bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of short-chain fatty acids produced by gut microbiota in the regulation of pre-eclampsia onset
Authors: Cui Jinghan , Wang Jun , Wang Ying
Published: July 2023

Background

Preeclampsia (PE) is a common pregnancy-related disorder characterized by disrupted maternal-fetal immune tolerance, involving diffuse inflammatory responses and vascular endothelial damage. Alterations in the gut microbiota (GM) during pregnancy can affect intestinal barrier function and immune balance.

Aims and purpose

This comprehensive review aims to investigate the potential role of short-chain fatty acids (SCFAs), essential metabolites produced by the GM, in the development of PE. The purpose is to examine their impact on colonic peripheral regulatory T (Treg) cells, the pathogenic potential of antigen-specific helper T (Th) cells, and the inflammatory pathways associated with immune homeostasis.

Key insights

An increasing body of evidence suggests that dysbiosis in the GM can lead to alterations in SCFA levels, which may significantly contribute to the development of PE. SCFAs enhance the number and function of colonic Treg cells, mitigate the pathogenic potential of GM-specific Th cells, and inhibit inflammatory progression, thereby maintaining immune homeostasis. These insights highlight the potential significance of GM dysregulation and SCFAs produced by GM in the pathogenesis of PE. While the exact causes of PE remain elusive, and definitive clinical treatments are lacking, the GM and SCFAs present promising avenues for future clinical applications related to PE, offering a novel approach for prophylaxis and therapy.
Autoimmune thyroid disease disrupts immune homeostasis in the endometrium of unexplained infertility women—a single-cell RNA transcriptome study during the implantation window
Authors: Xie Jilai , Gu Aiyuan , He Huangyi , Zhao Qiaohang , Yu Ya , Chen Jian , Cheng Zhangliang , Zhou Ping , Zhou Qi , Jin Min
Published: July 2023

Objective

Autoimmune thyroid disease (AITD) is known to be associated with unexplained infertility in women. Although the presence of antithyroid antibodies have been speculated to be a marker of an immune imbalance that might lead to implantation failure, its underlying mechanism influencing the endometrial receptivity remains to be elucidated. In this study, we used single-cell RNA sequencing (scRNA-seq) to dissect immune microenvironment in endometrium of AITD patients during window of implantation (WOI).

Methods

We collected CD45+ immune cell populations of endometrium samples of unexplained infertile women with AITD (n=3), as well as samples of AITD- controls (n=3). The cells were then processed with 10X Genomics Chromium for further analysis.

Results

We characterized 28 distinct immune cell subtypes totally, and uncovered differences in the composition and gene expression patterns between AITD patients and controls. The proportions of T CD4+, cNK, ILC3, T CD8+GZMK+, T CD8+ Cytotoxic and ILC3 CD3E- cells were increased, and CD366+ uNK1 was decreased in AITD+ patients. And the abnormal expression of GNLY and chemokines was observed in AITD patients. In addition, uNK and T CD8+ Cytotoxic cells showed lower cytotoxicity but activation of immune response. Genes enriched in cell adhesion of ILC3 and Tregs were downregulated, while the number of ILC3 and Tregs were increased.

Conclusion

Immune imbalance exists in endometrium during WOI, which may impact embryo implantation.
Physiological and biochemical indicators in Norway spruces freshly infested by Ips typographus: potential for early detection methods
Authors: Stříbrská Barbora , Hradecký Jaromír , Čepl Jaroslav , Modlinger Roman , Tomášková Ivana , Jirošová Anna
Published: July 2023

Intoduction

The bark beetle Ips typographus currently represents the primary pest of Norway spruce (Picea abies) in Central Europe. Early detection and timely salvage cutting of bark beetle-infested trees are functional management strategies for controlling bark beetle outbreaks. However, alternative detection methods are currently being developed, and possible indicators of bark beetle infestation can be assessed through changes in the physiological, biochemical, and beetle-acceptance characteristics of trees.

Method

This study monitored infested and non-infested Norway spruce trees before and 3 weeks after Ips typographus natural attack. Permanently installed sensors recorded physiological features, such as sap flow, tree stem increment, bark surface temperature, and soil water potential, to monitor water availability. Defensive metabolism characteristics, beetle host acceptance, and attractiveness to trees were monitored discretely several times per season. The forest stand that was later attacked by bark beetles had lower water availability during the 2018–2020 seasons compared to the non-attacked stands.

Results

After the attack, sap flow and tree stem increment were significantly lower in infested trees than in intact ones, and bark surface temperature moderately increased, even when measured in the inner forest stand from the shadowed side. Infested trees respond to attacks with a surge in monoterpene emissions. In addition, freshly infested trees were more accepted by males in the no-choice bioassays, and a significantly higher number of beetles were caught in passive traps in the first week of infestation.

Conclusion

The most promising characteristics for early detection methods of bark beetle-infested trees include tree bark temperature measured only in certain meteorological conditions, elevated monoterpene emissions, and significantly high catches in passive traps.
Development of a radiomics nomogram to predict the treatment resistance of Chinese MPO-AAV patients with lung involvement: a two-center study
Authors: Chen Juan , Meng Ting , Xu Jia , Ooi Joshua D. , Eggenhuizen Peter J. , Liu Wenguang , Li Fang , Wu Xueqin , Sun Jian , Zhang Hao , Zhou Ya-Ou , Luo Hui , Xiao Xiangcheng , Pei Yigang , Li Wenzheng , Zhong Yong
Published: July 2023

Background

Previous studies from our group and other investigators have shown that lung involvement is one of the independent predictors for treatment resistance in patients with myeloperoxidase (MPO)–anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). However, it is unclear which image features of lung involvement can predict the therapeutic response in MPO-AAV patients, which is vital in decision-making for these patients. Our aim was to develop and validate a radiomics nomogram to predict treatment resistance of Chinese MPO-AAV patients based on low-dose multiple slices computed tomography (MSCT) of the involved lung with cohorts from two centers.

Methods

A total of 151 MPO-AAV patients with lung involvement (MPO-AAV-LI) from two centers were enrolled. Two different models (Model 1: radiomics signature; Model 2: radiomics nomogram) were built based on the clinical and MSCT data to predict the treatment resistance of MPO-AAV with lung involvement in training and test cohorts. The performance of the models was assessed using the area under the curve (AUC). The better model was further validated. A nomogram was constructed and evaluated by DCA and calibration curves, which further tested in all enrolled data and compared with the other model.

Results

Model 2 had a higher predicting ability than Model 1 both in training (AUC: 0.948 vs. 0.824; p = 0.039) and test cohorts (AUC: 0.913 vs. 0.898; p = 0.043). As a better model, Model 2 obtained an excellent predictive performance (AUC: 0.929; 95% CI: 0.827–1.000) in the validation cohort. The DCA curve demonstrated that Model 2 was clinically feasible. The calibration curves of Model 2 closely aligned with the true treatment resistance rate in the training (p = 0.28) and test sets (p = 0.70). In addition, the predictive performance of Model 2 (AUC: 0.929; 95% CI: 0.875–0.964) was superior to Model 1 (AUC: 0.862; 95% CI: 0.796–0.913) and serum creatinine (AUC: 0.867; 95% CI: 0.802–0.917) in all patients (all p< 0.05).

Conclusion

The radiomics nomogram (Model 2) is a useful, non-invasive tool for predicting the treatment resistance of MPO-AAV patients with lung involvement, which might aid in individualizing treatment decisions.
Understanding a videogame home intervention for children with hemiplegia: a mixed methods multi-case study
Authors: Chan-Víquez Daniela , Khan Ajmal , Munce Sarah , Fehlings Darcy , Wright F. Virginia , Biddiss Elaine
Published: July 2023

Introduction

Access to rehabilitation therapies is a salient and growing issue for children with cerebral palsy (CP) and their families, motivating interest in home-based interventions. Bootle Blast is a low-cost, movement-tracking videogame that can be used at home to encourage upper limb (UL) functional exercise tailored to each child's abilities and therapy goals. The study objectives were to: 1) Establish the extent to which children achieve their self-directed play-time goal over a 12-week intervention, 2) Measure changes in UL motor outcomes, and 3) Explore participants' experiences of using Bootle Blast at home.

Methods

Mixed methods case series study of four children with hemiplegic cerebral palsy (HCP), each with a participating parent. Participants played Bootle Blast at home for 12 weeks. Study assessments occurred at baseline, post-intervention and four week follow up. A post-intervention interview explored participants' experiences. Game-logs provided play time and progress data.

Results

Three of four participants (8-13 yrs., Manual Ability Classification Level I-II) completed the intervention. One dropped out at week 6. Play-time goals were achieved in most weeks, with two of four children surpassing their overall intervention goals. Outcomes varied across the three participants, however consistent improvements were observed on the Canadian Occupational Performance Measure and the Box and Blocks Test. Inductive analysis generated four main themes: 1) Intrinsic motivators fostered play engagement, 2) Virtual play for real-world gains, 3) Therapy on demand (at home), and 4) Shifting the onus from the parent to the game. Integration of qualitative and quantitative data was important for interpreting play patterns/usage and clinical outcomes.

Discussion

This mixed methods study describes a novel videogaming intervention designed for home-rehabilitation for children with HCP and provides preliminary evidence to guide future study design and research.

Clinical Trial Registration

[https://clinicaltrials.gov/ct2/show/NCT04009031?recrs=h&cond=Cerebral+Palsy&cntry=CA&city=Toronto&draw=2&rank=1], identifier [NCT04009031].
Causal relationship between kidney stones and gut microbiota contributes to the gut-kidney axis: a two-sample Mendelian randomization study
Authors: Liu Minghui , Zhang Youjie , Wu Jian , Gao Meng , Zhu Zewu , Chen Hequn
Published: July 2023

Background

Gut microbiota, particularly Oxalobacter formigenes, has been previously reported to be associated with kidney stones. However, the conflicting results from both observational and intervention studies have created substantial uncertainty regarding the contribution of Oxalobacter formigenes to the formation of kidney stone.

Methods

We employed a two-sample MR analysis to investigate the causal relationship between gut microbiota and kidney stones using GWASs summary statistics obtained from the MiBioGen and FinnGen consortia. Moreover, we conducted a reserve MR analysis to assess the direction of the causal associations between gut microbiota and kidney stones. The inverse variance weighted (IVW) approach represents the primary method of Mendelian Randomization (MR) analysis.

Results

Our analyses do not yield supportive evidence for a causal link between the genus Oxalobacter (OR = 0.99, 95% CI: 0.90–1.09, p = 0.811) and the formation of kidney stones. The order Actinomycetales (OR = 0.79, 95% CI: 0.65–0.96, p = 0.020), family Actinomycetaceae (OR = 0.79, 95% CI: 0.65–0.96, p = 0.019), family Clostridiaceae 1 (OR = 0.80, 95% CI: 0.67–0.96, p = 0.015), genus Clostridiumsensustricto 1 (OR = 0.81, 95% CI: 0.67–0.98, p = 0.030) and genus Hungatella (OR = 0.86, 95% CI: 0.74–0.99, p = 0.040) had protective effects on kidney stones, and the genus Haemophilus (OR = 1.16, 95% CI: 1.01–1.33, p = 0.032), genus Ruminococcaceae (UCG010) (OR = 1.38, 95% CI: 1.04–1.84, p = 0.028), genus Subdoligranulum (OR = 1.27, 95% CI: 1.06–1.52, p = 0.009) were risk factors for kidney stones. Differential abundance analysis provide no evidence of a association between Oxalobacter formigenes and kidney stones, and showed genus Subdoligranulum were risk factors for kidney stones. Reverse MR analysis did not indicate any causal association of kidney stones on gut microbiota. No considerable heterogeneity of instrumental variables or horizontal pleiotropy was observed.

Conclusion

Our two-sample MR study did not find any causal relationship between genus Oxalobacter and kidney stones. The association between gut microbiota and kidney stones does not solely depend on the presence of genus Oxalobacter/Oxalobacter formigenes. A more integrated approach using multiple omics platforms is needed to better understand the pathogenesis of kidney stones in the context of complex gene–environment interactions over time.
Effects of warming and nitrogen addition on soil fungal and bacterial community structures in a temperate meadow
Authors: Jiang Ming , Tian Yibo , Guo Rui , Li Shuying , Guo Jixun , Zhang Tao
Published: July 2023

Soil microbial communities have been influenced by global changes, which might negatively regulate aboveground communities and affect nutrient resource cycling. However, the influence of warming and nitrogen (N) addition and their combined effects on soil microbial community composition and structure are still not well understood. To explore the effect of warming and N addition on the composition and structure of soil microbial communities, a five-year field experiment was conducted in a temperate meadow. We examined the responses of soil fungal and bacterial community compositions and structures to warming and N addition using ITS gene and 16S rRNA gene MiSeq sequencing methods, respectively. Warming and N addition not only increased the diversity of soil fungal species but also affected the soil fungal community structure. Warming and N addition caused significant declines in soil bacterial richness but had few impacts on bacterial community structure. The changes in plant species richness affected the soil fungal community structure, while the changes in plant cover also affected the bacterial community structure. The response of the soil bacterial community structure to warming and N addition was lower than that of the fungal community structure. Our results highlight that the influence of global changes on soil fungal and bacterial community structures might be different, and which also might be determined, to some extent, by plant community, soil physicochemical properties, and climate characteristics at the regional scale.
Endotrophin, a fibroblast matrikine, may be a driver of fibroblast activation in fibro-inflammatory diseases
Authors: Reese-Petersen Alexander L. , Genovese Federica , Zhao Lei , Banks Glen , Gordon David A. , Karsdal Morten A.
Published: July 2023

Extracellular matrix proteins harbor signaling domains that once released from the parent molecule can trigger cellular responses. One of these molecules is endotrophin, a type VI collagen derived fragment, whose circulatory levels have been associated to an increased risk of adverse outcome in heart failure with preserved ejection fraction (HFpEF). Here we show that the stimulation of human cardiac fibroblasts by endotrophin upregulates the synthesis of type I collagen, the main interstitial collagen that accumulates in the myocardium during fibrogenesis. These data provide a possible mechanistic explanation for the relation between circulating endotrophin levels and risk of outcome in HFpEF.
Acid-sensing ion channel blocker diminazene facilitates proton-induced excitation of afferent nerves in a similar manner that Na+/H+ exchanger blockers do
Authors: Tkachenko Yurii , Khmyz Volodymyr , Buta Andrii , Isaev Dmytro , Maximyuk Oleksandr , Krishtal Oleg
Published: July 2023

Tissue acidification causes sustained activation of primary nociceptors, which causes pain. In mammals, acid-sensing ion channels (ASICs) are the primary acid sensors; however, Na+/H+ exchangers (NHEs) and TRPV1 receptors also contribute to tissue acidification sensing. ASICs, NHEs, and TRPV1 receptors are found to be expressed in nociceptive nerve fibers. ASIC inhibitors reduce peripheral acid-induced hyperalgesia and suppress inflammatory pain. Also, it was shown that pharmacological inhibition of NHE1 promotes nociceptive behavior in acute pain models, whereas inhibition of TRPV1 receptors gives relief. The murine skin-nerve preparation was used in this study to assess the activation of native polymodal nociceptors by mild acidification (pH 6.1). We have found that diminazene, a well-known antagonist of ASICs did not suppress pH-induced activation of CMH-fibers at concentrations as high as 25 μM. Moreover, at 100 μM, it induces the potentiation of the fibers’ response to acidic pH. At the same time, this concentration virtually completely inhibited ASIC currents in mouse dorsal root ganglia (DRG) neurons (IC50 = 17.0 ± 4.5 μM). Non-selective ASICs and NHEs inhibitor EIPA (5-(N-ethyl-N-isopropyl)amiloride) at 10 μM, as well as selective NHE1 inhibitor zoniporide at 0.5 μM induced qualitatively the same effects as 100 μM of diminazene. Our results indicate that excitation of afferent nerve terminals induced by mild acidification occurs mainly due to the NHE1, rather than acid-sensing ion channels. At high concentrations, diminazene acts as a weak blocker of the NHE. It lacks chemical similarity with amiloride, EIPA, and zoniporide, so it may represent a novel structural motif for the development of NHE antagonists. However, the effect of diminazene on the acid-induced excitation of primary nociceptors remains enigmatic and requires additional investigations.
High level of agreement in a fixed vs. live cell-based assay for antibodies to myelin oligodendrocyte glycoprotein in a real-world clinical laboratory setting
Authors: Smith Tammy L. , Haven Thomas R. , Zuromski Lauren M. , Luong Kyphuong , Clardy Stacey L. , Peterson Lisa K.
Published: July 2023

Introduction

As recognition of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease becomes more widespread, the importance of appropriately ordering and interpreting diagnostic testing for this antibody increases. Several assays are commercially available for MOG testing, and based on a few small studies with very few discrepant results, some have suggested that live cell-based assays (CBA) are superior to fixed CBA for clinical MOG antibody testing. We aimed to determine the real-world agreement between a fixed and live CBA for MOG using two of the most commonly available commercial testing platforms.

Methods

We compared paired clinical samples tested at two national clinical reference laboratories and determined the real-world agreement between the fixed CBA and live CBA.

Results

Of 322 paired samples tested on both platforms, 53 were positive and 246 were negative by both methodologies (agreement 92.9%, Cohen’s kappa 0.78, [0.69-0.86]). Spearman correlation coefficient was 0.80 (p < 0.0001). Of the discrepant results, only 1 of 14 results positive by the live CBA had a titer greater than 1:100, and only 1 of 9 results positive by the fixed CBA had a titer of greater than 1:80. Lower titers on the fixed CBA correlate to higher titers on the live CBA.

Conclusion

Overall, there is excellent agreement between fixed and live CBA for MOG antibody testing in a real-world clinical laboratory setting. Clinicians should be aware of which method they use to assess any given patient, as titers are comparable, but not identical between the assays.
Acceptability, usability and feasibility of experienced sampling method in chronic secondary pain syndromes
Authors: Damci Aysun , Hoeijmakers Janneke G. J. , den Hollander Marlies , Köke Albère , de Mooij Marion , Faber Catharina G. , Verbunt Jeanine A. M. C. F.
Published: July 2023

Background

In chronic pain syndromes, symptoms can fluctuate and change over time. Standard questionnaires cannot register these fluctuations. Nonetheless, the experience sampling method (ESM) is developed to collect momentary measurements of everyday complaints, tracing fluctuations in symptoms and disabling factors over time. Although valuable information can be collected in this way, assessment may also be a burden. This study aimed to investigate the acceptability, usability, and feasibility of ESM in chronic secondary pain syndromes, in a single-center study in the Netherlands.

Methods

A prospective observational study with repeated measurements was conducted in patients with chronic secondary neuropathic and musculoskeletal pain syndromes, including small fiber neuropathy, spinal cord injury, and rheumatoid disorder.

Results

Thirty-four participants were included and filled in the ESM, of whom 19 were diagnosed with small fiber neuropathy, 11 with spinal cord injury, and 4 with a rheumatoid disorder. The mean age was 54.7 ± 13.9 years (range: 23–77) of whom 52.9% were female. In total, 19 participants filled in the general and user-friendliness evaluation about the acceptability and usability of the ESM. The general evaluation showed no influence of ESM on participants’ social contacts (mean 1.47, SD 1.12), activities (mean 1.74, SD 1.44), and mood (mean 1.89, SD 1.59). The answers options of ESM were a good representation of the experiences of participants (mean 4.58, SD 1.77). Regarding feasibility, the overall response rate for answering the beep signals of ESM was 44.5% in total. The missing rate per person varied from 13% to 97% with a median of 54.1%.

Conclusion

The general evaluation and the user-friendliness revealed sufficient outcomes in favor of the ESM application. ESM seems a promising measurement tool to use in secondary chronic pain syndromes.
A defined method for differentiating human iPSCs into midbrain dopaminergic progenitors that safely restore motor deficits in Parkinson’s disease
Authors: Nakamura Ryota , Nonaka Risa , Oyama Genko , Jo Takayuki , Kamo Hikaru , Nuermaimaiti Maierdanjiang , Akamatsu Wado , Ishikawa Kei-ichi , Hattori Nobutaka
Published: July 2023

Background

Parkinson’s disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting human-induced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction.

Methods

Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro. Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks.

Results

Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions.

Conclusion

This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD.
High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons
Authors: Huan Yu , Quan Huilin , Jia Bo , Hao Guangzhi , Shi Zuolin , Zhao Tianzi , Yuan Ying , Yuan Fang , Dong Yushu , Liang Guobiao
Published: July 2023

Introduction

Neuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches.

Methods

Acute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior.

Results

Results revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability.

Discussion

These findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia.
Resting-state functional magnetic resonance imaging reveals brain remodeling after Tuina therapy in neuropathic pain model
Authors: Wu Zhiwei , Guo Guangxin , Zhang Yuwen , Li Yunyi , He Tianxiang , Zhu Qingguang , Kong Lingjun , Fang Min
Published: July 2023

Tuina, a method of traditional Chinese manual manipulation, is an effective alternative therapy for neuropathic pain (NP), but its analgesic mechanism remains unclear. In this study, we used resting-state functional magnetic resonance imaging (R-fMRI) to explore the analgesic mechanism of Tuina in an NP rat model. After undergoing surgery to induce chronic compression of the dorsal root ganglion (CCD), one group of rats underwent Tuina at the ipsilateral BL40 acupoint once a day for 10 min during the 25 days following surgery while another group did not. Behavioral tests were performed at baseline, on the third day following surgery, and once a week for the next 4 weeks. R-fMRI was performed at baseline and 7 days and 28 days following surgery. Behavioral testing revealed that the Tuina group presented a significant response improvement to mechanical and thermal nociception stimuli compared to the untreated group 2 weeks following CCD surgery. Interestingly, rats submitted to Tuina presented higher measures of spontaneous neuronal activity in basal forebrain region, primary somatosensory cortex barrel field, dentate gyrus, secondary somatosensory cortex, striatum, descending corticofugal pathways, and globus pallidum of the left hemisphere 4 weeks after the CCD surgery compared to rats having undergone CCD only. In addition, on the 28th day, the ALFF signals of the left dentate gyrus, left secondary somatosensory cortex, left striatum, and bilateral primary cingulate cortex were significantly increased while those in the right dentate gyrus and bilateral periaqueductal gray were significantly decreased compared to those on the 7th day. Correlation analysis showed that the ALFF values of the left descending corticofugal pathways and globus pallidum had a positive correlation with mechanical withdrawal threshold and paw withdrawal thermal latency tests. Altogether, these results indicate that NPP induced by CCD surgery affects the plasticity of the cerebral cortex, and that Tuina alleviate pain behavior by promoting cortical remodeling.
Effects of agro-forestry systems on the physical and chemical characteristics of green coffee beans
Authors: Xu Su , Liu Yuze , Sun Zhenchun , Chen Guangjing , Ma Fengwei , Yang Ni , de Melo Virginio Filho Elias , Fisk Ian D.
Published: July 2023

Twenty agroforestry systems consisting of different management practices (conventional and organic) and shade types were set up for coffee plantations in 2,000 at the Tropical Agricultural Research and Higher Education Center (CATIE), Turrialba, Costa Rica. The physical (density, bulk density, moisture content, and roasting loss) and chemical attributes (mineral, total lipid, fatty acids, caffeine, and carbohydrate contents) of harvested green coffee beans were investigated. The full sun and Erythrina shade tree systems significantly improved (p < 0.05) the density of the green coffee beans and decreased (p < 0.05) the moisture content and roasting loss of the green coffee beans. The intensive organic (IO) management practice significantly increased some mineral contents, such as K, P, and Ca, in green coffee beans. The full sun system also significantly promoted (p < 0.05) some mineral contents, such as Ca and Mn, in green coffee beans. In terms of total lipid and fatty acids (FAs), compared with the moderate conventional (MC) management practice, the IO management practice was beneficial as it significantly increased (p < 0.05) the total lipid and FAs contents in the green coffee beans, while the Erythrina shade tree system significantly increased (p < 0.05) the total lipid and FAs contents of green coffee beans more efficiently than the other shade types. The caffeine content of green coffee beans was significantly higher (p < 0.05) under the intensive conventional (IC) and IO management practices than under the MC management practice and higher under the full sun system than under the shaded system. The Erythrina shade tree system significantly improved (p < 0.05) the carbohydrate content of green coffee beans. Overall, in consideration of sustainability, the IO management practice associated with the Erythrina shade tree system would be a useful combination for the local farmers to grow coffee trees.
Temporal genomic heterogeneity guiding individualized therapy in recurrent non-small cell lung cancer
Authors: Fang Qiyu , Wan Xiaoying , D’Aiello Angelica , Sun Hui , Gu Weiquing , Li Yixue , Zhou Caicun , Xie Boxiong , Deng Qinfang , Cheng Haiying , Zhou Songwen
Published: July 2023

Introduction

Despite the benefit of adjuvant systemic therapy for patients with resected non-small cell lung cancer (NSCLC), the risk of postoperative recurrence remains high. Our objective was to characterize temporal genetic heterogeneity between primary resected and recurrent tumors, and its impact on treatment outcomes.

Methods

In this study, next-generation sequencing (NGS) testing was performed on tissue specimens and circulating tumor DNA (ctDNA) collected at postoperative recurrence, and results were compared to the genotypes of initial surgical specimens.

Results

Of forty-five patients with matched primary and post-operative recurrent tumors, EGFR status switched in 17 patients (37.8%) at post-operative recurrence and 28 patients (62.2%) had no genotype change (17 mutant, 11 wild-type). Based on the changes of EGFR status, patients were divided into 4 groups. Following subsequent treatment with EGFR TKI o chemotherapy: In group A, with sustained sensitive mutation, the percentage achieving partial response (PR) was the highest, at 72.2%, the median progression-free survival (PFS) was 17 months, and the median overall survival (OS) was 44.0 months respectively; In group B, with genotype changed from wild-type to mutant, 50% achieved PR, PFS was 10 months, and OS was 35 months; In group C, in which mutant status shifted to wild-type or new co-mutation emerged, the percentage achieving PR was 30%, PFS was 9 months, and OS was 35 months. In group D, with sustained wild type, the percentage achieving PR was 27.3%, PFS was 8 months, and OS was 22 months.

Discussion

Genotypic shift between paired primary and post-operative recurrent tumors was not infrequent, and this temporal genomic heterogeneity substantially impacted subsequent treatment outcomes.
Predicting cancer relapse following lung stereotactic radiotherapy: an external validation study using real-world evidence
Authors: Davey Angela , Thor Maria , van Herk Marcel , Faivre-Finn Corinne , Rimner Andreas , Deasy Joseph O. , McWilliam Alan
Published: July 2023

Purpose

For patients receiving lung stereotactic ablative radiotherapy (SABR), evidence suggests that high peritumor density predicts an increased risk of microscopic disease (MDE) and local-regional failure, but only if there is low or heterogenous incidental dose surrounding the tumor (GTV). A data-mining method (Cox-per-radius) has been developed to investigate this dose-density interaction. We apply the method to predict local relapse (LR) and regional failure (RF) in patients with non-small cell lung cancer.

Methods

199 patients treated in a routine setting were collated from a single institution for training, and 76 patients from an external institution for validation. Three density metrics (mean, 90th percentile, standard deviation (SD)) were studied in 1mm annuli between 0.5cm inside and 2cm outside the GTV boundary. Dose SD and fraction of volume receiving less than 30Gy were studied in annuli 0.5-2cm outside the GTV to describe incidental MDE dosage. Heat-maps were created that correlate with changes in LR and RF rates due to the interaction between dose heterogeneity and density at each distance combination. Regions of significant improvement were studied in Cox proportional hazards models, and explored with and without re-fitting in external data. Correlations between the dose component of the interaction and common dose metrics were reported.

Results

Local relapse occurred at a rate of 6.5% in the training cohort, and 18% in the validation cohort, which included larger and more centrally located tumors. High peritumor density in combination with high dose variability (0.5 - 1.6cm) predicts LR. No interactions predicted RF. The LR interaction improved the predictive ability compared to using clinical variables alone (optimism-adjusted C-index; 0.82 vs 0.76). Re-fitting model coefficients in external data confirmed the importance of this interaction (C-index; 0.86 vs 0.76). Dose variability in the 0.5-1.6 cm annular region strongly correlates with heterogeneity inside the target volume (SD; ρ = 0.53 training, ρ = 0.65 validation).

Conclusion

In these real-world cohorts, the combination of relatively high peritumor density and high dose variability predicts increase in LR, but not RF, following lung SABR. This external validation justifies potential use of the model to increase low-dose CTV margins for high-risk patients.
HDAC-an important target for improving tumor radiotherapy resistance
Authors: Ling Rui , Wang Jingzhi , Fang Yuan , Yu Yunpeng , Su Yuting , Sun Wen , Li Xiaoqin , Tang Xiang
Published: July 2023

Radiotherapy is an important means of tumor treatment, but radiotherapy resistance has been a difficult problem in the comprehensive treatment of clinical tumors. The mechanisms of radiotherapy resistance include the repair of sublethal damage and potentially lethal damage of tumor cells, cell repopulation, cell cycle redistribution, and reoxygenation. These processes are closely related to the regulation of epigenetic modifications. Histone deacetylases (HDACs), as important regulators of the epigenetic structure of cancer, are widely involved in the formation of tumor radiotherapy resistance by participating in DNA damage repair, cell cycle regulation, cell apoptosis, and other mechanisms. Although the important role of HDACs and their related inhibitors in tumor therapy has been reviewed, the relationship between HDACs and radiotherapy has not been systematically studied. This article systematically expounds for the first time the specific mechanism by which HDACs promote tumor radiotherapy resistance in vivo and in vitro and the clinical application prospects of HDAC inhibitors, aiming to provide a reference for HDAC-related drug development and guide the future research direction of HDAC inhibitors that improve tumor radiotherapy resistance.
Computational study of SENP1 in cancer by novel natural compounds and ZINC database screening
Authors: Taghvaei Somayye , Taghvaei Alireza , Anvar Mohammad Saberi , Guo Chun , Sabouni Farzaneh , Minuchehr Zarrin
Published: July 2023

Introduction: Sentrin-specific protease 1 (SENP1) is a protein whose main function is deSUMOylation. SENP1 inhibits apoptosis, and increases angiogenesis, estrogen and androgen receptor transcription and c-Jun transcription factor, proliferation, growth, cell migration, and invasion of cancer. The in vivo and in vitro studies also demonstrated which natural compounds, especially phytochemicals, minerals, and vitamins, prevent cancer. More than 3,000 plant species have been reported in modern medicine. Natural compounds have many anti-cancerous andanti-turmeric properties such as antioxidative, antiangiogenic, antiproliferative, and pro-apoptotic properties.

Methods: In this study, we investigated the interaction of some natural compounds with SENP1 to inhibit its activity. We also screened the ZINC database including natural compounds. Molecular docking was performed, and toxicity of compounds was determined; then, molecular dynamics simulation (MDS) and essential dynamics (ED) were performed on natural compounds with higher free binding energies and minimal side effects. By searching in a large library, virtual screening of the ZINC database was performed using LibDock and CDOCKER, and the final top 20 compounds were allowed for docking against SENP1. According to the docking study, the top three leading molecules were selected and further analyzed by MDS and ED.

Results: The results suggest that resveratrol (from the selected compounds) and ZINC33916875 (from the ZINC database) could be more promising SENP1 inhibitory ligands.

Discussion: Because these compounds can inhibit SENP1 activity, then they can be novel candidates for cancer treatment. However, wet laboratory experiments are needed to validate their efficacy as SENP1 inhibitors.
Potential pharmacokinetic interactions with concurrent use of herbal medicines and a ritonavir-boosted COVID-19 protease inhibitor in low and middle-income countries
Authors: Smith Dallas J. , Bi Huichang , Hamman Josias , Ma Xiaochao , Mitchell Constance , Nyirenda Kumbukani , Monera-Penduka Tsitsi , Oketch-Rabah Hellen , Paine Mary F. , Pettit Syril , Pheiffer Wihan , Van Breemen Richard B. , Embry Michelle
Published: July 2023

The COVID-19 pandemic sparked the development of novel anti-viral drugs that have shown to be effective in reducing both fatality and hospitalization rates in patients with elevated risk for COVID-19 related morbidity or mortality. Currently, nirmatrelvir/ritonavir (Paxlovid™) fixed-dose combination is recommended by the World Health Organization for treatment of COVID-19. The ritonavir component is an inhibitor of cytochrome P450 (CYP) 3A, which is used in this combination to achieve needed therapeutic concentrations of nirmatrelvir. Because of the critical pharmacokinetic effect of this mechanism of action for Paxlovid™, co-administration with needed medications that inhibit or induce CYP3A is contraindicated, reflecting concern for interactions with the potential to alter the efficacy or safety of co-administered drugs that are also metabolized by CYP3A. Some herbal medicines are known to interact with drug metabolizing enzymes and transporters, including but not limited to inhibition or induction of CYP3A and P-glycoprotein. As access to these COVID-19 medications has increased in low- and middle-income countries (LMICs), understanding the potential for herb-drug interactions within these regions is important. Many studies have evaluated the utility of herbal medicines for COVID-19 treatments, yet information on potential herb-drug interactions involving Paxlovid™, specifically with herbal medicines commonly used in LMICs, is lacking. This review presents data on regionally-relevant herbal medicine use (particularly those promoted as treatments for COVID-19) and mechanism of action data on herbal medicines to highlight the potential for herbal medicine interaction Herb-drug interaction mediated by ritonavir-boosted antiviral protease inhibitors This work highlights potential areas for future experimental studies and data collection, identifies herbal medicines for inclusion in future listings of regionally diverse potential HDIs and underscores areas for LMIC-focused provider-patient communication. This overview is presented to support governments and health protection entities as they prepare for an increase of availability and use of Paxlovid™.
Generalizability of machine learning methods in detecting adverse drug events from clinical narratives in electronic medical records
Authors: Zitu Md Muntasir , Zhang Shijun , Owen Dwight H. , Chiang Chienwei , Li Lang
Published: July 2023

We assessed the generalizability of machine learning methods using natural language processing (NLP) techniques to detect adverse drug events (ADEs) from clinical narratives in electronic medical records (EMRs). We constructed a new corpus correlating drugs with adverse drug events using 1,394 clinical notes of 47 randomly selected patients who received immune checkpoint inhibitors (ICIs) from 2011 to 2018 at The Ohio State University James Cancer Hospital, annotating 189 drug-ADE relations in single sentences within the medical records. We also used data from Harvard’s publicly available 2018 National Clinical Challenge (n2c2), which includes 505 discharge summaries with annotations of 1,355 single-sentence drug-ADE relations. We applied classical machine learning (support vector machine (SVM)), deep learning (convolutional neural network (CNN) and bidirectional long short-term memory (BiLSTM)), and state-of-the-art transformer-based (bidirectional encoder representations from transformers (BERT) and ClinicalBERT) methods trained and tested in the two different corpora and compared performance among them to detect drug–ADE relationships. ClinicalBERT detected drug–ADE relationships better than the other methods when trained using our dataset and tested in n2c2 (ClinicalBERT F-score, 0.78; other methods, F-scores, 0.61–0.73) and when trained using the n2c2 dataset and tested in ours (ClinicalBERT F-score, 0.74; other methods, F-scores, 0.55–0.72). Comparison among several machine learning methods demonstrated the superior performance and, therefore, the greatest generalizability of findings of ClinicalBERT for the detection of drug–ADE relations from clinical narratives in electronic medical records.
Screening of wild species and transcriptome profiling to identify differentially regulated genes in response to late blight resistance in potato
Authors: Bhatia Nisha , Tiwari Jagesh Kumar , Kumari Chandresh , Zinta Rasna , Sharma Sanjeev , Thakur Ajay Kumar , Buckseth Tanuja , Dalamu Dalamu , Singh Rajesh Kumar , Kumar Vinod
Published: July 2023

Late blight (Phytophthora infestans) is a serious disease of potatoes. The aim of this study was to screen wild potato species and identify differentially expressed genes (DEGs) associated with late blight resistance. Wild potato species such as PIN45 (Solanum pinnatisectum), CPH62 (Solanum cardiophyllum), JAM07 (Solanum jamesii), MCD24 (Solanum microdontum), PLD47 (Solanum polyadenium), and cv. Kufri Bahar (control) were tested by artificial inoculation of P. infestans under controlled conditions. Transcriptomes of the leaf tissues (96 h post-inoculation) were sequenced using the Illumina platform. Statistically significant (p < 0.05) DEGs were analyzed in wild species by comparison with the control, and upregulated (>2 log2 fold change, FC) and downregulated (<−2 log2 FC) genes were identified. DEGs were functionally characterized with Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Selected genes were validated by real-time PCR analysis to confirm RNA-seq results. We identified some upregulated genes associated with late blight resistance in wild species such as cytochrome P450, proline-rich protein, MYB transcription factor MYB139, ankyrin repeat-containing protein, and LRR receptor-like serine/threonine-protein kinase in PIN45; glucosyltransferase, fructose-bisphosphate aldolase, and phytophthora-inhibited protease 1 in CPH62; steroid binding protein and cysteine proteinase 3 in JAM07; glycine-rich cell wall structural protein 1 and RING finger protein in MCD24; and cysteine proteinase 3 and major latex protein in PLD47. On the other hand, downregulated genes in these species were snakin-2 and WRKY transcription factor 3 in PIN45; lichenase and phenylalanine ammonia-lyase 1 in CPH62; metallothionein and LRR receptor-like serine/threonine-protein kinase in JAM07; UDP-glucoronosyl/UDP-glucosyl transferase family protein and steroid binding protein in MCD24; and cytoplasmic small heat shock protein class I and phosphatase PLD47. Our study identified highly resistant wild potato species and underlying genes such as disease resistance, stress response, phytohormones, and transcription factors (e.g., MYB, WRKY, AP2/ERF, and AN1) associated with late blight resistance in wild potato species.
Reduced suicidality after electroconvulsive therapy is linked to increased frontal brain activity in depressed patients: a resting-state fMRI study
Authors: Wang Xue , Wu Han , Wang Dan , Wang Wei , Wang Wen , Jin Wen-qing , Luo Jiong , Jiang Wei , Tang Yi-lang , Ren Yan-ping , Yang Chun-lin , Ma Xin , Li Rena
Published: July 2023

Objective

Suicidality is commonly observed in patients with depressive episodes, and electroconvulsive therapy (ECT) has been found to be effective in treating these patients. However, the role of ECT in suicidality remains unclear. This study used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the changes in brain function before and after ECT in depressed patients with suicidality.

Methods

In total, 26 depressed patients with suicidality underwent rs-fMRI at baseline and after 8–12 sessions of ECT. In addition, 32 healthy controls (HCs) matched for age, gender, and educational level underwent rs-fMRI once. The amplitude of low-frequency fluctuations (ALFF), the fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were measured to evaluate whole brain function. Differences between the groups and time points (before and after ECT) were compared. Clinical symptoms were assessed using the 17-item Hamilton Depression Scale (HAMD-17) and Beck Scale for Suicide Ideation (BSSI).

Results

At baseline, patients exhibited decreased ALFF in the right postcentral and precentral gyrus and decreased fALFF in the right supramarginal and postcentral gyrus, left superior frontal gyrus (SFG), as well as the superior and middle temporal gyrus compared to HCs. Patients also had lower ReHo in the left amygdala, anterior cingulate, and postcentral gyrus, and in the right thalamus, insula, and postcentral gyrus. They also exhibited higher ALFF in the bilateral temporal gyrus and insula as well as higher fALFF in the cerebellum. Following ECT, fALFF in the left SFG and orbital frontal cortex (OFC) significantly increased and was inversely correlated with the reduction of BSSI scores (r = −0.416, p = 0.048), whereas no correlation was found with changes in HAMD-17scores.

Conclusion

Our findings suggest that the left SFG and OFC may play a key role in the mechanism of ECT for suicidality. The decrease of fALFF in the left SFG and OFC may represent a potential mechanism through which ECT effectively treats suicidality in depressed patients.