Multi-scale brain attributes contribute to the distribution of diffuse glioma subtypes.

Gliomas are primary brain tumors and are among the most malignant types. Adult-type diffuse gliomas can be classified based on their histological and molecular signatures as IDH-wildtype glioblastoma, IDH-mutant astrocytoma, and IDH-mutant and 1p/19q-codeleted oligodendroglioma. Recent studies have shown that each subtype of glioma has its own specific distribution pattern. However, the mechanisms underlying the specific distributions of glioma subtypes are not entirely clear despite partial explanations such as cell origin. To investigate the impact of multi-scale brain attributes on glioma distribution, we constructed cumulative frequency maps for diffuse glioma subtypes based on T1w structural images and evaluated the spatial correlation between tumor frequency and diverse brain attributes, including postmortem gene expression, functional connectivity metrics, cerebral perfusion, glucose metabolism, and neurotransmitter signaling. Regression models were constructed to evaluate the contribution of these factors to the anatomic distribution of different glioma subtypes. Our findings revealed that the three different subtypes of gliomas had distinct distribution patterns, showing spatial preferences toward different brain environmental attributes. Glioblastomas were especially likely to occur in regions enriched with synapse-related pathways and diverse neurotransmitter receptors. Astrocytomas and oligodendrogliomas preferentially occurred in areas enriched with genes associated with neutrophil-mediated immune responses. The functional network characteristics and neurotransmitter distribution also contributed to oligodendroglioma distribution. Our results suggest that different brain transcriptomic, neurotransmitter, and connectomic attributes are the factors that determine the specific distributions of glioma subtypes. These findings highlight the importance of bridging diverse scales of biological organization when studying neurological dysfunction.

The Cytochrome P450 (CYP) 2C8*3 Variant (rs11572080) is Associated with Improved Asthma Symptom Control in Children and Altered Lipid Mediator Production and Inflammatory Response in Human Bronchial Epithelial Cells.

This study investigated an association between the cytochrome P450 (CYP) 2C8*3 polymorphism with asthma symptom control in children and changes in lipid metabolism and pro-inflammatory signaling by human bronchial epithelial cells (HBECs) treated with cigarette smoke condensate (CSC). CYP genes are inherently variable in sequence and while such variations are known to produce clinically relevant effects on drug pharmacokinetics and pharmacodynamics, the effects on endogenous substrate metabolism and associated physiological processes are less understood. In this study, CYP2C8*3 was associated with improved asthma symptom control among children: Mean asthma control scores were 3.68 [n=207] for patients with one or more copies of the CYP2C8*3 allele vs. 4.42 [n=965] for CYP2C8*1/*1 (p=0.0133). In vitro, CYP2C8*3 was associated with an increase in montelukast 36-hydroxylation and a decrease in linoleic acid (LA) metabolism despite lower mRNA and protein expression. Additionally, CYP2C8*3 was associated with reduced mRNA expression of interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL-8) by HBECs in response to CSC, which was replicated using the soluble epoxide hydrolase inhibitor, AUDA. Interestingly, 9(10)- and 12(13)-DiHOME, the hydrolyzed metabolites of 9(10)- and 12(13)-EpOME, increased the expression of IL-6 and CXCL-8 mRNA by HBECs. This study reveals previously undocumented effects of the CYP2C8*3 variant on the response of HBECs to exogenous stimuli. Significance Statement These findings suggest a role for CYP2C8 in regulating the EpOME:DiHOME ratio leading to a change in cellular inflammatory responses elicited by environmental stimuli that exacerbate asthma.

Effect of pre-plasma on terahertz radiation from two-color laser plasma filaments in a collinear geometry.

Terahertz (THz) radiation from air plasma in the presence of pre-plasma in a collinear geometry is investigated experimentally, where the pre-plasma is formed by a pre-pulse with a Gaussian beam profile and the measured THz radiation is driven by a main laser pulse. The pre-plasma has a de-focusing effect for the main pulse passing through it, which reduces the effective length of the plasma filament formed by the main laser pulse for THz radiation. It is found that only the part not overlapped by the pre-plasma can actually produce THz radiation. Thus, the amplitude of the THz pulse driven by the main pulse can be modified by changing the spatial separation between two plasma filaments. The experimental observations are qualitatively in agreement with our numerical simulation results. It is also found that the change of the time delay between the pre-pulse and the main pulse does not change the THz radiation amplitude for a given spatial separation. This study suggests a practical way for the manipulation of THz waves through an interaction between laser plasma filaments.

Safety and efficacy of flumatinib as later-line therapy in patients with chronic myeloid leukemia.

To evaluate the efficacy and safety of flumatinib in the later-line treatment of Chinese patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CP-CML previously treated with tyrosine kinase inhibitors (TKIs). Patients with CML-CP were evaluated for the probabilities of responses including complete hematologic response (CHR), cytogenetic response, and molecular response (MR) and adverse events (AEs) after the later-line flumatinib therapy. Of 336 enrolled patients with median age 50 years, median duration of treatment with flumatinib was 11.04 (2-25.23) months. Patients who achieved clinical responses at baseline showed maintenance of CHR, complete cytogenetic response (CCyR)/2-log molecular response (MR2), major molecular response (MMR), and 4-log molecular response or deep molecular response (MR4/DMR) in 100%, 98.9%, 98.6%, and 92.9% patients, respectively. CHR, CCyR/MR2, MMR, and MR4/DMR responses were achieved in 86.4%, 52.7%, 49.6%, and 23.5% patients respectively, which showed the lack of respective clinical responses at baseline. The patients without response at baseline, treated with flumatinib as 2L TKI, having no resistance to prior TKI or only resistance to imatinib, with response to last TKI, and with BCR::ABL ≤10% had higher CCyR/MR2, MMR, or MR4/DMR. The AEs observed during the later-line flumatinib treatment were tolerable and consistent with those reported with the first-line therapy. Flumatinib was effective and safe in patients who are resistant or intolerant to other TKIs. In particular, 2L flumatinib treatment induced high response rates and was more beneficial to patients without previous 2G TKI resistance, thus serving as a probable treatment option for these patients.

Platycodin D2 enhances P21/CyclinA2-mediated senescence of HCC cells by regulating NIX-induced mitophagy.

BACKGROUND: Hepatocellular carcinoma (HCC) cells usually show strong resistance to chemotherapy, which not only reduces the efficacy of chemotherapy but also increases the side effects. Regulation of autophagy plays an important role in tumor treatment. Cell senescence is also an important anti-cancer mechanism, which has become an important target for tumor treatment. Therefore, it is of great clinical significance to find anti-HCC drugs that act through this new mechanism. Platycodin D2 (PD2) is a new saponin compound extracted from the traditional Chinese medicine Platycodon grandiflorum. PURPOSE: Our study aimed to explore the effects of PD2 on HCC and identify the underlying mechanisms. METHODS: First, the CCK8 assay was used to detect the inhibitory effect of PD2 on HCC cells. Then, different pathways of programmed cell death and cell cycle regulators were measured. In addition, we assessed the effects of PD2 on the autophagy and senescence of HCC cells by flow cytometry, immunofluorescence staining, and Western blotting. Finally, we studied the in vivo effect of PD2 on HCC cells by using a mouse tumor-bearing model. RESULTS: Studies have shown that PD2 has a good anti-tumor effect, but the specific molecular mechanism has not been clarified. In this study, we found that PD2 has no obvious toxic effect on normal hepatocytes, but it can significantly inhibit the proliferation of HCC cells, induce mitochondrial dysfunction, enhance autophagy and cell senescence, upregulate NIX and P21, and downregulate CyclinA2. Gene silencing and overexpression indicated that PD2 induced mitophagy in HCC cells through NIX, thereby activating the P21/CyclinA2 pathway and promoting cell senescence. CONCLUSIONS: These results indicate that PD2 induces HCC cell death through autophagy and aging. Our findings provide a new strategy for treating HCC.

Millijoule Terahertz Radiation from Laser Wakefields in Nonuniform Plasmas.

We report the experimental measurement of millijoule terahertz (THz) radiation emitted in the backward direction from laser wakefields driven by a femtosecond laser pulse of few joules interacting with a gas target. By utilizing frequency-resolved energy measurement, it is found that the THz spectrum exhibits two peaks located at about 4.5 and 9.0 THz, respectively. In particular, the high frequency component emerges when the drive laser energy exceeds 1.26 J, at which electron acceleration in the forward direction is detected simultaneously. Theoretical analysis and particle-in-cell simulations indicate that the THz radiation is generated via mode conversion from the laser wakefields excited in plasma with an up-ramp profile, where radiations both at the local electron plasma frequency and its harmonics are produced. Such intense THz sources may find many applications in ultrafast science, e.g., manipulating the transient states of matter.

Sensing platform for the highly sensitive detection of catechol based on composite coupling with conductive Ni3(HITP)2 and nanosilvers.

Catechol, which has a high toxicity and low degradability, poses significant risks to both human health and the environment. Tracking of catechol residues is essential to protect human health and to assess the safety of the environment. We constructed sensing platforms to detect catechol based on the conductive metal-organic frameworks [Ni3(HITP)2] and their nanosilver composites. The reduction process of catechol at the Ni3(HITP)2/AgNP electrode is chemically irreversible as a result of the difference in compatibility of the oxidation stability and conductivity between the Ni3(HITP)2/AgNS and Ni3(HITP)2/AgNP electrodes. The electrochemical results show that the Ni3(HITP)2/AgNS electrode presents a lower detection limit of 0.053 µM and better sensitivity, reproducibility and repeatability than the Ni3(HITP)2/AgNP electrode. The kinetic mechanism of the catechol electrooxidation at the surface of the electrode is controlled by diffusion through a 2H+/2e- process. The transfer coefficient is the key factor used to illustrate this process. During the electrochemical conversion of phenol to ketone, more than half of ΔG is used to change the activation energy. We also studied the stability, anti-interference and reproducibility of these electrode systems.

Plaque features of the middle cerebral artery are associated with periprocedural complications of intracranial angioplasty and stenting.

PURPOSE: The identification of plaque features in the middle cerebral artery (MCA) may help minimize periprocedural complications and select patients suitable for percutaneous transluminal angioplasty and stenting (PTAS). However, relevant research is lacking. METHODS: We retrospectively included patients with symptomatic MCA stenosis who received PTAS. All patients underwent intracranial vessel wall MRI (VWMRI) before surgery. Periprocedural complications (PC) included ischemic and hemorrhagic stroke within 30 days. Stenosis location, MCA shape, plaque eccentricity and distribution, plaque thickness and length, and enhancement ratio were compared between patients with and without PC. RESULTS: Sixty-six patients were included in the study, of which 12.1% (8/66) had PC. Of the eight patients with PC, seven (87.5%) had superior wall plaques. In the non-PC group (n = 58), nine (17%) patients had superior wall plaques. Compared with patients without PC, those with PC had more frequent superior wall plaques (17% vs 87.5%, p < 0.001) and s-shaped MCAs (19% vs 50%, p = 0.071), different stenosis locations (p = 0.012), thicker plaques (1.58 [1.35, 2.00] vs 1.98 [1.73, 2.43], p = 0.038), and less frequent inferior wall plaques (79.2% vs 12.5%, p < 0.001). Multivariate analysis showed that only the presence of superior wall plaques (OR = 41.54 [2.31, 747.54]) was independently associated with PC. CONCLUSION: MCA plaque features were highly correlated with PC in patients with symptomatic MCA stenosis who underwent PTAS.

WD repeat domain 82 (Wdr82) facilitates mouse iPSCs generation by interfering mitochondrial oxidative phosphorylation and glycolysis.

BACKGROUND: Abundantly expressed factors in the oocyte cytoplasm can remarkably reprogram terminally differentiated germ cells or somatic cells into totipotent state within a short time. However, the mechanism of the different factors underlying the reprogramming process remains uncertain. METHODS: On the basis of Yamanaka factors OSKM induction method, MEF cells were induced and reprogrammed into iPSCs under conditions of the oocyte-derived factor Wdr82 overexpression and/or knockdown, so as to assess the reprogramming efficiency. Meanwhile, the cellular metabolism was monitored and evaluated during the reprogramming process. The plurpotency of the generated iPSCs was confirmed via pluripotent gene expression detection, embryoid body differentiation and chimeric mouse experiment. RESULTS: Here, we show that the oocyte-derived factor Wdr82 promotes the efficiency of MEF reprogramming into iPSCs to a greater degree than the Yamanaka factors OSKM. The Wdr82-expressing iPSC line showed pluripotency to differentiate and transmit genetic material to chimeric offsprings. In contrast, the knocking down of Wdr82 can significantly reduce the efficiency of somatic cell reprogramming. We further demonstrate that the significant suppression of oxidative phosphorylation in mitochondria underlies the molecular mechanism by which Wdr82 promotes the efficiency of somatic cell reprogramming. Our study suggests a link between mitochondrial energy metabolism remodeling and cell fate transition or stem cell function maintenance, which might shed light on the embryonic development and stem cell biology.

SOCS5, targeted by miR-155-5p, plays a negative regulatory role in pulmonary hypertension through inhibiting JAK2/STAT3 signaling pathway.

Pulmonary hypertension (PH) is a chronic pulmonary vascular disease and causes massive deaths. Here, we intended to investigate the function and mechanism of SOCS5 in PH. We engineered a hypoxia-induced PH model in mice. HE staining were implemented to evaluate pathological alterations in the lung tissues. The potential mechanism of SOCS5 in regulating hypoxia-induced pulmonary artery smooth muscle cell (PASMC) function was explored in vitro. RT-qPCR and western blot revealed that the level of SOCS5 was decreased both in PH mice and hypoxia-induced HPASMCs. Functional assays were performed for confirming the role of SOCS5 in modulating the cell phenotype and JAK2/STAT3 pathway in HPASMCs. Results revealed that overexpression of SOCS5 suppressed proliferation, migration and contraction of HPASMCs and negatively regulated the JAK2/STAT3 signaling pathway in HPASMCs under hypoxia in vitro, while knockdown of SOCS5 accelerated it. As evidenced by mechanism studies, SOCS5 was targeted and regulated by miR-155-5p, hence affecting on HPASMC proliferation, migration and contraction. These outcomes indicated that the decreased level of SOCS5 in hypoxia-induced HPASMCs promoted the cell proliferation, cell migration, and cell contraction through activating JAK2/STAT3 signaling pathway. Moreover, SOCS5 was targeted by miR-155-5p. All in all, our work hinted that miR-155-5p/SOCS5/JAK2/STAT3 axis played a crucial part in PH.

IgA nephropathy in a child with X-linked agammaglobulinemia: a case report.

BACKGROUND: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton tyrosine kinase (BTK) gene. Individuals diagnosed with XLA are at an increased risk of developing autoimmune diseases. However, renal involvement are rare in cases of XLA. CASE PRESENTATION: In this report, we discussed a specific case involving a 6-year-old boy with XLA who experienced recurrent upper respiratory tract infections since the age of one. He presented with symptoms of hematuria and proteinuria, and renal pathology confirmed the presence of immunoglobulin (Ig) A nephropathy. Treatment comprised glucocorticoids, mycophenolate mofetil, and intermittent intravenous immunoglobulin replacement therapy. Consequently, there was a remission of proteinuria and a partial improvement in hematuria. CONCLUSIONS: In this study, we describe the first case of IgA nephropathy associated with XLA. This is an interesting phenotype found in XLA, and it provides valuable insights into the process of autoimmunity and the regulation of immune function in individuals with XLA. Based on our findings, we recommend the evaluation of immunoglobulin levels in patients diagnosed with IgA nephropathy.

Factors impeding physical activity in older hospitalised patients: A qualitative meta-synthesis.

BACKGROUND: Older hospitalised patients have low levels of physical activity and multiple impairing factors. AIMS: To systematically evaluate the perceived barriers to physical activity among older patients during hospitalisation, and provide reference for future intervention programs. DESIGN: Following ENTREQ, do a systematic evaluation and synthesis of qualitative investigations. METHODS: An exhaustive exploration was conducted across the CNKI, Wanfang Database, VIP Database, China Biomedical Literature Database, PubMed, Embase, Cochrane Library and Web of Science from their inception until August, 2023 to identify qualitative research on obstacles to physical activity among older hospital patients. The quality of the literature was evaluated using the Joanna Briggs Institute's critical appraisal tool for qualitative research. Meta-synthesis method was used to integrate the results. RESULTS: In total, 8 literatures were included, 43 themes were extracted, and analogous research results were amalgamated to generate 10 categories and 3 syntheses: individual level, interpersonal influencing factors and hospital environment and resources level. CONCLUSION: Older inpatients are faced with multiple barriers to physical activity. Medical staff should pay attention to changes in physical activity during hospitalisation, identify barriers to physical activity in older inpatients and provide references for promoting physical activity programs for the older. NO PATIENT OR PUBLIC CONTRIBUTION: This study is a meta-synthesis and does not require relevant contributions from patients or the public. WHAT IS ALREADY KNOWN: Older patients are at low physical activity levels during hospitalisation. Older inpatients are faced with multiple barriers to physical activity. WHAT THIS PAPER ADDS: Factors of physical activity impairment in hospitalised older patients should be considered in the context of health status, psychological factors, motivation and social support. Disease-induced psychological fallout has a greater impact on physical activity in the older.

Fall status and risk factors in older Chinese adults: A cross-sectional study.

AIM: To analyse the risk factors and incidence of falls in geriatric outpatients in a university hospital ward in Hangzhou, China. METHODS: From May 2020 to August 2022, 1712 geriatric outpatients in a university hospital ward in Hangzhou, China, were screened using a socio-demographic questionnaire (e.g. gender, age, living arrangement, etc.) and assessment scales. The correlation between each factor and falls was preliminarily analysed by chi-squared tests. Finally, binary logistic regression analysis was conducted to further analyse the risk factors of falls. The STROBE checklist was used in reporting this study. RESULTS: Of the 1712 geriatric outpatients recruited, 1626 participants (60-79 and ≥ 80 years old) with complete questionnaire and assessment data were included. The occurrence of falls for those in the 60-79 age group was 8.4%, and for those in the ≥80 age group it was 13.4%. Age (p = .007), use of a walking assistance device (p < .001), the Stay Independent Brochure Questionnaire (SIB) (OR = 7.751, 95% CI = 5.089-11.806, p < .001), living arrangement (p = .004), timed up and go test (TUGT) (p = .007) and three diseases or above (OR = 2.496, 95% CI = 1.358-11.4.586, p = .003) reached statistical significance. CONCLUSIONS: Older people have a high incidence of falls. In this study, age, disease history, SIB scores (≥4 points), living arrangement, TUGT and walking assistance device increased the probability of falls in older Chinese adults. Personalised interventions should be carried out according to the specific situation of older people to effectively reduce their incidence of falls and improve their quality of life. RELEVANCE TO CLINICAL PRACTICE: The basic characteristics and fall risk factors of the older can help nurses identify fall risk, and early intervention by caregivers can reduce fall-related injuries, which has practical significance for promoting healthy aging. PATIENT OR PUBLIC CONTRIBUTION: The subjects of this study were older patients ≥60 years old, and the demographic characteristics and fall-related information of patients were obtained by questionnaire. The team worked closely with a team of experts in the field of health care. Some researchers collect data and rewrite them, while other researchers analyse the information and write a paper. All authors read and approved the final manuscript.

Recent Advances in Grayanane Diterpenes: Isolation, Structural Diversity, and Bioactivities from Ericaceae Family (2018-2024).

Diterpenes represent one of the most diverse and structurally complex families of natural products. Among the myriad of diterpenoids, grayanane diterpenes are particularly notable. These terpenes are characterized by their unique 5/7/6/5 tetracyclic system and are exclusive to the Ericaceae family of plants. Renowned for their complex structures and broad spectrum of bioactivities, grayanane diterpenes have become a primary focus in extensive phytochemical and pharmacological research. Recent studies, spanning from 2018 to January 2024, have reported a series of new grayanane diterpenes with unprecedented carbon skeletons. These compounds exhibit various biological properties, including analgesic, antifeedant, anti-inflammatory, and inhibition of protein tyrosine phosphatase 1B (PTP1B). This paper delves into the discovery of 193 newly identified grayanoids, representing 15 distinct carbon skeletons within the Ericaceae family. The study of grayanane diterpenes is not only a deep dive into the complexities of natural product chemistry but also an investigation into potential therapeutic applications. Their unique structures and diverse biological actions make them promising candidates for drug discovery and medicinal applications. The review encompasses their occurrence, distribution, structural features, and biological activities, providing invaluable insights for future pharmacological explorations and research.

Exploring the Biomedical Potential of Terpenoid Alkaloids: Sources, Structures, and Activities.

Terpenoid alkaloids are recognized as a class of compounds with limited numbers but potent biological activities, primarily derived from plants, with a minor proportion originating from animals and microorganisms. These alkaloids are synthesized from the same prenyl unit that forms the terpene skeleton, with the nitrogen atom introduced through ß-aminoethanol, ethylamine, or methylamine, leading to a range of complex and diverse structures. Based on their skeleton type, they can be categorized into monoterpenes, sesquiterpenes, diterpenes, and triterpene alkaloids. To date, 289 natural terpenoid alkaloids, excluding triterpene alkaloids, have been identified in studies published between 2019 and 2024. These compounds demonstrate a spectrum of biological activities, including anti-inflammatory, antitumor, antibacterial, analgesic, and cardioprotective effects, making them promising candidates for further development. This review provides an overview of the sources, chemical structures, and biological activities of natural terpenoid alkaloids, serving as a reference for future research and applications in this area.

Experiences of formal caregivers of elderly inpatients with physical disabilities in China: a qualitative study.

AIM: To explore the views and experiences of formal caregivers caring for older inpatients with physical disabilities. METHODS: It was a qualitative phenomenological study. Using purposive sampling, twelve formal caregivers were chosen in a tertiary comprehensive hospital in Hangzhou, China. Semi-structured, face-to-face interviews were conducted, guided by open-ended questions that focused on gaining rich insights into participants' views and experiences. Coding reliability thematic analysis was used to guide data analysis and categorize, based on Lazarus and Folkman's theory of transactional coping. RESULTS: Four themes emerged from the data analysis: (1) Caregiving Threats. (2) motivations. (3) Responsibility Management. (4) Fear. CONCLUSION: Despite facing significant pressure at work, formal caregivers of elderly inpatients with physical disabilities possess the drive and various coping strategies to excel in their role. Identifying caregivers' experiences of care can be helpful in improving resilience to stress and maintaining stability in formal caregivers.

Prognostic Risk Stratification and End-of-Life Care Outcomes in Patients With Metastatic Melanoma Treated With Immune Checkpoint Inhibitors.

INTRODUCTION: The emergence of immune checkpoint inhibitors (ICIs) has improved survival outcomes in patients with metastatic melanoma, while potentially increasing the use of systemic therapy near the end of life (EOL). Yet, less is known on how to facilitate treatment decision making and identify patients who might benefit from early palliative care comanagement. MATERIALS AND METHODS: We determined baseline clinical and laboratory factors that are associated with poor prognosis for patients with advanced melanoma treated with ICIs. We subsequently identified prognostic subgroups to evaluate association with EOL outcomes and determine if EOL care varied across prognostic strata. RESULTS: Our cohort included 398 patients with metastatic melanoma treated with ICIs. Factors associated with overall survival (OS) included: lactate dehydrogenase, neutrophil/lymphocyte ratio, performance status, prior therapies, liver metastases, and lung metastases. Patients were stratified by risk of death using risk scores developed from multivariable analyses. A total of 205 patients died: 45/133 (34%) low-risk, 63/133 (47%) medium-risk, and 97/132 (73%) of high-risk patients. Among those who died, higher risk patients were more likely to receive ICIs within 14, 30, and 90 days of death. We found no association between risk group and hospice referrals or location of death. CONCLUSION: Patients with metastatic melanoma at highest risk of death as defined by our model were more likely than lower-risk patients to receive ICIs near the EOL. Prognostic risk stratification may guide early palliative care interventions to appropriately utilize ICIs and optimize EOL care.

Esophageal Epithelium and Lamina Propria Are Unevenly Involved in Eosinophilic Esophagitis.

BACKGROUND & AIMS: The nature of the involvement of esophageal tissue in eosinophilic esophagitis (EoE) is unclear. We estimated the intrabiopsy site agreements of the EoE Histologic Scoring System (EoEHSS) scores for the grade (degree) and stage (extent) of involvement of the esophageal epithelial and lamina propria and examined if the EoE activity status influenced the intrabiopsy site agreement. METHODS: Demographic, clinical, and EoEHSS scores collected as part of the prospective Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages study were analyzed. A weighted Cohen's kappa agreement coefficient (k) was used to calculate the pairwise agreements for proximal:distal, proximal:middle, and middle:distal esophageal biopsy sites, separately for grade and stage scores, for each of the 8 components of EoEHSS. A k > 0.75 was considered uniform involvement. Inactive EoE was defined as fewer than 15 eosinophils per high-powered field. RESULTS: EoEHSS scores from 1263 esophageal biopsy specimens were analyzed. The k for the stage of involvement of the dilated intercellular spaces across all 3 sites in inactive EoE was consistently greater than 0.75 (range, 0.87-0.99). The k for lamina propria fibrosis was greater than 0.75 across some of the biopsy sites but not across all 3. Otherwise, the k for all other features, for both grade and stage, irrespective of the disease activity status, was 0.75 or less (range, 0.00-0.74). CONCLUSIONS: Except for the extent of involvement of dilated intercellular spaces in inactive EoE, the remaining epithelial features and lamina propria are involved unevenly across biopsy sites in EoE, irrespective of the disease activity status. This study enhances our understanding of the effects of EoE on esophageal tissue pathology.

ETHYLENE INSENSITIVE 3 suppresses plant de novo root regeneration from leaf explants and mediates age-regulated regeneration decline.

Powerful regeneration ability enables plant survival when plants are wounded. For example, adventitious roots can regenerate from the cutting site in detached Arabidopsis thaliana leaf explants, even in the absence of any exogenous plant hormone treatment. This process is known as de novo root regeneration (DNRR). Although the developmental program underlying DNRR is known, the precise regulatory mechanisms underlying DNRR are not completely understood. Here, we show that ethylene treatment or genetic activation of transcription factor ETHYLENE INSENSITIVE 3 (EIN3) strongly suppresses DNRR rates, while a mutant lacking EIN3 and its homolog EIL1 (ein3 eil1) displays a higher DNRR capacity. Previous reports have shown that the sequential induction of WUSCHEL RELATED HOMEOBOX 11 (WOX11)/WOX12 and WOX5/WOX7 expression is required for the establishment of DNRR. We found that EIN3 directly targets WOX11 and WOX5 promoter regions to suppress their transcription. Furthermore, older plants show enhanced EIN3 activity, and repressed expression of WOX11 and WOX5 Taken together, these results illustrate that plant aging at least partially takes advantage of EIN3 as a negative regulator to suppress DNRR through inhibiting the activation of WOX genes.

Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation.

BACKGROUND: Janus kinase 1 (JAK1) plays a critical role in most cytokine-mediated inflammatory, autoimmune responses and various cancers via the JAK/STAT signaling pathway. Inhibition of JAK1 is therefore an attractive therapeutic strategy for several diseases. Recently, high-performance machine learning techniques have been increasingly applied in virtual screening to develop new kinase inhibitors. Our study aimed to develop a novel layered virtual screening method based on machine learning (ML) and pharmacophore models to identify the potential JAK1 inhibitors. METHODS: Firstly, we constructed a high-quality dataset comprising 3834 JAK1 inhibitors and 12,230 decoys, followed by establishing a series of classification models based on a combination of three molecular descriptors and six ML algorithms. To further screen potential compounds, we constructed several pharmacophore models based on Hiphop and receptor-ligand algorithms. We then used molecular docking to filter the recognized compounds. Finally, the binding stability and enzyme inhibition activity of the identified compounds were assessed by molecular dynamics (MD) simulations and in vitro enzyme activity tests. RESULTS: The best performance ML model DNN-ECFP4 and two pharmacophore models Hiphop3 and 6TPF 08 were utilized to screen the ZINC database. A total of 13 potentially active compounds were screened and the MD results demonstrated that all of the above molecules could bind with JAK1 stably in dynamic conditions. Among the shortlisted compounds, the four purchasable compounds demonstrated significant kinase inhibition activity, with Z-10 being the most active (IC50 = 194.9 nM). CONCLUSION: The current study provides an efficient and accurate integrated model. The hit compounds were promising candidates for the further development of novel JAK1 inhibitors.