 feedback projections in tree shrews. Both connections are spatially organized into maps according to the preferred orientations of axon boutons. Dual-color calcium imaging showed that V1 intrinsic inputs are precisely aligned to the orientation map of V1 cell bodies, while the V2-V1 feedback projections are aligned to the V1 map with less accuracy. Nonselective integration of intrinsic presynaptic inputs around the dendritic tree is sufficient to reproduce cell body orientation preference. These results indicate that a precisely aligned map of intrinsic inputs could reinforce the neuronal map in V1, a principle that may be prevalent for brain areas with function maps.

Early events in axon/dendrite polarization.

Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure.

Spontaneous expression of mirror self-recognition in monkeys after learning precise visual-proprioceptive association for mirror images.

Mirror self-recognition (MSR) is generally considered to be an intrinsic cognitive ability found only in humans and a few species of great apes. Rhesus monkeys do not spontaneously show MSR, but they have the ability to use a mirror as an instrument to find hidden objects. The mechanism underlying the transition from simple mirror use to MSR remains unclear. Here we show that rhesus monkeys could show MSR after learning precise visual-proprioceptive association for mirror images. We trained head-fixed monkeys on a chair in front of a mirror to touch with spatiotemporal precision a laser pointer light spot on an adjacent board that could only be seen in the mirror. After several weeks of training, when the same laser pointer light was projected to the monkey's face, a location not used in training, all three trained monkeys successfully touched the face area marked by the light spot in front of a mirror. All trained monkeys passed the standard face mark test for MSR both on the monkey chair and in their home cage. Importantly, distinct from untrained control monkeys, the trained monkeys showed typical mirror-induced self-directed behaviors in their home cage, such as using the mirror to explore normally unseen body parts. Thus, bodily self-consciousness may be a cognitive ability present in many more species than previously thought, and acquisition of precise visual-proprioceptive association for the images in the mirror is critical for revealing the MSR ability of the animal.

Regulating ferroportin-1 and transferrin receptor-1 expression: A novel function of hydrogen sulfide.

Hydrogen sulfide (H2 S) has a significant effect on the regulation of interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) activities, while IL-6 directly regulates hepcidin expression via STAT3. We therefore hypothesized that H 2 S has a role in body iron homeostasis by regulating the expression of iron transport proteins via the IL-6/STAT3/Hepcidin pathway. Here, we investigated the effects of two H 2 S donors sodium hydrosulfide and GYY4137 on the expression of ferroportin-1 (Fpn1), transferrin receptor-1 (TfR1), hepcidin, IL-6 and pSTAT3 in the spleen of mice in vivo and peritoneal macrophage in vitro. We also examined the effects of H 2 S on serum iron, transferrin saturation, and ferritin light chain contents in the spleen, and on nitrite content, nuclear factor erythroid 2-related factor-2 (Nrf2) and iron regulatory protein 1 (IRP1) in the macrophages. We demonstrated that H 2 S regulates the expression of TfR1 and Fpn1 in the spleen in vivo and in peritoneal macrophages in vitro predominantly via the IL-6/pSTAT3/hepcidin pathway, under the conditions of inflammation induced by lipopolysaccharides. We also provide evidence that under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H 2 S, both in vivo and in vitro, are mediated by the nitric oxide (NO)/Nrf2 and iron regulatory protein/iron responsive element pathways, respectively, which are independent of IL-6/pSTAT3/hepcidin signals. These findings show that H 2 S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions.

Cystathionine ß-synthase is required for body iron homeostasis.

Cystathionine ß-synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide. In view of the exceptionally high expression of CBS in the liver and the common interleukin-6 pathway used in the regulatory systems of hydrogen sulfide and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knockout (CBS-/- ) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen, and heart, along with severe damage to the liver, displaying a hemochromatosis-like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron overload is the reduced iron usage due to suppressed erythropoiesis, which is consistent with an increase in interleukin-6 and reduced expression of erythropoietin. Importantly, in the liver, absence of CBS caused both a reduction in the transcriptional factor nuclear factor erythroid 2-related factor-2 and an up-regulation of hepcidin that led to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS-overexpressing adenovirus into CBS mutant mice could partially reverse the iron-related phenotype. CONCLUSION: Our findings point to a critical role of CBS in iron homeostasis of the body, and the liver in particular; it is likely that a hemochromatosis-like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway but also of those related to CBS. (Hepatology 2018;67:21-35).