Soil source, not the degree of urbanization determines soil physicochemical properties and bacterial composition in Ningbo urban green spaces.

Urban green spaces provide multiple ecosystem services and have great influences on human health. However, the compositions and properties of urban soil are not well understood yet. In this study, soil samples were collected from 45 parks in Ningbo to investigate the relationships among soil physicochemical properties, heavy metals and bacterial communities. The results showed that soil dissolved organic matter (DOM) was of high molecular weight, high aromaticity, and low degree of humification. The contents of heavy metals were all below the China's national standard safety limit (GB 3660-2018). The bioavailability of heavy metals highly correlated with soil pH, the content of DOC, the fluorescent component, the degree of humification and the source of DOM. The most abundant genera were Gemmatimonadaceae_uncultured, Xanthobacteraceae_uncultured, and Acidothermus in all samples, which were related to nitrogen cycle and bioavailability of heavy metals. Soil pH, bioavailability of Zn, Cd, Pb, and Ni (CaCl2 extracted) were the main edaphic factors influencing bacterial community composition. It should be noted that there was no significant impact of urbanization on soil physicochemical properties and bacterial composition, but they were determined by the source of soil in urban green spaces. However, with the passage of time, the effect of urbanization on urban green spaces cannot be ignored. Overall, this study provided new insight for understanding the linkage among soil physicochemical properties, heavy metals, and bacterial communities in urban green spaces.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

Reduction of DHHC5-mediated beclin 1 S-palmitoylation underlies autophagy decline in aging.

Autophagy is a lysosome-dependent degradation pathway essential for cellular homeostasis, which decreases with age. However, it is unclear how aging induces autophagy decline. Here we show the role of protein S-palmitoylation in autophagy. We identify the palmitoyl acyltransferase DHHC5 as a regulator of autophagy by mediating the palmitoylation of beclin 1, which in turn promotes the formation of ATG14L-containing class III phosphatidylinositol-3-kinase complex I and its lipid kinase activity by promoting the hydrophobic interactions between beclin 1 and adapter proteins ATG14L and VPS15. In aging brains of human and nonhuman primate, the levels of DHHC5 exhibit a marked decrease in expression. We show that DHHC5 deficiency in neurons leads to reduced cellular protein homeostasis in two established murine models of Alzheimer's disease, which exaggerates neurodegeneration in an autophagy-dependent manner. These findings identify reduction of DHHC5-mediated beclin 1 S-palmitoylation as an underlying mechanism by which aging induces autophagy decline.

miR-34a regulates silent synapse and synaptic plasticity in mature hippocampus.

AMPAR-lacking silent synapses are prevailed and essential for synaptic refinement and synaptic plasticity in developing brains. In mature brain, they are sparse but could be induced under several pathological conditions. How they are regulated molecularly is far from clear. miR-34a is a highly conserved and brain-enriched microRNA with age-dependent upregulated expression profile. Its neuronal function in mature brain remains to be revealed. Here by analyzing synaptic properties of the heterozygous miR-34a knock out mice (34a_ht), we have discovered that mature but not juvenile 34a_ht mice have more silent synapses in the hippocampus accompanied with enhanced synaptic NMDAR but not AMPAR function and increased spine density. As a result, 34a_ht mice display enhanced long-term potentiation (LTP) in the Schaffer collateral synapses and better spatial learning and memory. We further found that Creb1 is a direct target of miR-34a, whose upregulation and activation may mediate the silent synapse increment in 34a_ht mice. Hence, we reveal a novel physiological role of miR-34a in mature brains and provide a molecular mechanism underlying silent synapse regulation.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Circadian time- and sleep-dependent modulation of cortical parvalbumin-positive inhibitory neurons.

Parvalbumin-positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time- and sleep-dependent manner throughout the 24-h day. We first show that PV-evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus-evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.

Clinical analysis of subxiphoid vs. lateral approaches for treating early anterior mediastinal thymoma.

Objective: To investigate the clinical efficacy of the subxiphoid approach for early anterior mediastinal thymoma and evaluate its advantages over the lateral intercostal approach. Methods: A total of 345 patients with early anterior mediastinal thymoma were retrospectively analyzed from January 2016 to December 2020 in the First Affiliated Hospital of Soochow University. Out of these, 99 patients underwent subxiphoid video-assisted thoracoscopic thymectomy and 246 patients underwent transthoracic video-assisted thoracoscopic thymectomy. We compared the intraoperative conditions (such as operation time and intraoperative blood loss), postoperative conditions [such as postoperative pleural drainage volume, extubation time, postoperative hospital stay, and postoperative visual analogue scale (VAS) pain score], and postoperative complications (such as death, pneumonia, delayed wound healing, cardiac arrhythmia, and phrenic nerve injury) of the two groups and analyzed the clinical advantages of the subxiphoid approach for treating early anterior mediastinal thymoma. Results: There was no significant difference between the two groups in terms of general clinical features, operation time, and postoperative complications (P > 0.05).However, there was a significant difference in terms of intraoperative blood loss, postoperative pleural drainage volume, tube extubation time, postoperative hospital stay, postoperative VAS pain score, and postoperative analgesics (a significantly decreased flurbiprofen axetil amount) (P < 0.05). Conclusion: Compared with the lateral intercostal thoracic approach, the subxiphoid approach had advantages in terms of intraoperative blood loss, postoperative hospital stay, tube extubation time, postoperative pleural drainage volume, postoperative VAS pain score, and analgesics dosage. It could provide a better view of the bilateral pleural cavities and more thorough thymectomy and superior cosmesis, and it proved to be a safe and feasible minimally invasive surgical method.

The precision medicine process for treating rare disease using the artificial intelligence tool mediKanren.

There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments. A promising avenue for treatment is drug repurposing, where FDA-approved drugs are repositioned as novel treatments. However, linking disease mechanisms to drug action can be extraordinarily difficult and requires a depth of knowledge across multiple fields, which is complicated by the rapid pace of biomedical knowledge discovery. To address these challenges, The Hugh Kaul Precision Medicine Institute developed an artificial intelligence tool, mediKanren, that leverages the mechanistic insight of genetic disorders to identify therapeutic options. Using knowledge graphs, mediKanren enables an efficient way to link all relevant literature and databases. This tool has allowed for a scalable process that has been used to help over 500 rare disease families. Here, we provide a description of our process, the advantages of mediKanren, and its impact on rare disease patients.

Correlations of FRMD7 gene mutations with ocular oscillations.

Mutations in the FERM domain containing 7 (FRMD7) gene have been proven to be responsible for infantile nystagmus (IN). The purpose of this study is to investigate FRMD7 gene mutations in patients with IN, and to evaluate the nystagmus intensity among patients with and without FRMD7 mutations. The affected males were subdivided into three groups according to whether or not having FRMD7 mutations and the types of mutations. Fifty-two mutations were detected in FRMD7 in 56 pedigrees and 34 sporadic patients with IN, including 28 novel and 24 previous reported mutations. The novel identified mutations further expand the spectrum of FRMD7 mutations. The parameters of nystagmus intensity and the patients' best corrected visual acuity were not statistically different among the patients with and without identified FRMD7 mutations, and also not different among patients with different mutant types. The FERM-C domain, whose amino acids are encoded by exons 7, 8 and 9, could be the harbor region for most mutations. Loss-of-function is suggested to be the common molecular mechanism for the X-linked infantile nystagmus.

Mutations of TOPORS identified in families with retinitis pigmentosa.

PURPOSE: To identify TOPORS mutations in patients with retinitis pigmentosa (RP) from our cohort and summarize the genotypes and phenotypes of TOPORS reported previously. METHOD: Probands with RP phenotypes were recruited from our genetic retinopathy screening work. DNA was extracted from the peripheral venous blood, and exome sequencing was performed. We further examined the clinical data and family history in detail in these patients. TOPORS mutations associated with RP were searched and summarized from the previous reports, and the results were combined with the data presented in our study. The mutation spectrum of TOPORS was systematically analyzed, and the phenotypes of truncated mutations and missense mutations were compared and described. RESULT: Mutations in TOPORS were detected in three families, including two novel mutations (c.2017C>T, p.Arg673Cys, c.2371A>T, p.Lys791Term) and a known frameshift mutation (c.2554_2557delGAGA, p. Glu852fsTer13). A comprehensive analysis showed that 64.1% (25/39) of the mutant alleles are truncated mutations, and 34.3% (12/39) are missense mutations. About 89.7% (35/39) of the mutations are located in the terminal half of exon 3, which affected the C-terminal of the TOPORS protein. Night blindness was a common onset symptom, and TOPORS-related ERG changes can be observed in early stage. In addition, patients with missense mutations retained better central vision in older age compared to the patients with truncated mutations. CONCLUSION: We expand the mutation spectrum and assess the possible genotype-phenotype correlations of TOPORS, which can provide a valuable reference for exploring the pathogenesis of adRP caused by TOPORS mutations.

A Multisubcellular Compartment Model of AMPA Receptor Trafficking for Neuromodulation of Hebbian Synaptic Plasticity.

Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull-push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull-push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.

Ion mobility-based sterolomics reveals spatially and temporally distinctive sterol lipids in the mouse brain.

Aberrant sterol lipid metabolism is associated with physiological dysfunctions in the aging brain and aging-dependent disorders such as neurodegenerative diseases. There is an unmet demand to comprehensively profile sterol lipids spatially and temporally in different brain regions during aging. Here, we develop an ion mobility-mass spectrometry based four-dimensional sterolomics technology leveraged by a machine learning-empowered high-coverage library (>2000 sterol lipids) for accurate identification. We apply this four-dimensional technology to profile the spatially resolved landscapes of sterol lipids in ten functional regions of the mouse brain, and quantitatively uncover ~200 sterol lipids uniquely distributed in specific regions with concentrations spanning up to 8 orders of magnitude. Further spatial analysis pinpoints age-associated differences in region-specific sterol lipid metabolism, revealing changes in the numbers of altered sterol lipids, concentration variations, and age-dependent coregulation networks. These findings will contribute to our understanding of abnormal sterol lipid metabolism and its role in brain diseases.

Wild-type α-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding.

Heterozygous point mutations of α-synuclein (α-syn) have been linked to the early onset and rapid progression of familial Parkinson's diseases (fPD). However, the interplay between hereditary mutant and wild-type (WT) α-syn and its role in the exacerbated pathology of α-syn in fPD progression are poorly understood. Here, we find that WT mice inoculated with the human E46K mutant α-syn fibril (hE46K) strain develop early-onset motor deficit and morphologically different α-syn aggregation compared with those inoculated with the human WT fibril (hWT) strain. By using cryo-electron microscopy, we reveal at the near-atomic level that the hE46K strain induces both human and mouse WT α-syn monomers to form the fibril structure of the hE46K strain. Moreover, the induced hWT strain inherits most of the pathological traits of the hE46K strain as well. Our work suggests that the structural and pathological features of mutant strains could be propagated by the WT α-syn in such a way that the mutant pathology would be amplified in fPD.

The Diagnosis of Intrapulmonary Metastasis Multifocal Pulmonary Ground-Glass Nodules Based on Oncogenic Driver Mutation: Two Case Reports and Review of Literature.

With the increased use of low-dose computed tomography (LDCT), the detection of multifocal pulmonary ground-glass nodules (GGNs) has increased. According to the current clinical guidelines, multifocal GGNs tend to be treated as the multiple primary early-stage lung adenocarcinoma. However, studies have indicated that parts of multiple GGNs may originate from single nodules via intrapulmonary metastasis (IPM). Such IPM indicates the advanced stages even when the multiple GGNs are present as the early characteristics in pathological assessments. However, no gold standard exists for the differential diagnosis of multiple IPM GGNs. Here, we report two multifocal pulmonary GGNs cases where panel sequencing (672 driver mutation loci) showed that patient 1 (P1) shared two rare epidermal growth factor receptor (EGFR) mutations (primary L747_T751del and primary T790M) in the left upper lobe anterior segment and left lower lobe superior segment, respectively. Patient 2 (P2) shared a low-frequency human epidermal growth factor receptor 2 (HER2) mutation (primary Tyr772_Ala775dup) in two GGNs located in the apicoposterior and superior lingular segment of the left lower lobe (LLL). Oncogenic driver mutations were concordant between primary tumors and metastasis. Thus, shared low-frequency driver mutations in multiple GGNs strongly suggested that IPM existed with a high probability in these patients. Also, tumor cell spread through air spaces (STAS) was identified in pathological sections of the left upper lobe (LUL) nodule of P1, suggesting aerogenous spread may have been an effective pathway for IPM. Our report suggests that oncogenic driver mutations have prominent diagnostic value for IPM. Also, GGN IPM may occur in one lung lobe and between in different lung lobes.

Personalized Federated Learning for Intelligent IoT Applications: A Cloud-Edge based Framework.

Internet of Things (IoT) have widely penetrated in different aspects of modern life and many intelligent IoT services and applications are emerging. Recently, federated learning is proposed to train a globally shared model by exploiting a massive amount of user-generated data samples on IoT devices while preventing data leakage. However, the device, statistical and model heterogeneities inherent in the complex IoT environments pose great challenges to traditional federated learning, making it unsuitable to be directly deployed. In this paper we advocate a personalized federated learning framework in a cloud-edge architecture for intelligent IoT applications. To cope with the heterogeneity issues in IoT environments, we investigate emerging personalized federated learning methods which are able to mitigate the negative effects caused by heterogeneities in different aspects. With the power of edge computing, the requirements for fast-processing capacity and low latency in intelligent IoT applications can also be achieved. We finally provide a case study of IoT based human activity recognition to demonstrate the effectiveness of personalized federated learning for intelligent IoT applications.

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa.

Although an increasing number of disease genes have been identified, the exact cellular mechanisms of retinitis pigmentosa (RP) remain largely unclear. Retinal organoids (ROs) derived from the induced pluripotent stem cells (iPSCs) of patients provide a potential but unvalidated platform for deciphering disease mechanisms and an advantageous tool for preclinical testing of new treatments. Notably, early-onset RP has been extensively recapitulated by patient-iPSC-derived ROs. However, it remains a challenge to model late-onset disease in a dish due to its chronicity, complexity, and instability. Here, we generated ROs from late-onset RP proband-derived iPSCs harboring a PDE6B mutation. Transcriptome analysis revealed a remarkably distinct gene expression profile in the patient ROs at differentiation day (D) 230. Changes in the expression genes regulating cGMP hydrolysis prompted the elevation of cGMP levels, which was verified by a cGMP enzyme-linked immunosorbent assay (ELISA) in patient ROs. Furthermore, significantly higher cGMP levels in patient ROs than in control ROs at D193 and D230 might lead to impaired formation of synaptic connections and the connecting cilium in photoreceptor cells. In this study, we established the first late-onset RP model with a consistent phenotype using an in vitro cell culture system and provided new insights into the PDE6B-related mechanism of RP.

Daily Oscillation of the Excitation-Inhibition Balance in Visual Cortical Circuits.

A balance between synaptic excitation and inhibition (E/I balance) maintained within a narrow window is widely regarded to be crucial for cortical processing. In line with this idea, the E/I balance is reportedly comparable across neighboring neurons, behavioral states, and developmental stages and altered in many neurological disorders. Motivated by these ideas, we examined whether synaptic inhibition changes over the 24-h day to compensate for the well-documented sleep-dependent changes in synaptic excitation. We found that, in pyramidal cells of visual and prefrontal cortices and hippocampal CA1, synaptic inhibition also changes over the 24-h light/dark cycle but, surprisingly, in the opposite direction of synaptic excitation. Inhibition is upregulated in the visual cortex during the light phase in a sleep-dependent manner. In the visual cortex, these changes in the E/I balance occurred in feedback, but not feedforward, circuits. These observations open new and interesting questions on the function and regulation of the E/I balance.