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BackgroundGeriatric depression is a common psychiatric problem among older adults. Animal-assisted interventions （AAI） can aid in the treatment of psychiatric disorders， but their effectiveness in geriatric depression remains controversial.ObjectiveTo provide an overview of the current research on AAI in alleviating geriatric depression， in order to provide references for developing AAI programs for this population.MethodsBased on Arksey's scoping review method， a comprehensive literature search was conducted on April 16， 2023. The databases searched included China Knowledge Network， VIP， Wanfang Medical Network， China Biomedical Literature Database， Web of Science， PubMed， CINAHL， Cochrane Library and Embase. The search aimed to collect studies related to AAI and geriatric depression from the inception of each database until April 15， 2023. Two trained researchers independently screened the literature and extracted data on basic information.ResultsA total of 13 studies were included in the final review. AAI settings included nursing homes， hospitals， communities， day care centers and residences. Interventions involved touching and naming the animals， verbally interacting with the animals， playing games with the animals， communicating with the therapists and learning to care for the animals. AAI was found to improve social interaction and communication abilities， bring positive emotional experiences and enhance life satisfaction in geriatric depression. However， its effect on cognitive function improvement was inconclusive.ConclusionAAI can potentially alleviate negative mood and depressive symptoms in geriatric depression. ［Funded by National Natural Science Foundation of China （number， 82001444）］

To assess the possibility of using aerobic denitrification (AD) bacteria with high NO2−-N accumulation for nitrogen removal in wastewater treatment, conditional optimization, as well as sole and mixed nitrogen source tests involving AD bacterium, Comamonas sp. pw-6 was performed. The results showed that the optimal carbon source, pH, C/N ratio, rotational speed, and salinity for this strain were determined to be succinate, 7, 20, 160 rpm, and 0%, respectively. Further, this strain preferentially utilized NH4+-N, NO3−-N, and NO2−-N, and when NO3−-N was its sole nitrogen source, 92.28% of the NO3−-N (150 mg·L−1) was converted to NO2−-N. However, when NH4+-N and NO3−-N constituted the mixed nitrogen source, NO3−-N utilization by this strain was significantly lower (p < 0.05). Therefore, a strategy was proposed to combine pw-6 bacteria with traditional autotrophic nitrification to achieve the application of pw-6 bacteria in NH4+-N-containing wastewater treatment. Bioaugmented application experiments showed significantly higher NH4+-N removal (5.96 ± 0.94 mg·L−1·h−1) and lower NO3−-N accumulation (2.52 ± 0.18 mg·L−1·h−1) rates (p < 0.05) than those observed for the control test. Thus, AD bacteria with high NO2−-N accumulation can also be used for practical applications, providing a basis for expanding the selection range of AD strains for wastewater treatment. HIGHLIGHTS Optimal C source, pH, C/N ratio, and salinity for Comamonas sp. pw-6 were found.; Strain pw-6 preferentially utilized NH4+-N, NO3−-N, and NO2−-N, successively.; When NO3−-N was the sole nitrogen source, 92.28% of the NO3−-N converted to NO2−-N.; Addition of pw-6 into sequencing batch reactor can enhance NH4+-N and total inorganic nitrogen removal and reduce NO3−-N accumulation.;

Abstract Background To predict pathological complete response (pCR) in patients receiving neoadjuvant immunochemotherapy (nICT) for esophageal squamous cell carcinoma (ESCC), we explored the factors that influence pCR after nICT and established a combined nomogram model. Methods We retrospectively included 164 ESCC patients treated with nICT. The radiomics signature and hematology model were constructed utilizing least absolute shrinkage and selection operator (LASSO) regression, and the radiomics score (radScore) and hematology score (hemScore) were determined for each patient. Using the radScore, hemScore, and independent influencing factors obtained through univariate and multivariate analyses, a combined nomogram was established. The consistency and prediction ability of the nomogram were assessed utilizing calibration curve and the area under the receiver operating factor curve (AUC), and the clinical benefits were assessed utilizing decision curve analysis (DCA). Results We constructed three predictive models.The AUC values of the radiomics signature and hematology model reached 0.874 (95% CI: 0.819–0.928) and 0.772 (95% CI: 0.699–0.845), respectively. Tumor length, cN stage, the radScore, and the hemScore were found to be independent factors influencing pCR according to univariate and multivariate analyses (P

Abstract Anti‐cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin‐I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin‐I, which can self‐assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin‐I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin‐I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K‐AKT‐mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin‐I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin‐I can provide new insights into the mechanism of ACPs, and Lycosin‐I, which is characterized by high potency and specificity, can be a promising lead for the development of anti‐leukemia drugs.

Inflammatory bowel diseases (IBD) significantly contribute to high mortality globally and negatively affect patients' qualifications of life. The gastrointestinal tract has unique anatomical characteristics and physiological environment limitations. Moreover, certain natural or synthetic anti-inflammatory drugs are associated with poor targeting, low drug accumulation at the lesion site, and other side effects, hindering them from exerting their therapeutic effects. Colon-targeted drug delivery systems represent attractive alternatives as novel carriers for IBD treatment. This review mainly discusses the treatment status of IBD, obstacles to drug delivery, design strategies of colon-targeted delivery systems, and perspectives on the existing complementary therapies. Moreover, based on recent reports, we summarized the therapeutic mechanism of colon-targeted drug delivery. Finally, we addressed the challenges and future directions to facilitate the exploitation of advanced nanomedicine for IBD therapy.

Anti-CD117 monoclonal antibody (mAb) agents have emerged as exciting alternative conditioning strategies to traditional genotoxic irradiation or chemotherapy conditioning for both allogeneic and autologous gene-modified hematopoietic stem cell transplantation. Further, these agents are concurrently being explored in the treatment of mast cell disorders. Despite promising results in animal models and more recently in patients, the short-term and long-term effects of these treatments have not been fully explored. We conducted rigorous assessments to evaluate the effects of antagonistic anti-mCD117 mAb, ACK2, on hematopoiesis in wild-type (WT) and Fanconi Anemia (FA) mice. Importantly, we found no evidence of short-term DNA damage in either setting following this treatment suggesting that ACK2 does not induce immediate genotoxicity, providing crucial insights into its safety profile. Surprisingly, FA mice exhibited an increase in colony formation post-ACK2 treatment without accompanying DNA damage, indicating a potential targeting of hematopoietic stem cells (HSCs) and expansion of hematopoietic progenitor cells. Moreover, the long-term phenotypic and functional changes in hematopoietic stem and progenitor cells did not significantly differ between the ACK2-treated and control groups, in either setting, supporting that ACK2 does not adversely affect hematopoietic capacity. These finding underscore the safety of these agents when utilized as a short-course treatment in the conditioning context, as they did not induce significant changes in DNA damage amongst hematopoietic stem or progenitor cells. However, through a comparison of gene expression via single-cell RNA sequencing between untreated and treated mice, it was revealed that the ACK2 mAb, via c-Kit downregulation, effectively modulated the MAPK pathway with Fos down-regulation in WT and FA mice. Importantly, this modulation was achieved without causing prolonged disruptions. These findings validate the safety of the treatment and also enhance our understanding of its intricate mode of action at the molecular level.

Background: Fibroblast growth factor 1 (FGF1) is extensively amplified in many tumors and accelerates tumor invasion and metastasis. However, the role and precise molecular mechanism by which FGF1 participates in thyroid cancer (TC) are still unclear. Methods: Quantitative real-time polymerase chain reaction- and western blotting were used to detect the mRNA and protein levels of FGF1, high mobility group A (HMGA1), epithelial-to-mesenchymal transition (EMT)-related factors, and FGF receptors in both TC tissues and cell lines. Immunohistochemistry was conducted to examine the expression of FGF1 and HMGA1. Immunofluorescence staining was used to detect the coexpression of FGF1 and HMGA1. Transwell and wound healing assays were conducted to evaluate the effects of FGF1 on the capacity of invasion and migration in cells. Results: FGF1 was upregulated in papillary thyroid carcinoma (PTC) tissues and cell lines and was relatively higher in PTC tissues with cervical lymph node metastasis. Furthermore, FGF1 promotes invasion and metastasis through the EMT pathway. Mechanistically, FGF1 promotes EMT through intracellular function independent of FGF receptors. Interestingly, we demonstrated that FGF1 could upregulate HMGA1 in TC cells, and the correlation of FGF1 and HMGA1 was positive in PTC tissues. FGF1 and HMGA1 had obvious colocalization in the nucleus. We further revealed that FGF1 promotes the invasion and migration of TC cells through the upregulation of HMGA1. Conclusion: Intracellular FGF1 could promote invasion and migration in TC by mediating the expression of HMGA1 independent of FGF receptors, and FGF1 may be an effective therapeutic target in TC.

The kinase inhibitor Ponatinib inhibits an ABL1-JUN signalling axis and alters telomere homeostasis, reduces telomere synthesis, and provokes telomere dysfunction in cancer cells which employ the alternative lengthening of telomeres mechanisms.

Objective To evaluate the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with menstrual changes, and analyze the possible related factors to menstrual changes. Methods A cross-sectional study based on online survey was conducted. Women who had been infected with SARS-CoV-2 completed the questionnaires voluntarily and were enrolled in this study. Participants were divided into menstrual change group and no menstrual change group, based on the presence or absence of menstrual changes. Results A total of 1016 women were enrolled, including 530 in the menstrual change group and 486 in the no menstrual change group. The three most common abnormalities were changes of menstruation cycles, menstruation flow and menstruation duration. Compared with the no menstrual change group, participants in the menstrual change group were significantly younger (32.55 ± 7.00 vs. 33.67 ± 7.39, p = .013), reported more severe symptoms with score ≥ 6 (32.1% vs. 21.1%), and had more severe mental health problems, showing nervous (22.6% vs. 17.3%, p = .009), anxiety (34.9% vs. 24.5%, p

Ferritin is an endogenous protein which is self-assembled by 24 subunits into a highly uniform nanocage structure. Due to the drug-encapsulating ability in the hollow inner cavity and abundant modification sites on the outer surface, ferritin nanocage has been demonstrated great potential to become a multi-functional nanomedicine platform. Its good biocompatibility, low toxicity and immunogenicity, intrinsic tumor-targeting ability, high stability, low cost and massive production, together make ferritin nanocage stand out from other nanocarriers. In this review, we summarized ferritin-based nanomedicine in field of disease diagnosis, treatment and prevention. The different types of drugs to be loaded in ferritin, as well as drug-loading methods were classified. The strategies for site-specific and non-specific functional modification of ferritin were investigated, then the application of ferritin for disease imaging, drug delivery and vaccine development were discussed. Finally, the challenges restricting the clinical translation of ferritin-based nanomedicines were analyzed.

The correlated color temperature (CCT) and color rendering index (CRI) are two significant indicators related to the color appearance and visual effects of illumination. This paper concentrates on dynamic dimming for phosphor-converted (PC) white LEDs to achieve tunable CCT and adequate CRI, via compensation of red/green spectra. The LED systems described have a simple configuration consisting of a PC white LED, a monochrome green LED and a monochrome red LED, which can be individually driven. Compared to individual PC white LEDs, both the spectral continuity and uniformity of the mixed white light are enhanced. The tunable dimming models are proposed by combination of spectral colorimetry and photo-electro-thermal (PET) theory, thus multi-physics effects are involved. From the modeling process and results, the nonlinear characteristics are observed. Experimental verifications present good agreement existing between calculations and measurements, both in terms of values and variation trends. These proposed models could be effective tools to figure out photometric characteristics and visual perception of illumination. On the other hand, they could provide schemes of reference to improve the illumination environment adapting to various special occasions and personal preferences.

The last decade has witnessed the rapid development of immersive virtual reality (IVR) and its application in various contexts. However, its application in supporting real-time virtual collaboration has been quite rare due to technical barriers and the lack of validated design principles. To address this research gap, this study designed and developed an IVR space to enable multiuser synchronous co-located collaboration to complete a fantasy game. An evaluation study (N = 95) was conducted to explore its useful design considerations and the influencing factors for collaboration experience in the game. The IVR space was enabled by the simultaneous localization and mapping (SLAM)-based inside-out tracking technique and was informed by four essential design considerations for promoting effective collaboration in IVR, namely, the role script, learning task, collaboration mechanism, and communication design. The study results revealed that students in general were satisfied with their collaboration experience in IVR, with social presence and collaboration competency as significant predictors of collective efficacy and social experience. Based on both quantitative and qualitative results, this study proposes four validated principles for designing effective IVR spaces to support synchronous co-located collaboration.

This academic article delves into the intersection of sustainable urbanism, architectural design, and human-computer interaction (HCI). It explores the dynamic relationships between these fields, highlighting the potential for creating more sustainable, user-centric cities through innovative design practices. By examining case studies, research findings, and emerging trends, this article provides insights into the collaborative efforts of designers, architects, and HCI experts to shape the cities of the future.

This paper presents an innovative methodology known as New Extreme Meteorological Years (NEMY) for comprehensively understanding extreme weather patterns. In contrast to conventional approaches, NEMY meticulously accounts for meteorological parameters, their respective weights, and explores critical factors such as intensity, duration, and the establishment of dynamic thresholds. This dynamic and adaptable framework facilitates precise simulations of extreme weather conditions. In an era characterized by climate change, where preparedness and mitigation of extreme weather impacts are imperative, this research holds paramount significance. The heart of this study revolves around the development and examination of the NEMY framework, which significantly enhances the accuracy in simulating extreme weather scenarios. It is worth emphasizing that, within the context of this paper, the consideration of both the intensity and duration of extreme weather events, as well as the meticulous discussion on the establishment of dynamic thresholds, are central to our approach. The importance of this framework extends beyond meteorology, with practical implications for assessing wind and solar energy resources. This paper not only outlines the methodology of NEMY but also vividly discusses the critical aspects of accounting for the intensity and duration of extreme weather events, as well as the nuanced process of dynamically setting thresholds. Furthermore, it demonstrates the application of NEMY in energy assessment, thereby contributing significantly to the global energy revolution. Additionally, it underscores the urgency of climate change adaptation and mitigation. The subsequent sections delve deeper into the NEMY framework’s design, testing, and potential applications, with a particular focus on the intricate considerations of extreme weather event intensity, duration, and dynamic threshold establishment.

The role of nocturnal transpiration in plant growth is debatable, presumably due to the soil moisture-dependent characteristics of transpiration. To address this issue, we analyzed the relationship between nocturnal and diurnal transpiration and plant growth across various soil moisture and atmospheric CO2 levels. We investigated the ratio of nocturnal to diurnal transpiration under eight soil moisture conditions (30 %, 35 %, 40 %, 50 %, 60 %, 80 %, 100 %, and 120 % [w/w]) and three CO2 concentrations (approximately 407, 610, and 843 ppm) in five rice genotypes (cv. Nipponbare, IRAT109, NERICA 1, Taichung 65 [T65], and DV85). The total plant biomass increased linearly with increase in diurnal transpiration but showed a saturated response to increase in nocturnal transpiration, suggesting that nocturnal transpiration did not contribute to growth when the soil water content was above 60 %. CO2 enrichment did not decrease the nocturnal transpiration rate (En) but decreased the diurnal transpiration rate (Ed), thereby causing an increase in the En /Ed value. The En /Ed value was the lowest when the soil water content was approximately 50 %. The graphical curves representing the change in En /Ed values plotted along with the soil water content showed a V-shaped pattern for all genotypes examined. Furthermore, the patterns of variation of En /Ed values with respect to changes in soil moisture contents were similar under different CO2 concentrations. Therefore, we concluded that suppression of nocturnal transpiration in the absence of drought would be an important target for reducing water consumption without compromising biomass production, and estimation of the En /Ed values will help in selecting individuals showing low nocturnal transpiration regardless of the CO2 concentration in the environment.

Background: The insidious nature of BCG-osteomyelitis makes it challenging for clinicians to detect it early on. Methods: This 12-year retrospective analysis was conducted at a single tertiary hospital in central Taiwan. Electronic medical records of pediatric patients treated for BCG-osteomyelitis were reviewed. Demographics, clinical features, and laboratory findings were compared with patients diagnosed with culture-proven pyogenic osteomyelitis. Results: In total, eight patients fulfilled our inclusion criteria. Their median age was 16 months, and no obvious gender prevalence was found. Six of the eight patients had lesions involving the lower extremities. When compared with the pyogenic osteomyelitis group, age of disease onset was found to be significantly younger in the BCG osteomyelitis group (p=0.038). Absence of fever and pain in the BCG osteomyelitis group was found to be statistically significant when compared with the pyogenic group (p=0.002 and p=0.026 respectively). CRP and ESR were found to be significantly higher in the pyogenic osteomyelitis group (p=0.000 and p=0.004 respectively). Conclusion: BCG-related osteomyelitis must be considered when evaluating an afebrile child presenting with an unexplainable swelling or limp, and especially when the lesion is located on a lower limb. Laboratory studies may reveal normal WBC and CRP, with a normal to modest elevation of ESR. Imaging studies, including plain radiographs, magnetic resonance imaging (MRI), or computed tomography (CT) should be employed to rule out BCG-related osteomyelitis. Early diagnosis help minimize inappropriate antibiotics use, and may lead to a better outcome.

The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.

Objective: This study aimed to fully develop the utilization value of yam bark. Methods: The extraction of polysaccharides from yam bark and the residue of polyphenols and flavonoids extracted by ethanol was carried out by water extraction and alcohol precipitation method. The polysaccharides of yam peel (P1) and yam peel residue (P2) were obtained. The structural characteristics and antioxidant activities of P1 and P2 were analyzed. Results: The yield of P1 and P2 were similar, but the polysaccharide content of P2 (33.5%) was about twice that of P1 (17.8%). Both P1 and P2 have loose and porous structures, and P2 has dense pores on its surface. Mannose, glucose, and galactose were the main monosaccharides in P1, while mannose was the main monosaccharide in P2. P1 and P2 not only have microcrystalline structures but also have polycrystalline system with crystal and amorphous structures. The two polysaccharide samples had the same functional groups and no protein was found in both the samples. Both P1 and P2 have three-helix helix structures, and their average molecular weight is 37 153.52 and 3 467.37, respectively. P2 is not as stable as P1. In the range of 0.2～1.0 mg/mL, and the antioxidant activities of P1 and P2 increased with their concentrations. P2 had better antioxidant activity than P1. The IC50 values of the DPPH radical scavenging rate of P1 and P2 were 0.964 and 0.586 mg/mL, respectively, and the IC50 values of hydroxyl radical scavenging ability were 0.962 and 0.711 mg/mL, respectively. Conclusion: After ethanol extraction of polyphenols and flavonoids, the residue of yam peel still contains rich polysaccharides. Moreover, P2 has better structural characteristics and antioxidant activity than P1.

Cheqianzi Decoction (CQD) is a Traditional Chinese Medicine (TCM) formula comprising four herbs and is recorded in the Ancient Materia Medica “Shengji Zonglu”. Individually, these four herbs have been shown to reduce uric acid (UA) levels, to treat hyperuricemia (HUA), and alleviate kidney damage. However, the therapeutic efficacy of the CQD and related mechanism are not yet clear.In this study, high performance liquid chromatography (HPLC) analysis confirmed that the contents of the chemical components of the four herbal medicines were in accordance with the provisions of the Chinese Pharmacopoeia. A total of 99 potential targets were identified in the network pharmacology analysis of CQD, indicating its involvement in the regulation of inflammatory and apoptotic signaling pathways, and potential value for treating HUA and alleviating kidney injury. In vivo pharmacodynamic studies showed that compared with the Model group, significantly decreased levels of serum uric acid (SUA), serum creatinine (SCr), blood urea nitrogen (BUN) (all P < 0.05), and inflammatory factors (P < 0.01) were detected in the CQD group. Quantitative real-time PCR and Western blot analyses showed that compared with the Model group, adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) expression in the CQD group was significantly upregulated (P

Neural stem cell (NSC) has gained considerable attention in traumatic brain injury (TBI) treatment because of their ability to replenish dysfunctional neurons and stimulate endogenous neurorestorative processes. However, their therapeutic effects are hindered by the low cell retention rate after transplantation into the dynamic brain. In this study, we found cerebrospinal fluid (CSF) flow after TBI is an important factor associated with cell loss following NSC transplantation. Recently, several studies have shown that hydrogels could serve as a beneficial carrier for stem cell transplantation, which provides a solution to prevent CSF flow-induced cell loss after TBI. For this purpose, we evaluated three different hydrogel scaffolds and found the gelatin methacrylate (GelMA)/sodium alginate (Alg) (GelMA/Alg) hydrogel scaffold showed the best capabilities for NSC adherence, growth, and differentiation. Additionally, we detected that pre-differentiated NSCs, which were loaded on the GelMA/Alg hydrogel and cultured for 7 days in neuronal differentiation medium (NSC [7d]), had the highest cell retention rate after CSF impact. Next, the neuroprotective effects of the NSC-loaded GelMA/Alg hydrogel scaffold were evaluated in a rat model of TBI. NSC [7d]-loaded GelMA/Alg markedly decreased microglial activation and neuronal death in the acute phase, reduced tissue loss, alleviated astrogliosis, promoted neurogenesis, and improved neurological recovery in the chronic phase. In summary, we demonstrated that the integration with the GelMA/Alg and modification of NSC differentiation could inhibit the influence of CSF flow on transplanted NSCs, leading to increased number of retained NSCs and improved neuroprotective effects, providing a promising alternative for TBI treatment.

Narrow Band Internet of Things (NB-IoT) has many kinds of secondary synchronization signals, which need a lot of space to store. Therefore, the requirement of low power consumption is difficult to be satisfied. In order to solve this problem, we propose a low complexity cell Identity (ID) detection algorithm. Firstly, the algorithm splits the secondary synchronization signal, and reduces the multiplication operation by using the law of phase offset changing with frame number. Then it uses the symmetry of Zadoff-Chu (ZC) sequence in the secondary synchronization signal to calculate the autocorrelation value of the received signal. Combined with the cross-correlation between the local signal and the received signal, the secondary synchronization signal can be detected and the cell ID number can be calculated. By comparing with other algorithms, the proposed algorithm can greatly reduce the complexity of the algorithm while maintaining the acceptable performance.

The self-assembly of actinides represents a cutting-edge research topic in the field of chemical materials, among which the actinide metal organic frameworks(An-MOF) emerge as the most shining star due to their tailorable structure, abundant coordination modes and versatile functionality, and have gained significant progress in recent years. In this review, the domestic and foreign advances of the synthesis and property investigation of An-MOF are first summary. Then a systematic introduction of uranium- and thorium- MOFs developed in our group is presented. Finally, the future direction of actinide self-assembly chemistry is briefly prospected.

Abstract Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein–protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.

Background: The causative pathogen of pediatric osteomyelitis is often unidentified despite culturing attempts. This study evaluated and compared the clinical characteristics, therapeutic approach, and outcomes of osteomyelitis caused by unknown pathogens and identified microorganisms. Method: This 17-year retrospective study was conducted at a tertiary hospital in central Taiwan. Medical records of children aged less than 18 years with a diagnosis of osteomyelitis between 2003 and 2019 were reviewed. Result: In total, 70 patients (median age = 6.4 years; male = 65.7%) fulfilled the inclusion criteria, of whom 33 (47.1%) were culture negative. Staphylococcus aureus was the main pathogen (67.6% of identified bacteria). The proportion of methicillin-resistant S. aureus (MRSA) was 44% and 54.5% of the MRSA isolates exhibited clindamycin resistance. Compared to children with culture-positive osteomyelitis, those with culture-negative osteomyelitis had a lower rate of concomitant septic arthritis (40.5% vs. 15.2%, p = 0.019) and leukocytosis on presentation (45.9% vs. 21.2%, p = 0.030); they also required fewer surgical interventions (56.8% vs. 24.2%, p = 0.006) and received a shorter course of total antibiotic therapy (49.0 vs. 43.0 days, p = 0.045). In the culture-negative group, the MRSA coverage rate was 18.8% during initial empirical therapy and increased to 59.4% during further adjusted therapy. The overall complication rate was 18.6% and was lower in the culture-negative group (32.4% vs. 3.0%, p = 0.002). Conclusion: In areas where community-associated MRSA and clindamycin resistance strains are a concern, empirical glycopeptide-based therapy is suggested in pediatric osteomyelitis, particularly in those with culture-negative infections.

Abstract IL6 is one of the most elevated cytokines during chimeric antigen receptor (CAR) T cell cytokine release syndrome (CRS), and IL6R blockade by Tocilizumab has successfully relieved the most life-threatening aspects of CRS in patients. In addition, latest studies demonstrated the essential role of IL1 in driving CART induced neurotoxicity in mouse models. Here we present a clinical investigation (ChiCTR2000032124; ChiCTR2000031868) of anti-CD19 and anti-BCMA CART (41BBζ) secreting an anti-IL6 scFv and IL1 receptor antagonist (IL1RA) in treating patients with hematologic malignancy. Our results revealed that IL6 and IL1B were maintained at low levels without significant elevation during CRS, rendering Tocilizumab dispensable. Moreover, treated patients did not show neurotoxicity during CRS and exhibited mild to moderate CRS. Notably, we observed high rate of complete response (CR) and significant CART expansion during treatment. In sum, we conclude that CART-secreting anti-IL6 scFv and IL1RA could self-neutralize IL6 storm and maintain low levels of IL1B during CART therapy to minimize IL6- and IL1-associated cytokine toxicity and neurotoxicity without impairing therapeutic efficacy.

Metabolites/impurities (MIs) of penicillin are normally considered to be the main substances inducing immediate hypersensitivity reactions in penicillin treatment. Our previous research found that penicillin can cause non-allergic hypersensitivity reactions (NAHRs) by directly triggering vascular hyperpermeability and exudative inflammation. However, the chief culprits and underlying mechanisms involved in penicillin-induced NAHRs have not yet been fully elucidated. In this study, we used a combination of approaches including a mouse non-allergic hypersensitivity reaction model, UPLC-MS/MS analyses of arachidonic acid metabolites (AAMs), immunoblotting technique, and molecular docking, etc to investigate the culprits involved in penicillin-induced hypersensitivity reactions. We found penilloic acid, one of the main MIs of penicillin, could trigger NAHRs via inducing increased vascular permeability, while the other MIs did no exhibit similar effect. Penilloic acid-induced reactions were not IgE-dependent. Significantly increased arachidonic acids and cascade metabolites in lungs, and activation of RhoA/ROCK signaling pathway in the ears and lungs of mice were noticed after once administration of penilloic acid. This study revealed that penilloic acid was the chief culprit involved in penicillin-induced immediate NAHRs in mice, which mainly associated with direct stimulation of vascular hyperpermeability and exudative inflammation. The activations of AAMs and RhoA/ROCK signaling pathway played important roles in these reactions.

Pathogenic root/wood rot fungal species infect multiple urban tree species in Singapore. There is a need for sustainable and environmentally friendly mitigation. We report the local Trichoderma strains as potential biocontrol agents (BCAs) for pathogenic wood rot fungal species such as Phellinus noxius, Rigidoporus microporus, and Fulvifomes siamensis. Isolated Trichoderma strains were DNA-barcoded for their molecular identities and assessed for their potential as a BCA by their rate of growth in culture and effectiveness in inhibiting the pathogenic fungi in in vitro dual culture assays. Trichoderma harzianum strain CE92 was the most effective in inhibiting the growth of the pathogenic fungi tested. Preliminary results suggested both volatile organic compound (VOC) production and direct hyphal contact contributed to inhibition. SPME GC-MS identified known fungal inhibitory volatiles. Trichoderma harzianum strain CE92 hyphae were found to coil around Phellinus noxius and Lasiodiplodia theobromae upon contact in vitro and were possibly a part of the mycoparasitism. In summary, the work provides insight into Trichoderma inhibition of pathogenic fungi and identifies local strains with good potential for broad-spectrum BCAs against root/wood rot fungi in Singapore.

Mature tropical urban trees are susceptible to root and trunk rot caused by pathogenic fungi. A metagenomic survey of such fungi was carried out on 210 soil and tissue samples collected from 134 trees of 14 common species in Singapore. Furthermore, 121 fruiting bodies were collected and barcoded. Out of the 22,067 OTUs (operational taxonomic units) identified, 10,646 OTUs had annotation information, and most were either ascomycetes (63.4%) or basidiomycetes (22.5%). Based on their detection in the diseased tissues and surrounding soils and/or the presence of fruiting bodies, fourteen basidiomycetes (nine Polyporales, four Hymenochaetales, one Boletales) and three ascomycetes (three species of Scytalidium) were strongly associated with the diseased trees. Fulvifomes siamensis affected the largest number of tree species surveyed. The association of three fungi was further supported by in vitro wood decay studies. Genetic heterogeneity was common in the diseased tissues and fruiting bodies (Ganoderma species especially). This survey identified the common pathogenic fungi of tropical urban trees and laid the foundation for early diagnosis and targeted mitigation efforts. It also illustrated the complexity of fungal ecology and pathogenicity.

Abstract Revolutionary CART therapy still faces the challenge of severe cytokine release syndrome (CRS). While IL6 and IL1 have been demonstrated as essential contributors, GM-CSF is one of the most abundant inflammatory cytokines secreted by CART and has also been suggested in contributing to CRS. To minimize GM-CSF production from CART to reduce its associated toxicity, we conducted a pilot study (ChiCTR2000032124) of CRISPR-edited GM-CSF knockout (KO) in CART secreting anti-IL6 scFv and IL1RA, with additional TCR KO for tracing edited CART. The initial results of three patients (1 Non-Hodgkin lymphoma (NHL) and 2 multiple myelomas (MMs)) are summarized as: 3/3 complete response, 2/3 none CRS, 1/3 grade 2 CRS, and 0/3 neurotoxicity. The analysis revealed low levels of GM-CSF, IL6 and IL1B at the time of interferon-gamma (IFNG) peaks, and elevated IL1RA. We also observed significant expansion of CD3– CART during treatment and no aberrant expansion of CD3– CART in the follow-up. Re-expansion of CD3– CART was observed in two patients while recurring CD19+ cells were eradicated in the patient with NHL. In summary, our study supported the safety and durable potency of CRISPR-edited CART in patients, providing a novel platform for developing autologous or allogeneic CART to minimize GM-CSF-associated toxicity in addition to autonomous IL6/IL1 blockade.

ObjectivesIn order to solve the problems of the local buckling effect and obvious structural response and buckling failure force caused by high concentrated load, a meshless numerical method is proposed to simulate the problem.MethodsBased on discrete nodes in the problem domain, this method establishes a compact support function and uses the weighted residual method to establish a discrete equation of the system displacement field. Then uses the moving least square method to construct the shape function of the discrete nodes to finally obtain the approximation function of the displacement function. Finally, combined with the simplified buckling evaluation method, the eigenvalues of the buckling equation are effectively solved to reduce the order, and a more accurate buckling load factor is obtained.Results The effectiveness of the proposed method is verified by the comparison between the proposed method and the traditional calculation method through the demonstration of an example. The calculation results of the proposed method also have a higher degree of agreement with the original structure.ConclusionBy analyzing the characteristics of meshless numerical analysis of perforated plate beam, a new method is provided for the analysis of various shapes of honeycomb plate beam structure.

Introduction: Prolonged uncontrolled hyperglycaemia has shown to cause oxidative stress, inflammation, thrombosis and upregulation of angiogenesis in diabetics, which all contributes to diabetic retinopathy development and progression. Vitamin E is found to have anti-inflammatory, anti-oxidative, anti-thrombogenic and anti-angiogenesis which could play an important role in early treatment of diabetic retinopathy. This study aims to investigate the effect of Tocotrienol-rich vitamin E (Tocovid) on the progression of retinal microhaemorrhages and diabetic macular oedema in patients with diabetic retinopathy. Method: This is a multi-centred, randomized, double-blinded, placebo-controlled trial which involved 55 eligible participants. The participants in the treatment group ( n = 22) received Tocovid 200 mg twice daily while those in the placebo group ( n = 23) would receive placebo twice daily. Both groups will be on the treatment for a total duration of 12 months. Both retinal signs will be assessed at baseline, 2 months, 6 months and 12 months of treatment to determine the progression of diabetic retinopathy. Serum vascular endothelial growth factor which reflects on the angiogenesis process in the eye was analysed as well at similar time points as the retinal findings. Results: After 12 months of treatment, the placebo group had a significant increase of 23.42% in retinal microhaemorrhages ( p

The purpose of this study was to prepare a kind of Zearalenone fast quantitative test strip based on time-resolved fluorescence immunochromatographic assay.Europium nanoparticles were used as fluorescent probes to label anti-zearalenone monoclonal antibodies,and a quantitative immunochromatography method was established based on competitive inhibition principle.The results showed that the sensitivity of Zearalenone fluorescent detection strip was 0.1 ng/mL,the linear range was 0.1～5.0 ng/mL,the standard recovery rate of negative samples of corn and wheat was between 93.45% and 112.2%,and the coefficient of variation of 5 repeats for the same sample was less than 15%.The results show that the Zearalenone fluorescent test strip has the technical characteristics of high sensitivity,short reaction time and accurate quantification,which is suitable for the rapid quantitative detection of Zearalenone in grain and its products.

Dew is a part of the water cycle of ecosystems and is a source of water and humidity. The climate characteristics of the frost-free period in Northeast China are suitable for dew condensation, and dew is an important factor of water balance in this area. Northeast China is among the most significant warming areas in China, with an obvious “warm and dry” climate trend, which may affect dew condensation. To determine the dew amounts in different ecosystems in Northeast China and the influence of climate change on these amounts, dew condensation in farmland (corn), wetland (Carex lasiocarpa) and urban ecosystems (Syringa oblata Lindl.) was monitored during the growing period (May to October) from 2005 to 2021. The results showed that the annual average number of dew days was 132.8 in a wetland in Fujin, 122.9 in a farmland in Lishu and 118.1 in an urban area in Changchun. The daily dew intensity in the three ecosystems was lowest in May and highest in July and August. The average daily dew intensity was higher in the wetland (0.125 ± 0.069 mm) than the farmland (0.061 ± 0.026 mm) and urban area (0.028 ± 0.009 mm). The annual dew amount was also highest in the wetland (44.09 ± 7.51 mm) compared to the farmland (34.46 ± 3.54 mm) and much higher than that in the urban ecosystem (25.32 ± 3.29 mm). The annual dew in the farmland, wetland and urban ecosystems accounted for 7.92 ± 2.76%, 14.98 ± 5.93% and 6.71 ± 2.66% of the rainfall in the same period, respectively. The results indicated that dew was an important source of water and that wetlands had greater dew deposition than farmlands and urban areas. Considering the climate data during the dew condensation period from 1957 to 2021, the annual dew amount showed a decreasing trend of −0.40 mm/10a (p < 0.05) in Changchun. However, under the joint influence of relative humidity (RH) and wind speed (V), the impact of climate change on dew condensation was not obvious. This study further clarified the impact of climate change on the near-surface water cycle.

E’Jiao is a traditional Chinese medicine derived from donkey skin. E’Jiao is reported to suppress elevated bone remodelling in ovariectomised rats but its mechanism of action is not known. To bridge this research gap, the current study aims to investigate the effects of E’Jiao on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. Female Sprague–Dawley rats (3 months old) were ovariectomised and supplemented with E’Jiao at 0.26 g/kg, 0.53 g/kg and 1.06 g/kg, or 1% calcium carbonate (w/v) in drinking water. The rats were euthanised after two months of supplementation and their bones were collected for Fourier-transform infrared spectroscopy, histomorphometry and protein analysis. Neither ovariectomy nor treatment affected the skeletal mineral/matrix ratio, osteocyte number, empty lacunar number, and Dickkopf-1 and sclerostin protein levels (p > 0.05). Rats treated with calcium carbonate had a higher Dickkopf-1 level than baseline (p = 0.002) and E’Jiao at 0.53 g/kg (p = 0.002). In conclusion, E’Jiao has no significant effect on skeletal mineralisation, osteocyte and WNT signalling inhibitors in ovariectomised rats. The skeletal effect of E’Jiao might not be mediated through osteocytes.

Objective To examine the morphological characteristics of the bone structure in the posterior cranial fossa in adult patients with Chiari malformation type Ⅰ (CMⅠ) without basilar invagination. Methods Thirty-eight adult patients with CMⅠ without basilar invagination treated in our department between January, 2018 and June, 2020 were enrolled in this study as the observation group, and 38 gender- and age-matched healthy adults served as the control group. The differences in the linear and angular variables in the posterior cranial fossa were analyzed between the 2 groups based on thin-slice CT data. Results Compared with the control subjects, the patients with CMⅠ showed significantly decreased clivus length (P < 0.001), supra-occipital length (P < 0.01), occipital length (P < 0.01), Klaus height index (P < 0.001), posterior compressive value (P < 0.01), tentorial angle (P < 0.05) and sagittal area of the bony posterior cranial fossa (P < 0.001) and significantly increased odontoid compressive value (P < 0.01), odontoid and soft tissue compressive value (P < 0.01), anterior compressive value (P < 0.01) and basal angle (P < 0.01). Conclusion In adult patients with CMⅠ patients but without basilar invagination, the clivus and occipital bone are shortened and elevated with co-existing ventral cervicomedullary compression by the posterior margin of the odontoid process.

At present, the existing prediction algorithm of a port cargo throughput neglects the correction of the initial value of the cargo series data model, which leads to a large error in a port cargo throughput prediction. Therefore, a prediction algorithm of a port cargo throughput based on the ES-Markov model is designed. A decompose function is used to decompose the time series of a port cargo throughput, and the trend elements of a port cargo throughput are divided into long-term trend, seasonal trend, fluctuation trend, and irregular trend. In this study, the ES-Markov model is introduced, and the initial prediction is obtained by using the cubic exponential smoothing method, and the state transition matrix is obtained by the Markov principle. Based on the results of the time-series analysis and the ES-Markov model, the prediction algorithm of a port cargo throughput is designed. In the experimental design, the Elman neural network is used to construct an experimental sample data model. The monthly cargo throughput data of a certain port for eight months from May 2020 to December 2020 are collected and sorted according to the time series. The experimental results show that the prediction results of the proposed algorithm are closer to the actual value and the fluctuation of the prediction results is less than that of the reference.

Background: The identification of aortic dissection (AD) at baseline plays a crucial role in clinical practice. Non-contrast CT scans are widely available, convenient, and easy to perform. However, the detection of AD on non-contrast CT scans by radiologists currently lacks sensitivity and is suboptimal.Methods: A total of 452 patients who underwent aortic CT angiography (CTA) were enrolled retrospectively from two medical centers in China to form the internal cohort (341 patients, 139 patients with AD, 202 patients with non-AD) and the external testing cohort (111 patients, 46 patients with AD, 65 patients with non-AD). The internal cohort was divided into the training cohort (n = 238), validation cohort (n = 35), and internal testing cohort (n = 68). Morphological characteristics were extracted from the aortic segmentation. A deep-integrated model based on the Gaussian Naive Bayes algorithm was built to differentiate AD from non-AD, using the combination of the three-dimensional (3D) deep-learning model score and morphological characteristics. The areas under the receiver operating characteristic curve (AUCs), accuracy, sensitivity, and specificity were used to evaluate the model performance. The proposed model was also compared with the subjective assessment of radiologists.Results: After the combination of all the morphological characteristics, our proposed deep-integrated model significantly outperformed the 3D deep-learning model (AUC: 0.948 vs. 0.803 in the internal testing cohort and 0.969 vs. 0.814 in the external testing cohort, both p < 0.05). The accuracy, sensitivity, and specificity of our model reached 0.897, 0.862, and 0.923 in the internal testing cohort and 0.730, 0.978, and 0.554 in the external testing cohort, respectively. The accuracy for AD detection showed no significant difference between our model and the radiologists (p > 0.05).Conclusion: The proposed model presented good performance for AD detection on non-contrast CT scans; thus, early diagnosis and prompt treatment would be available.

The dew condensation frequency is high, and the dew amount is heavy in urban ecosystems. During the condensation process, particulate matter acts as a condensation core, playing an important role in purifying the air. At night, dew mainly condenses on plant leaf surfaces, the plant leaves settle the particles in the dew, and some of the particles are resuspended into the atmosphere in the process of dew evaporation after sunrise. This paper monitored the condensation and evaporation processes of dew on four common plants in Changchun city from June to September 2020. By analyzing the mass and size of particles on different leaves after dew condensation and evaporation, the ability of different plants to retain particles in dew was analyzed. The results showed that there was no significant difference in the TSP capture ability during dew condensation between Buxus sinica (Rehd. et Wils.) Cheng subsp. sinica var. parvifolia M. Cheng, Syringa oblata Lindl., Hemiptelea davidii (Hance) Planch., and Pinus tabuliformis Carrière, with a TSP content of 0.21 ± 0.06 μg/cm2. Coarse particulate matter is the main type of deposit in the dew condensation stage. Particulate deposition varied according to species, leaf shape, and microstructure. The proportion of TSP remaining on leaves after dew evaporation from Pinus tabuliformis Carrière, Hemiptelea davidii (Hance) Planch., Buxus sinica (Rehd. et Wils.) Cheng subsp. sinica var. parvifolia M. Cheng, and Syringa oblata Lindl. tree was 89.7 ± 3.9%, 80.6 ± 3.6%, 75.9 ± 4.5%, and 71.4 ± 3.7%, respectively. The ability of the leaves to trap fine particles was significantly higher than that for coarse particles (P

Context Aristolochia manshuriensis Kom (Aristolochiaceae) (AMK) is known for toxicity and mutagenicity. Objective The tumorigenic role of AMK has yet to be understood. Materials and methods AMK extracts were extracted from root crude drug. SD (Sprague Dawley) rats underwent gavage with AMK (0.92 g/kg) every other day for 10 (AMK-10) or 20 (AMK-20) weeks. Stomach samples were gathered for histopathological evaluation, microarray and mRNA analysis. Results The gastric weight to body weight ratio (GW/BW) is 1.7 in the AMK-10 cohort, and 1.8 in AMK-20 cohort compared to control (CTL) cohort. Liver function was damaged in AMK-10 and AMK-20 rats compared to CTL rats. There were no significant changes of CRE (creatinine) in AMK-10 and AMK-20 rats. Histopathological analysis revealed that rats developed dysplasia in the forestomach in AMK-10 rats, and became gastric carcinoma in AMK-20 rats. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, and Amt were found to be critical in AMK-10 and AMK-20 rats. Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, and Fgfr3 worked in AMK-10 rats, and PDE2a and PDE3a played a pivotal role in AMK-20 rats. Discussion and conclusions AMK induced benign or malignant gastric tumours depends on the period of AMK administration. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, Amt, Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, Fgfr3, PDE2a, and PDE3a were found to be critical in aristolochic acid-induced gastric tumour process.

Context Shuxuening injection (SXNI), derived from the leaf of Ginkgo biloba L. (Ginkgoaceae), is widely used to treat cardio-cerebral vascular system related disease due to the efficacy of dilating the blood vessels and improving the function of microcirculation. Nevertheless, SXNI induces immediate hypersensitivity reactions in clinics and the molecular mechanisms are unknown. Objective The present study investigates the molecular mechanism of SXNI mediated hypersensitivity reactions. Materials and methods Naive male ICR mice (n = 10) were administered (i.v.) with negative control combined with Evans blue (EB) (CTL-EB), SXNI (14 or 70 mg/kg) combined with EB (SXNI/1-EB or SXNI/4-EB), vascular leakage was evaluated, ears and lungs were collected for histopathological analysis. In vitro, TSC1 was knockdown in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with SXNI, and the alterations of endothelial cell permeability were observed. Rapamycin (mTOR inbibitor) was used to investigate SXNI-induced hypersensitivity reactions both in mice and HUVECs. Results SXNI (70 mg/kg) induced vascular leakage in mice. Slight oedema and microvascular dilation in the ears, and broaden of alveolar septal and monocyte infiltration in the lungs were observed in SXNI (70 mg/kg) treated mice. mTOR inhibitor alleviates SXNI mediated vascular endothelial hyperpermeability both in vitro and in vivo. Discussion and conclusions SXNI stimulates pseudo-allergic reactions through hyperactivation of mTOR signalling pathway. Our work provides the new molecular mechanism of drug related pseudo-allergic reactions, and a potential drug to prevent and treat SXNI mediated hypersensitivity reactions.

Objectives: The objective of this study was to explore the diagnostic value of deep learning-based image reconstruction (DLR) and hybrid iterative reconstruction (HIR) for calcification-related obstructive coronary artery disease (CAD) evaluation by using coronary CT angiography (CCTA) images and subtraction CCTA images.Methods: Forty-two consecutive patients with known or suspected coronary artery disease who underwent coronary CTA on a 320-row CT scanner and subsequent invasive coronary angiography (ICA), which was used as the reference standard, were enrolled. The DLR and HIR images were reconstructed as CTADLR and CTAHIR, and, based on which, the corresponding subtraction CCTA images were established as CTAsDLR and CTAsHIR, respectively. Qualitative images quality comparison was performed by using a Likert 4 stage score, and quantitative images quality parameters, including image noise, signal-to-noise ratio, and contrast-to-noise ratio were calculated. Diagnostic performance on the lesion level was assessed and compared among the four CCTA approaches (CTADLR, CTAHIR, CTAsDLR, and CTAsHIR).Results: There were 166 lesions of 86 vessels in 42 patients (32 men and 10 women; 62.9 ± 9.3 years) finally enrolled for analysis. The qualitative and quantitative image qualities of CTAsDLR and CTADLR were superior to those of CTAsHIR and CTAHIR, respectively. The diagnostic accuracies of CTAsDLR, CTADLR, CTAsHIR, and CTAHIR to identify calcification-related obstructive diameter stenosis were 83.73%, 69.28%, 75.30%, and 65.66%, respectively. The false-positive rates of CTAsDLR, CTADLR, CTAsHIR, and CTAHIR for luminal diameter stenosis ≥50% were 15%, 31%, 24%, and 34%, respectively. The sensitivity and the specificity to identify ≥50% luminal diameter stenosis was 90.91% and 83.23% for CTAsDLR.Conclusion: Our study showed that deep learning–based image reconstruction could improve the image quality of CCTA images and diagnostic performance for calcification-related obstructive CAD, especially when combined with subtraction technique.

An increase in plant biomass under elevated CO2 (eCO2) is usually lower than expected. N-deficiency induced by eCO2 is often considered to be a reason for this. Several hypotheses explain the induced N-deficiency: (1) eCO2 inhibits nitrate assimilation, (2) eCO2 lowers nitrate acquisition due to reduced transpiration, or (3) eCO2 reduces plant N concentration with increased biomass. We tested them using C3 (wheat, rice, and potato) and C4 plants (guinea grass, and Amaranthus) grown in chambers at 400 (ambient CO2, aCO2) or 800 (eCO2) μL L−1 CO2. In most species, we could not confirm hypothesis (1) with the measurements of plant nitrate accumulation in each organ. The exception was rice showing a slight inhibition of nitrate assimilation at eCO2, but the biomass was similar between the nitrate and urea-fed plants. Contrary to hypothesis (2), eCO2 did not decrease plant nitrate acquisition despite reduced transpiration because of enhanced nitrate acquisition per unit transpiration in all species. Comparing to aCO2, eCO2 remarkably enhanced water-use efficiency, especially in C3 plants, decreasing water demand for CO2 acquisition. As our results supported hypothesis (3) without any exception, we then examined if lowered N concentration at eCO2 indeed limits the growth using C3 wheat and C4 guinea grass under various levels of nitrate-N supply. While eCO2 significantly increased relative growth rate (RGR) in wheat but not in guinea grass, each species increased RGR with higher N supply and then reached a maximum as no longer N was limited. To achieve the maximum RGR, wheat required a 1.3-fold N supply at eCO2 than aCO2 with 2.2-fold biomass. However, the N requirement by guinea grass was less affected by the eCO2 treatment. The results reveal that accelerated RGR by eCO2 could create a demand for more N, especially in the leaf sheath rather than the leaf blade in wheat, causing N-limitation unless the additional N was supplied. We concluded that eCO2 amplifies N-limitation due to accelerated growth rate rather than inhibited nitrate assimilation or acquisition. Our results suggest that plant growth under higher CO2 will become more dependent on N but less dependent on water to acquire both CO2 and N.

Asarum (Xixin), which contains analogues of aristolochic acid (AA), is the only species of the genus Aristolochia included in the Chinese Pharmacopoeia 2020. However, the contents and nephrotoxic effects of AA analogs in Asarum (Xixin) and its formulations have not been clarified. An automatic, effective solid phase extraction process and UPLC-MS/MS method were established for the pretreatment and quantitative detection of AA analogues in commercially available traditional Chinese patent medicines. The cytotoxicity and DNA damage induced by five analogues of AA were evaluated by CCK8 using human kidney cells (HK-2) and comet assays. HPLC was used to detect the analogues of AA in Asarum heterotropoides F. Schmidt (Xixin). The results showed that the contents of AA I, AA II, and AA IIIa were below the detection limit, while AA IVa and AL I presented relatively high contents of Asarum heterotropoides F. Schmidt (Xixin), within the range of 66.50–121.03 μg/g and 19.73–43.75 μg/g, respectively. The levels of AA analogues were in the nanogram-per-gram level in the main traditional Chinese patent medicines. AA I and AL I exhibited relatively high cytotoxicity at 48 h in CCK8 assays, while AA II, AA IIIa, and AA IVa showed weak cytotoxicity even at 800–1,000 μM. AA I induced significant pathological alterations and direct DNA damage at 40 mg/kg and 20 mg/kg, respectively. No distinct nephrotoxicity or hepatotoxicity was observed in mice treated with AA II, AA IIIa, AA IVa, or AL I at 40 mg/kg in this study. Consumption of Asarum heterotropoides F. Schmidt (Xixin) with controlled doses and periods is relatively safe as the contents of AA analogues in Asarum heterotropoides F. Schmidt (Xixin) and its formulations were far below those causing acute toxicity in this study. But, the long-term toxicity of Asarum heterotropoides F. Schmidt (Xixin) still needs further study.

Previous reports demonstrated that aristolochic acids (AAs) exposure-induced nephrotoxicity, mutations, and tumorigenesis are mainly due to aristolochic acid I (AAI). Notably, the chemical structure of aristolochic acid IVa (AAIVa), which exists at higher levels in many Aristolochiaceae herbs, is extremely similar to AAI. In lack of toxicological data, it is unknown whether AAIVa exposure leads to aristolochic acid nephropathy (AAN), mutations, and tumorigenesis as of AAI. To answer these questions, mice were administered AAIVa by single or repeated long-term gavage, while AAI was used as a positive control. We found that single gavage of 40 mg/kg of AAIVa exhibited no obvious toxicity. Also, there were no tumors or death in mice administrated with 1 and 10 mg/kg of AAIVa for 6 months followed by a 12-month recovery time. There were no noteworthy alterations in gene mutation frequency in the kidney, liver, and stomach between the AAIVa and control mice. Fascinatingly, AA-associated mutational signatures, adenine-to-thymine (A>T) transversions, were absent in AAIVa-treated mice. Nonetheless, 10 mg/kg of AAIVa triggered lymphocytic infiltration and slight fibrous hyperplasia in the kidney at the 6th month; however, these were alleviated at the 12th and 18th months. On the contrary, AAI (positive control) caused severe diffuse fibrosis, tubular atrophy, necrosis, tumors in the forestomach and kidney, and death after the 6th month. It seems that long-term AAIVa exposure induced mild renal lesions could be due to the activation of the canonical or noncanonical transforming growth factor-β (TGFβ) pathway. Overall, these findings suggest that the mutagenicity and carcinogenic risk of AAIVa are very low.

Abstract Background Hereditary spherocytosis (HS) is a common type of hereditary hemolytic anemia. According to the current diagnostic criteria of HS, patients with a family history of HS, typical clinical features and laboratory investigations could be diagnosed without the requirement of any additional tests, including genetic analysis. However, the clinical heterogeneities incur difficulties in HS diagnosis. We therefore aimed to investigate the application of genetic diagnosis in a family-based cohort. Case presentation In the present Chinese family, two probands sharing similar clinical manifestations, including jaundice, cholelithiasis, splenomegaly and spherocytes, while the clinical features of other family members were inconclusive. Whole-exome sequencing (WES) unexpectedly unveiled two separate disease-causing mutations in the two probands. SPTB R1625X mutation detected in proband D was a de novo mutation; while proband W inherited the SLC4A1 c.G1469A mutation from her mother, which was also inherited by her brother. However, the clinical features of proband W and her mother and brother were discrepant: proband W suffered from significant splenomegaly, jaundice and cholelithiasis, which resulted in cholecystectomy and splenectomy; while her mother and brother’s HS were not complicated by cholelithiasis, and their splenomegaly and elevated serum bilirubin were moderate. In addition, additional genomic defects involved with HS-related symptoms have not been detected in this family. Conclusions Both genotypes and phenotypes could be heterogeneous in the same HS family. The analysis of pathogenic gene mutations may endeavor to play an indispensable role in the accurate diagnosis and genetic consultation of HS individuals and their family members.