Deciphering spatial domains from spatial multi-omics with SpatialGlue.

Advances in spatial omics technologies now allow multiple types of data to be acquired from the same tissue slice. To realize the full potential of such data, we need spatially informed methods for data integration. Here, we introduce SpatialGlue, a graph neural network model with a dual-attention mechanism that deciphers spatial domains by intra-omics integration of spatial location and omics measurement followed by cross-omics integration. We demonstrated SpatialGlue on data acquired from different tissue types using different technologies, including spatial epigenome-transcriptome and transcriptome-proteome modalities. Compared to other methods, SpatialGlue captured more anatomical details and more accurately resolved spatial domains such as the cortex layers of the brain. Our method also identified cell types like spleen macrophage subsets located at three different zones that were not available in the original data annotations. SpatialGlue scales well with data size and can be used to integrate three modalities. Our spatial multi-omics analysis tool combines the information from complementary omics modalities to obtain a holistic view of cellular and tissue properties.

Transcriptome analysis of Kluyveromyces marxianus under succinic acid stress and development of robust strains.

Kluyveromyces marxianus has become an attractive non-conventional yeast cell factory due to its advantageous properties such as high thermal tolerance and rapid growth. Succinic acid (SA) is an important platform molecule that has been applied in various industries such as food, material, cosmetics, and pharmaceuticals. SA bioproduction may be compromised by its toxicity. Besides, metabolite-responsive promoters are known to be important for dynamic control of gene transcription. Therefore, studies on global gene transcription under various SA concentrations are of great importance. Here, comparative transcriptome changes of K. marxianus exposed to various concentrations of SA were analyzed. Enrichment and analysis of gene clusters revealed repression of the tricarboxylic acid cycle and glyoxylate cycle, also activation of the glycolysis pathway and genes related to ergosterol synthesis. Based on the analyses, potential SA-responsive promoters were investigated, among which the promoter strength of IMTCP2 and KLMA_50231 increased 43.4% and 154.7% in response to 15 g/L SA. In addition, overexpression of the transcription factors Gcr1, Upc2, and Ndt80 significantly increased growth under SA stress. Our results benefit understanding SA toxicity mechanisms and the development of robust yeast for organic acid production. KEY POINTS: • Global gene transcription of K. marxianus is changed by succinic acid (SA) • Promoter activities of IMTCP2 and KLMA_50123 are regulated by SA • Overexpression of Gcr1, Upc2, and Ndt80 enhanced SA tolerance.

The Role of Bioactive Small Molecules in COPD Pathogenesis.

Chronic obstructive pulmonary disease (COPD) is recognized as a predominant contributor to mortality worldwide, which causes significant burdens to both society and individuals. Given the limited treatment options for COPD, there lies a critical realization: the imperative for expeditious development of novel therapeutic modalities that can effectively alleviate disease progression and enhance the quality of life experienced by COPD patients. Within the intricate field of COPD pathogenesis, an assortment of biologically active small molecules, encompassing small protein molecules and their derivatives, assumes crucial roles through diverse mechanisms. These mechanisms relate to the regulation of redox balance, the inhibition of the release of inflammatory mediators, and the modulation of cellular functions. Therefore, the present article aims to explore and elucidate the distinct roles played by different categories of biologically active small molecules in contributing to the pathogenesis of COPD.

Lactating striped hamsters (Cricetulus barabensis) do not decrease the thermogenic capacity to cope with extreme cold temperature.

For small non-hibernating mammals, a high thermogenic capacity is important to increase activity levels in the cold. It has been previously reported that lactating females decrease their thermogenic activity of brown adipose tissue (BAT), whereas their capacity to cope with extreme cold remains uncertain. In this study we examined food intake, body temperature and locomotor behavior, resting metabolic rate, non-shivering thermogenesis, and cytochrome c oxidase activity, and the rate of state 4 respiration of liver, skeletal muscle, and BAT in striped hamsters (Cricetulus barabensis) at peak lactation and non- breeding hamsters (controls). The lactating hamsters and non- breeding controls were acutely exposed to -15°C, and several markers indicative of thermogenic capacity were examined. In comparison to non-breeding females, lactating hamsters significantly increased food intake and body temperature, but decreased locomotor behavior, and the BAT mass, indicative of decreased BAT thermogenesis at peak lactation. Unexpectedly, lactating hamsters showed similar body temperature, resting metabolic rate, non-shivering thermogenesis with non-breeding females after acute exposure to -15°C. Furthermore, cytochrome c oxidase activity of liver, skeletal muscle and BAT, and serum thyroid hormone concentration, and BAT uncoupling protein 1 expression, in lactating hamsters were similar with that in non-breeding hamsters after acute extreme cold exposure. This suggests that lactating females have the same thermogenic capacity to survive cold temperatures compared to non-breeding animals. This is particularly important for females in the field to cope with cold environments during the period of reproduction. Our findings indicate that the females during lactation, one of the highest energy requirement periods, do not impair their thermogenic capacity in response to acute cold exposure.

SAW: an efficient and accurate data analysis workflow for Stereo-seq spatial transcriptomics.

The basic analysis steps of spatial transcriptomics require obtaining gene expression information from both space and cells. The existing tools for these analyses incur performance issues when dealing with large datasets. These issues involve computationally intensive spatial localization, RNA genome alignment, and excessive memory usage in large chip scenarios. These problems affect the applicability and efficiency of the analysis. Here, a high-performance and accurate spatial transcriptomics data analysis workflow, called Stereo-seq Analysis Workflow (SAW), was developed for the Stereo-seq technology developed at BGI. SAW includes mRNA spatial position reconstruction, genome alignment, gene expression matrix generation, and clustering. The workflow outputs files in a universal format for subsequent personalized analysis. The execution time for the entire analysis is ∼148 min with 1 GB reads 1 × 1 cm chip test data, 1.8 times faster than with an unoptimized workflow.

Screening and early warning system for chronic obstructive pulmonary disease with obstructive sleep apnoea based on the medical Internet of Things in three levels of healthcare: protocol for a prospective, multicentre, observational cohort study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea (OSA) are prevalent respiratory diseases in China and impose significant burdens on the healthcare system. Moreover, the co-occurrence of COPD and OSA exacerbates clinical outcomes significantly. However, comprehensive epidemiological investigations in China remain scarce, and the defining characteristics of the population affected by COPD and OSA, alongside their intrinsic relationship, remain ambiguous. METHODS AND ANALYSIS: We present a protocol for a prospective, multicentre, observational cohort study based on a digital health management platform across three different healthcare tiers in five sites among Chinese patients with COPD. The study aims to establish predicative models to identify OSA among patients with COPD and to predict the prognosis of overlap syndrome (OS) and acute exacerbations of COPD through the Internet of Things (IoT). Moreover, it aims to evaluate the feasibility, effectiveness and cost-effectiveness of IoT in managing chronic diseases within clinical settings. Participants will undergo baseline assessment, physical examination and nocturnal oxygen saturation measuring. Specific questionnaires screening for OSA will also be administered. Diagnostic lung function tests and polysomnography will be performed to confirm COPD and OSA, respectively. All patients will undergo scheduled follow-ups for 12 months to record the changes in symptoms, lung functions and quality of life. Primary outcomes include the prevalence and characteristics of OS, while secondary outcomes encompass OS prognosis and the feasibility of the management model in clinical contexts. A total of 682 patients with COPD will be recruited over 12-24 months. ETHICS AND DISSEMINATION: The study has been approved by Peking University Third Hospital, and all study participants will provide written informed consent. Study results will be published in an appropriate journal and presented at national and international conferences, as well as relevant social media and various stakeholder engagement activities. TRIAL REGISTRATION NUMBER: NCT04833725.

Complement Factor B Inhibition or Deletion Is Not Sufficient to Prevent Neurodegeneration in a Murine Model of Glaucoma.

Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of FB in HAGM model was evaluated with an oral FB inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.

Pleiotropic role of endoplasmic reticulum stress in the protection of psoralidin against sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE.

Ambient ultrafine particles exacerbate oxygen desaturation during sleep in patients with chronic obstructive pulmonary disease: New insights into the effect spectrum of ultrafine particles on susceptible populations.

The health effects of ultrafine particles (UFPs) are of growing global concern, but the epidemiological evidence remains limited. Sleep-disordered breathing (SDB) characterized by hypoxemia is a prevalent condition linked to many debilitating chronic diseases. However, the role of UFPs in the development of SDB is lacking. Therefore, this prospective panel study was performed to specifically investigate the association of short-term exposure to UFPs with SDB parameters in patients with chronic obstructive pulmonary disease (COPD). Ninety-one COPD patients completed 226 clinical visits in Beijing, China. Personal exposure to ambient UFPs of 0-7 days was estimated based on infiltration factor and time-activity pattern. Real-time monitoring of sleep oxygen saturation, spirometry, respiratory questionnaires and airway inflammation detection were performed at each clinical visit. Generalized estimating equation was used to estimate the effects of UFPs. Exposure to UFPs was significantly associated with increased oxygen desaturation index (ODI) and percent of the time with oxygen saturation below 90 % (T90), with estimates of 21.50 % (95%CI: 6.38 %, 38.76 %) and 18.75 % (95%CI: 2.83 %, 37.14 %), respectively, per 3442 particles/cm3 increment of UFPs at lag 0-3 h. Particularly, UFPs' exposure within 0-7 days was positively associated with the concentration of alveolar nitric oxide (CaNO), and alveolar eosinophilic inflammation measured by CaNO exceeding 5 ppb was associated with 29.63 % and 33.48 % increases in ODI and T90, respectively. In addition, amplified effects on oxygen desaturation were observed in current smokers. Notably, individuals with better lung function and activity tolerance were more affected by ambient UFPs due to longer time spent outdoors. To our knowledge, this is the first study to link UFPs to hypoxemia during sleep and uncover the key role of alveolar eosinophilic inflammation. Our findings provide new insights into the effect spectrum of UFPs and potential environmental and behavioral intervention strategies to protect susceptible populations.

Processing Technology Optimization of Prepared Morinda Officinalis Based on Nystose Content / 中国药师

Objective:To optimize the processing technology of prepared Morinda officinalis based on nystose content. Methods:Orthogonal experiments and the nystose determination method in Chinese Pharmacopoeia (2010 edition) were used to optimize the pro-cessing technology. A Welch AQ-C18(250 mm ×4.6 mm,5 μm)chromatographic column was applied with methanol-water(3∶97)as the mobile phase, the column temperature was at 25℃, the flow rate was 0. 8 ml·min-1 , the injection volume was 10μl, and the drift tube temperature was at 40℃ with low temperature atomization. Results:The linearity of nystose was good within the range of 0. 214 8-0. 644 4 mg·ml-1 and the recovery was 99. 5%(RSD=3. 5%,n=6). Conclusion: On the basis of nystose content determination, the optimal processing technology of prepared Morinda officinalis is as follows:liquorice of 4%, stir fry time of 15min and the boiling pot temperature of 200℃.