Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems.

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

A brainstem map for visceral sensations.

The nervous system uses various coding strategies to process sensory inputs. For example, the olfactory system uses large receptor repertoires and is wired to recognize diverse odours, whereas the visual system provides high acuity of object position, form and movement1-5. Compared to external sensory systems, principles that underlie sensory processing by the interoceptive nervous system remain poorly defined. Here we developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives vagal and other inputs from the body. Focusing on gut and upper airway stimuli, we observed that individual NTS neurons are tuned to detect signals from particular organs and are topographically organized on the basis of body position. Moreover, some mechanosensory and chemosensory inputs from the same organ converge centrally. Sensory inputs engage specific NTS domains with defined locations, each containing heterogeneous cell types. Spatial representations of different organs are further sharpened in the NTS beyond what is achieved by vagal axon sorting alone, as blockade of brainstem inhibition broadens neural tuning and disorganizes visceral representations. These findings reveal basic organizational features used by the brain to process interoceptive inputs.

Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase.

Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

Modality-Specific Modulation of Temperature Representations in the Spinal Cord after Injury.

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENT In this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics, and persistent pain models to study how tissue injury alters the sensation of temperature. We discover modality-specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bidirectional change of thermosensitivity by injury and suggests that the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception toward a unique thermal modality that was observed clinically in chronic pain patients.

Brain age vector: A measure of brain aging with enhanced neurodegenerative disorder specificity.

Neuroimaging-driven brain age estimation has become popular in measuring brain aging and identifying neurodegenerations. However, the single estimated brain age (gap) compromises regional variations of brain aging, losing spatial specificity across diseases which is valuable for early screening. In this study, we combined brain age modeling with Shapley Additive Explanations to measure brain aging as a feature contribution vector underlying spatial pathological aging mechanism. Specifically, we regressed age with volumetric brain features using machine learning to construct the brain age model, and model-agnostic Shapley values were calculated to attribute regional brain aging for each subject's age estimation, forming the brain age vector. Spatial specificity of the brain age vector was evaluated among groups of normal aging, prodromal Parkinson disease (PD), stable mild cognitive impairment (sMCI), and progressive mild cognitive impairment (pMCI). Machine learning methods were adopted to examine the discriminability of the brain age vector in early disease screening, compared with the other two brain aging metrics (single brain age gap, regional brain age gaps) and brain volumes. Results showed that the proposed brain age vector accurately reflected disorder-specific abnormal aging patterns related to the medial temporal and the striatum for prodromal AD (sMCI vs. pMCI) and PD (healthy controls [HC] vs. prodromal PD), respectively, and demonstrated outstanding performance in early disease screening, with area under the curves of 83.39% and 72.28% in detecting pMCI and prodromal PD, respectively. In conclusion, the proposed brain age vector effectively improves spatial specificity of brain aging measurement and enables individual screening of neurodegenerative diseases.

High-resolution mapping of the global silicate weathering carbon sink and its long-term changes.

Climatic and non-climatic factors affect the chemical weathering of silicate rocks, which in turn affects the CO2 concentration in the atmosphere on a long-term scale. However, the coupling effects of these factors prevent us from clearly understanding of the global weathering carbon sink of silicate rocks. Here, using the improved first-order model with correlated factors and non-parametric methods, we produced spatiotemporal data sets (0.25° × 0.25°) of the global silicate weathering carbon-sink flux (SCSFα ) under different scenarios (SSPs) in present (1950-2014) and future (2015-2100) periods based on the Global River Chemistry Database and CMIP6 data sets. Then, we analyzed and identified the key regions in space where climatic and non-climatic factors affect the SCSFα . We found that the total SCSFα was 155.80 ± 90 Tg C yr-1 in present period, which was expected to increase by 18.90 ± 11 Tg C yr-1 (12.13%) by the end of this century. Although the SCSFα in more than half of the world was showing an upward trend, about 43% of the regions were still showing a clear downward trend, especially under the SSP2-4.5 scenario. Among the main factors related to this, the relative contribution rate of runoff to the global SCSFα was close to 1/3 (32.11%), and the main control regions of runoff and precipitation factors in space accounted for about 49% of the area. There was a significant negative partial correlation between leaf area index and silicate weathering carbon sink flux due to the difference between the vegetation types. We have emphasized quantitative analysis the sensitivity of SCSFα to critical factors on a spatial grid scale, which is valuable for understanding the role of silicate chemical weathering in the global carbon cycle.

Chronological Changes of Viral Shedding in Adult Inpatients With COVID-19 in Wuhan, China.

BACKGROUND: In December 2019, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan. Epidemiological and clinical characteristics of patients with COVID-19 have been reported, but the relationships between laboratory features and viral load has not been comprehensively described. METHODS: Adult inpatients (≥18 years old) with COVID-19 who underwent multiple (≥5 times) nucleic acid tests with nasal and pharyngeal swabs were recruited from Renmin Hospital of Wuhan University, including general patients (n = 70), severe patients (n = 195), and critical patients (n = 43). Laboratory data, demographic data, and clinical data were extracted from electronic medical records. The fitted polynomial curve was used to explore the association between serial viral loads and illness severity. RESULTS: Viral load of SARS-CoV-2 peaked within the first few days (2-4 days) after admission, then decreased rapidly along with virus rebound under treatment. Critical patients had the highest viral loads, in contrast to the general patients showing the lowest viral loads. The viral loads were higher in sputum compared with nasal and pharyngeal swab (P = .026). The positive rate of respiratory tract samples was significantly higher than that of gastrointestinal tract samples (P < .001). The SARS-CoV-2 viral load was negatively correlated with portion parameters of blood routine and lymphocyte subsets and was positively associated with laboratory features of cardiovascular system. CONCLUSIONS: The serial viral loads of patients revealed whole viral shedding during hospitalization and the resurgence of virus during the treatment, which could be used for early warning of illness severity, thus improve antiviral interventions.

Potential influence of COVID-19/ACE2 on the female reproductive system.

The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2.

Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation.

Paired box 6 (Pax6) is considered to be the master control gene for eye development in all seeing animals studied so far. In vertebrates, it is required not only for lens/retina formation but also for the development of the CNS, olfactory system, and pancreas. Although Pax6 plays important roles in cell differentiation, proliferation, and patterning during the development of these systems, the underlying mechanism remains poorly understood. In the fruit fly, Drosophila melanogaster, Pax6 also functions in a range of tissues, including the eye and brain. In this report, we describe the function of Pax6 in Drosophila eye-antennal disc development. Previous studies have suggested that the two fly Pax6 genes, eyeless (ey) and twin of eyeless (toy), initiate eye specification, whereas eyegone (eyg) and the Notch (N) pathway independently regulate cell proliferation. Here, we show that Pax6 controls eye progenitor cell survival and proliferation through the activation of teashirt (tsh) and eyg, thereby indicating that Pax6 initiates both eye specification and proliferation. Although simultaneous loss of ey and toy during early eye-antennal disc development disrupts the development of all head structures derived from the eye-antennal disc, overexpression of N or tsh in the absence of Pax6 rescues only antennal and head epidermis development. Furthermore, overexpression of tsh induces a homeotic transformation of the fly head into thoracic structures. Taking these data together, we demonstrate that Pax6 promotes development of the entire eye-antennal disc and that the retinal determination network works to repress alternative tissue fates, which ensures proper development of adult head structures.

Input-specific control of reward and aversion in the ventral tegmental area.

Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

Parasites and asthma.

Nowadays, many studies have found low morbidity of asthma in epidemic areas of parasitic diseases, as shown by the hygiene hypothesis. It is obvious that some parasite infections can prevent asthma and studies have been carried out to clarify the mechanism of the preventive effect and search for the future asthmatic therapies. Previous findings have indicated that this mechanism may be related to the immune response switching from Th1 to Th2 and important cells induced by parasites, including the regulatory T cells, regulatory B cells, dendrite cells, and alternatively activated macrophages. Cytokine IL-10 also plays a nonredundant role in protection against allergic airway inflammation in asthma. This review focuses on the relationship between parasites and asthma, and the potential protection mechanism involved.

Recent Progress in Brain Network Models for Medical Applications: A Review.

Importance: Pathological perturbations of the brain often spread via connectome to fundamentally alter functional consequences. By integrating multimodal neuroimaging data with mathematical neural mass modeling, brain network models (BNMs) enable to quantitatively characterize aberrant network dynamics underlying multiple neurological and psychiatric disorders. We delved into the advancements of BNM-based medical applications, discussed the prevalent challenges within this field, and provided possible solutions and future directions. Highlights: This paper reviewed the theoretical foundations and current medical applications of computational BNMs. Composed of neural mass models, the BNM framework allows to investigate large-scale brain dynamics behind brain diseases by linking the simulated functional signals to the empirical neurophysiological data, and has shown promise in exploring neuropathological mechanisms, elucidating therapeutic effects, and predicting disease outcome. Despite that several limitations existed, one promising trend of this research field is to precisely guide clinical neuromodulation treatment based on individual BNM simulation. Conclusion: BNM carries the potential to help understand the mechanism underlying how neuropathology affects brain network dynamics, further contributing to decision-making in clinical diagnosis and treatment. Several constraints must be addressed and surmounted to pave the way for its utilization in the clinic.

Effects of different adding methods of fermentation medium on the quality of cigar.

Background: To investigate the effects of different media and media addition methods on the fermentation of tobacco. Methods: A plant extract and a bacterial agent are used for fermenting cigar tobacco leaves in a different order of addition. The chemical composition, cellulose, and pectin content, as well as changes in the microbial community, were measured. Results: The addition method of the fermentation medium affects the quality of fermented tobacco. The optimal medium formula and addition method involve first adding plant extracts and then microbial agents. The medium formula and addition method can significantly reduce cellulose in tobacco, with a reduction rate of 46%, and significantly increase the content of ß-carotene, thereby enhancing the aroma of cigarettes. There is an increase in aroma components, such as alcohols, alkanes, and olefins, in tobacco. By reducing the proportion of Aspergillus, it can alter the microbial community structure of tobacco. Conclusion: Adding plant extracts before introducing microbial agents can significantly improve the quality and alter the microbial community structure of Dexue No.1 tobacco.

Unexpected response of terrestrial carbon sink to rural depopulation in China.

China is experiencing large-scale rural-urban migration and rapid urbanization, which have had significant impact on terrestrial carbon sink. However, the impact of rural-urban migration and its accompanying urban expansion on the carbon sink is unclear. Based on multisource remote sensing product data for 2000-2020, the soil microbial respiration equation, relative contribution rate, and threshold analysis, we explored the impact of rural depopulation on the carbon sink and its threshold. The results revealed that the proportion of the rural population in China decreased from 63.91 % in 2000 to 36.11 % in 2020. Human pressure decreased by 1.82% in rural depopulation areas, which promoted vegetation restoration in rural areas (+8.45 %) and increased the carbon sink capacity. The net primary productivity (NPP) and net ecosystem productivity (NEP) of the vegetation in the rural areas increased at rates of 2.95 g C m-2 yr-1 and 2.44 g C m-2 yr-1. Strong rural depopulation enhanced the carbon sequestration potential, and the NEP was 1.5 times higher in areas with sharp rural depopulation than in areas with mild rural depopulation. In addition, the rural depopulation was accompanied by urban expansion, and there was a positive correlation between the comprehensive urbanization level (CUL) and NEP in 75.29 % of urban areas. In the urban areas, the vegetation index increased by 88.42 %, and the urban green space partially compensated for the loss of carbon sink caused by urban expansion, with a growth rate of 4.96 g C m-2 yr-1. Changes in rural population have a nonlinear impact on the NEP. When the rural population exceeds 545.686 people/km2, an increase in the rural population will have a positive impact on the NEP. Our research shows that rural depopulation offers a potential opportunity to restore natural ecosystems and thus increase the carbon sequestration capacity.

Threat of soil formation rate to health of karst ecosystem.

Karst ecosystems are important to several billion people, so it is necessary to accurately diagnose and evaluate the health of these ecosystems for socioeconomic development; however, the existing evaluation methods have many limitations, so they cannot accurately evaluate the ecosystem health in karst areas. In particular, they ignore the influence and restriction of the soil formation rate on the ecosystem health. To this end, we established a new index to represent the actual health status of karst ecosystems. The soil formation rate was found to pose a threat to the health of 28 % of the world's karst ecosystems, covering an area of 594 km2. In addition, a dataset of global karst ecosystem health index values with a spatial resolution of about 8 km × 8 km from 2000 to 2014 was created, and the proportion of unhealthy areas was found to be as high as 75.91 %. This study highlights the contribution of the soil formation rate to karst ecosystem health and provides a new method and deeper scientific understanding for further accurate evaluation of karst ecosystem health, which can improve future ecosystem health research and social management.

Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala.

Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala. In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.

Accelerating the Improvement of Human Well-Being in China through Economic Growth and Policy Adjustment.

Human well-being in many countries lags behind the gross domestic product (GDP) due to the rapid changes in the socio-economic environment that have occurred for decades. However, the mechanisms behind this complex phenomenon are still unclear. This study revealed the changes in human well-being in China from 1995 to 2017 by revising the genuine progress indicator (GPI) at the national level and further quantified the contribution of interfering factors that have driven the increase in the GPI. The results indicated that: (1) The per capita GPI of China showed an increasing trend with an annual growth rate of 12.43%. The changes in the GPI followed the same pattern as economic development, rather than presenting the phenomenon of economic growth combined with a decline in welfare that has been recorded in some countries and regions. (2) The increase in human well-being was mainly driven by economic growth, but it was most sensitive to social factors. (3) Increasing income inequality and the cost of lost leisure time contributed obvious negative impacts (24.69% and 23.35%, respectively) to the per capita GPI. However, the increase in personal consumption expenditures, the value of domestic labor, ecosystem service value, and net capital growth accelerated the rise in the GPI, with positive contribution rates of 30.69%, 23%, 20.54%, and 20.02%, respectively. (4) The continuous increase in economic investment and the strengthening of social management due to policy adjustments completely counteracted the negative impacts on human well-being, thus leading to a great increase in the per capita GPI. Such insights could provide theoretical support for decision making and policy implementation to improve global human well-being.

Limitations of soil moisture and formation rate on vegetation growth in karst areas.

Vegetation changes in karst areas are controlled by the soil formation rate (SFR) and soil moisture (SM). However, little is known about their thresholds and global control patterns. To this end, based on high-precision climate and vegetation data for 2000-2014, using Pearson correlation analysis, the Hurst index, and change-point analysis, the thresholds of the SFR and SM in vegetation growth in karst areas were identified. Furthermore, a spatial map (0.125° × 0.125°) of the global karst ecosystem with a static/dynamic limitation zone was established. We found that the net primary productivity (NPP) in 70% of the global climate zones exhibited a dual restriction relationship with the SM and SFR. The limitations of the SFR and SM in vegetation growth were most obvious in subpolar and semi-arid climates. In addition, their ecological thresholds were 25.2 t km-2 yr-1 and 0.28 m3 m-3, respectively. The static limitation of the SFR on the NPP in karst areas accounted for 28.37%, and the influence of the SM enhanced this limit (21.79%). The limitation of the SFR on vegetation was mainly concentrated in Boreal forests (17%), and the limitation of the SM was mainly concentrated in tropical savannas (12%). The NPP and the Normalized Difference Vegetation Index (NDVI) were the most sensitive to changes in the SM and SFR. Moreover, the analysis based on 14 ecologically limitation karst areas further revealed that the reduction in these factors may cause the tropical rain forest to experience degradation. It can be seen that the SM enhanced the limiting effect of the SFR on vegetation in karst areas. In short, this interpretation of karst vegetation limitations provides a deeper understanding of and approach to ecosystem evolution and vegetation restoration in these regions.

The responses of weathering carbon sink to eco-hydrological processes in global rocks.

Eco-hydrological processes affect the chemical weathering carbon sink (CS) of rocks. However, due to data quality limitations, the magnitude of the CS of rocks and their responses to eco-hydrological processes are not accurately understood. Therefore, based on Global Erosion Model for CO2 fluxes (GEM-CO2 model), hydrological site data, and multi-source remote sensing data, we produced a 0.05° × 0.05° resolution dataset of CS for 11 types of rocks from 2001 to 2018. The results show that the total amount of CS of global rocks is 0.32 ± 0.02 Pg C, with an average flux of 2.7 t C km-2 yr-1, accounting for 53% and 3% of the "missing" carbon sink and fossil fuel emissions, respectively. This is 23% higher than previous research results, which may be due to the increased resolution. Although about 60% of the CS of global rocks are in a stable state, there are obvious differences among rocks. For example, the CS of carbonate rocks exhibited a significant increase (0.30 Tg C/yr), while the CS of siliceous clastic sedimentary rocks exhibited a significant decrease (-0.06 Tg C/yr). Although temperature is an important factor affecting the CS, the proportion of soil moisture in arid and temperate climate zones is higher (accounting for 24%), which is 3.6 times that of temperature. Simulations based on representative concentration pathways scenarios indicate that the global CS of rocks may increase by about 28% from 2050 to 2100. In short, we produced a set of high-resolution datasets for the CS of global rocks, which makes up for the lack of datasets in previous studies and improves our understanding of the magnitude and spatial pattern of the CS and its responses to eco-hydrological processes.