bluuebunny/crossref_metadata_2025 huggingface dataset:
Environmental filtering drives the establishment of the distinctive rhizosphere, bulk, and root nodule bacterial communities of Sophora davidii in hilly and gully regions of the Loess Plateau of China
Authors: Jing Li , Jia-min Ai , Xiao-dong Liu , Ying-ying Jiang , Chao-chao Zheng , Rui-hua Zhao , Zhen-shan Deng
Published: July 2022

In addition to the rhizobia, other non-rhizobial endophytes (NREs) have been simultaneously isolated from the root nodules. The existence of NREs in leguminous root nodules is a universal phenomenon, and they have the potential to enhance legume survival, especially under conditions of environmental stress. However, the diversity and biogeographic patterns of microbial communities inhabiting root nodules are not well studied or understood. Here, we explored and characterized the diversity of NRE bacteria by using 16S rRNA gene high-throughput amplicon sequencing. Additionally, we compared the biogeography and co-occurrence patterns in review of the bacterial microbiota inhabiting the rhizosphere, the bulk soil and the root nodule bacterial communities associated with Sophora davidii, a native N-fixing wild leguminous shrub in hilly and gully regions of the Loess Plateau of China. The results showed the presence of a large diversity of bacteria belonging to 81 phyla, 154 classes, 333 orders, 463 families, and 732 genera inside the nodules. Proteobacteria were dominant in the nodule and rhizosphere soil samples, and Actinomycetes were dominant in the bulk soil samples. Mesorhizobium was the dominant genus in the nodules, accounting for between 60.15 and 83.74% of the bacteria. The microbial community composition of the NRE in the root nodules differed from that in the rhizosphere soil and the bulk soil of S. davidii. Moreover, we found that the biogeographic patterns and assembly process of the rhizobia and non-rhizobia communities differed in the root nodule, the rhizosphere soil and the bulk soil. Furthermore, the correlation analysis between the soil’s physical and chemical properties and the bacteria showed that available phosphorus was the predominant factor affecting the bacterial diversity within the rhizosphere soil. Finally, our results revealed that the microbial network diagram of co-occurrence patterns showed more complexes in the soil than in the root nodules. This indicates that only specific microorganisms could colonize and thrive in the rhizosphere through the selection and filtering effects of roots. In conclusion, there are significant differences in bacterial community composition in the nodules, rhizosphere and bulk soil in the hilly and gully region of the Loess Plateau, which is the result of environmental filtration. Our study improves the understanding of the biogeographic patterns and diversity of bacterial microbiota inhabiting root nodules and can help quantify and define the root nodule assemblage process of S. davidii.
Bacterial Succession in Microbial Biofilm as a Potential Indicator for Postmortem Submersion Interval Estimation
Authors: Dmitrijs Finkelbergs , Guo Juanjuan , Huang Yecao , Liu Yafei , Fang Xinyue , Jiang Kankan , Zha Lagabaiyila , Cai Jifeng , Fu Xiaoliang
Published: July 2022

Bacteria acts as the main decomposer during the process of biodegradation by microbial communities in the ecosystem. Numerous studies have revealed the bacterial succession patterns during carcass decomposition in the terrestrial setting. The machine learning algorithm-generated models based on such temporal succession patterns have been developed for the postmortem interval (PMI) estimation. However, the bacterial succession that occurs on decomposing carcasses in the aquatic environment is poorly understood. In the forensic practice, the postmortem submersion interval (PMSI), which approximately equals to the PMI in most of the common drowning cases, has long been problematic to determine. In the present study, bacterial successions in the epinecrotic biofilm samples collected from the decomposing swine cadavers submerged in water were analyzed by sequencing the variable region 4 (V4) of 16S rDNA. The succession patterns between the repeated experimental settings were repeatable. Using the machine learning algorithm for establishing random forest (RF) models, the microbial community succession patterns in the epinecrotic biofilm samples taken during the 56-day winter trial and 21-day summer trial were determined to be used as the PMSI predictors with the mean absolute error (MAE) of 17.87 ± 2.48 ADD (≈1.3 day) and 20.59 ± 4.89 ADD (≈0.7 day), respectively. Significant differences were observed between the seasons and between the substrates. The data presented in this research suggested that the influences of the environmental factors and the aquatic bacterioplankton on succession patterns of the biofilm bacteria were of great significance. The related mechanisms of such influence need to be further studied and clarified in depth to consider epinecrotic biofilm as a reliable predictor in the forensic investigations.
Cross-kingdom co-occurrence networks in the plant microbiome: Importance and ecological interpretations
Authors: Lee Kiseok Keith , Kim Hyun , Lee Yong-Hwan
Published: July 2022

Microbial co-occurrence network analysis is being widely used for data exploration in plant microbiome research. Still, challenges lie in how well these microbial networks represent natural microbial communities and how well we can interpret and extract eco-evolutionary insights from the networks. Although many technical solutions have been proposed, in this perspective, we touch on the grave problem of kingdom-level bias in network representation and interpretation. We underscore the eco-evolutionary significance of using cross-kingdom (bacterial-fungal) co-occurrence networks to increase the network’s representability of natural communities. To do so, we demonstrate how ecosystem-level interpretation of plant microbiome evolution changes with and without multi-kingdom analysis. Then, to overcome oversimplified interpretation of the networks stemming from the stereotypical dichotomy between bacteria and fungi, we recommend three avenues for ecological interpretation: (1) understanding dynamics and mechanisms of co-occurrence networks through generalized Lotka-Volterra and consumer-resource models, (2) finding alternative ecological explanations for individual negative and positive fungal-bacterial edges, and (3) connecting cross-kingdom networks to abiotic and biotic (host) environments.
Differential response of bacterial diversity and community composition to different tree ages of pomelo under red and paddy soils
Authors: Zheng Chaoyuan , Kong Kunpeng , Zhang Yi , Yang Wenhao , Wu Liangquan , Munir Muhammad Zeeshan , Ji Baoming , Muneer Muhammad Atif
Published: July 2022

Rhizosphere soil microbial communities substantially impact plant growth by regulating the nutrient cycle. However, dynamic changes in soil microbiota under different tree ages have received little attention. In this study, changes in soil physicochemical properties, as well as bacterial diversity and community structures (by high-throughput Illumina MiSeq sequencing), were explored in pomelo trees of different ages (i.e., 10, 20, and 30 years) under red and paddy soils cultivated by farmers with high fertilizer input. Moreover, soil factors that shape the bacterial community, such as soil pH, AP (available phosphorous), AK (available potassium), and AN (available nitrogen), were also investigated. Results showed that pH significantly decreased, while AP, AK, and AN increased with increasing tree age under red soil. For paddy soil, pH was not changed, while AP was significantly lower under 10-year-old pomelo trees, and AK and AN contents were minimum under 30-year-old pomelo trees. Both soil types were dominated by Proteobacteria, Acidobacteria, and Actinobacteria and showed contrasting patterns of relative abundance under different tree age groups. Bacterial richness and diversity decreased with increasing tree age in both soil types. Overall, bacterial community composition was different under different tree ages. RDA analysis showed that soil pH, AP, and AN in red soil, and pH and AP in paddy soil showed the most significant effects in changing the bacterial community structure. A random forest model showed Sinomonas and Streptacidiphilus in red soil, while Actinoallomurus and Microbacterium in paddy soil were the most important genera explaining the differences among different age groups. The ternary plot further revealed that genera enrichment for Age_30 was higher than that for Age_10 and Age_20 in red soil, whereas specific genera enrichment decreased with increasing tree age under paddy soil. Co-occurrence network revealed that bacterial species formed a complex network structure with increasing tree age, indicating a more stable microbial association under 20 and 30 years than 10-year-old pomelo trees. Hence, contrasting patterns of changes in soil physicochemical properties and soil microbial communities were recorded under different tree ages, and tree ages significantly affected the bacterial community structure and richness. These findings provide valuable information regarding the importance of microbes for the sustainable management of pomelo orchards by optimizing fertilizer input for different ages of trees.
Inositol hexakisphosphate kinases differentially regulate trafficking of vesicular glutamate transporters 1 and 2
Authors: Li Haiyan , Datunashvili Maia , Reyes Reno C. , Voglmaier Susan M.
Published: July 2022

Inositol pyrophosphates have been implicated in cellular signaling and membrane trafficking, including synaptic vesicle (SV) recycling. Inositol hexakisphosphate kinases (IP6Ks) and their product, diphosphoinositol pentakisphosphate (PP-IP5 or IP7), directly and indirectly regulate proteins important in vesicle recycling by the activity-dependent bulk endocytosis pathway (ADBE). In the present study, we show that two isoforms, IP6K1 and IP6K3, are expressed in axons. The role of the kinases in SV recycling are investigated using pharmacologic inhibition, shRNA knockdown, and IP6K1 and IP6K3 knockout mice. Live-cell imaging experiments use optical reporters of SV recycling based on vesicular glutamate transporter isoforms, VGLUT1- and VGLUT2-pHluorins (pH), which recycle differently. VGLUT1-pH recycles by classical AP-2 dependent endocytosis under moderate stimulation conditions, while VGLUT2-pH recycles using AP-1 and AP-3 adaptor proteins as well. Using a short stimulus to release the readily releasable pool (RRP), we show that IP6K1 KO increases exocytosis of both VGLUT1-and VGLUT2-pH, while IP6K3 KO decreases the amount of both transporters in the RRP. In electrophysiological experiments we measure glutamate signaling with short stimuli and under the intense stimulation conditions that trigger bulk endocytosis. IP6K1 KO increases synaptic facilitation and IP6K3 KO decreases facilitation compared to wild type in CA1 hippocampal Schaffer collateral synapses. After intense stimulation, the rate of endocytosis of VGLUT2-pH, but not VGLUT1-pH, is increased by knockout, knockdown, and pharmacologic inhibition of IP6Ks. Thus IP6Ks differentially affect the endocytosis of two SV protein cargos that use different endocytic pathways. However, while IP6K1 KO and IP6K3 KO exert similar effects on endocytosis after stimulation, the isoforms exert different effects on exocytosis earlier in the stimulus and on the early phase of glutamate release. Taken together, the data indicate a role for IP6Ks both in exocytosis early in the stimulation period and in endocytosis, particularly under conditions that may utilize AP-1/3 adaptors.
Regulation of microglia phagocytosis and potential involvement of exercise
Authors: Li Congqin , Wang Yong , Xing Ying , Han Jing , Zhang Yuqian , Zhang Anjing , Hu Jian , Hua Yan , Bai Yulong
Published: July 2022

Microglia are considered the main phagocytic cells in the central nervous system, remodeling neural circuits by pruning synapses during development. Microglial phagocytosis is also a crucial process in maintaining adult brain homeostasis and clearing potential toxic factors, which are recognized to be associated with neurodegenerative and neuroinflammatory disorders. For example, microglia can engulf amyloid-β plaques, myelin debris, apoptotic cells, and extracellular harmful substances by expressing a variety of specific receptors on the cell surface or by reprogramming intracellular glucose and lipid metabolism processes. Furthermore, physical exercise has been implicated to be one of the non-pharmaceutical treatments for various nervous system diseases, which is closely related to neuroplasticity and microglia functions including proliferation, activation, and phagocytosis. This review focuses on the central regulatory mechanisms related to microglia phagocytosis and the potential role of exercise training in this process.
Effects of remote ischemic conditioning on sleep complaints in Parkinson's disease–rationale, design, and protocol for a randomized controlled study
Authors: Ji Qiling , Wang Xuemei , Zhao Wenbo , Wills Melissa , Yun Ho Jun , Tong Yanna , Cai Lipeng , Geng Xiaokun , Ding Yuchuan
Published: July 2022

Objective

Sleep disturbances are common non-motor symptoms of Parkinson's disease. The symptoms affect the quality of patients' life by impeding normal sleep cycles and causing excessive daytime sleepiness. Remote Ischemic Conditioning (RIC) is a therapy often used for ischemic stroke patients to minimize infarct size and maximize post-stroke neurological function. Animal experiments have shown that RIC plays a protective role for retinal ganglion cells and other critical areas of the brain of Parkinson's disease. However, whether RIC improves excessive daytime sleepiness (EDS) for patients with Parkinson's disease remains to be determined.

Methods

This is a single-center, double-blind, and randomized controlled trial, which includes patients with Parkinson's disease with EDS. All recruited patients will be randomly assigned either to the RIC or the control group (i.e., sham-RIC) with 20 patients in each group. Both groups receive RIC or sham-RIC treatment once a day for 28 days within 24 h of enrollment. Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Parkinson Disease Sleep Scale-2 (PDSS-2), Parkinson's Disease Questionnaire39 (PDQ39) score scales, and adverse events, such as inability to tolerate the treatment leading to suspension of the study or objective signs of tissue or neurovascular injury caused by RIC and/or sham-RIC are evaluated at 7, 14, 28, and 90 days after enrollment.

Results

The primary goal of this study is to assess the feasibility of the treatments in patients with Parkinson's disease by measuring serious RIC-related adverse events and any reduced incidence of adverse events during the trial and to study potential efficacy, improvement of patients' excessive daytime sleepiness, quality of life-based on ESS, PSQI, PDSS-2, and PDQ39 scores. The secondary goal is to confirm the safety of the treatments.

Conclusion

This study is a prospective randomized controlled trial to determine the safety, feasibility, and potential efficacy of RIC for patients with Parkinson's disease associated with EDS.
Information transmission in action video gaming experts: Inferences from the lateralized readiness potential
Authors: Xie Jiaxin , Cui Ruifang , Ma Weiyi , Lu Jingqing , Wang Lin , Ying Shaofei , Yao Dezhong , Gong Diankun , Yan Guojian , Liu Tiejun
Published: July 2022

Research showed that action real-time strategy gaming (ARSG) experience is related to cognitive and neural plasticity, including visual selective attention and working memory, executive control, and information processing. This study explored the relationship between ARSG experience and information transmission in the auditory channel. Using an auditory, two-choice, go/no-go task and lateralized readiness potential (LRP) as the index to partial information transmission, this study examined information transmission patterns in ARSG experts and amateurs. Results showed that experts had a higher accuracy rate than amateurs. More importantly, experts had a smaller stimulus-locked LRP component (250 – 450 ms) than amateurs on no-go trials, while the response-locked LRP component (0 – 300 ms) on go trials did not differ between groups. Thus, whereas amateurs used an asynchronous information transmission pattern, experts used a reduced asynchronous information transmission pattern or a synchronous pattern where most of processing occurred prior to response execution – an information transmission pattern that supports rapid, error-free performance. Thus, experts and amateurs may use different information transmission patterns in auditory processing. In addition, the information transmission pattern used by experts is typically observed only after long-term auditory training according to past research. This study supports the relationship between ARSG experience and the development of information processing patterns.
An MRI-based pelvimetry nomogram for predicting surgical difficulty of transabdominal resection in patients with middle and low rectal cancer
Authors: Yuan Yuan , Tong Dafeng , Liu Minglu , Lu Haidi , Shen Fu , Shi Xiaohui
Published: July 2022

Objective

The current work aimed to develop a nomogram comprised of MRI-based pelvimetry and clinical factors for predicting the difficulty of rectal surgery for middle and low rectal cancer (RC).

Methods

Consecutive mid to low RC cases who underwent transabdominal resection between June 2020 and August 2021 were retrospectively enrolled. Univariable and multivariable logistic regression analyses were carried out for identifying factors (clinical factors and MRI-based pelvimetry parameters) independently associated with the difficulty level of rectal surgery. A nomogram model was established with the selected parameters for predicting the probability of high surgical difficulty. The predictive ability of the nomogram model was assessed by the receiver operating characteristic (ROC) curve and decision curve analysis (DCA).

Results

A total of 122 cases were included. BMI (OR = 1.269, p = 0.006), pelvic inlet (OR = 1.057, p = 0.024) and intertuberous distance (OR = 0.938, p = 0.001) independently predicted surgical difficulty level in multivariate logistic regression analysis. The nomogram model combining these predictors had an area under the ROC curve (AUC) of 0.801 (95% CI: 0.719–0.868) for the prediction of a high level of surgical difficulty. The DCA suggested that using the nomogram to predict surgical difficulty provided a clinical benefit.

Conclusions

The nomogram model is feasible for predicting the difficulty level of rectal surgery, utilizing MRI-based pelvimetry parameters and clinical factors in mid to low RC cases.
The prognostic value and biological significance of gap junction beta protein 2 (GJB2 or Cx26) in cervical cancer
Authors: Meng Silu , Liu Yuhuan , Wang Xiaoyan , Wu Xue , Xie Wan , Kang Xiaoyan , Liu Xiaoyu , Guo Lili , Wang Changyu
Published: July 2022

Objective

To evaluate the prognostic value and explore the biological significance of gap junction protein beta 2 (GJB2 or Cx26) in cervical cancer (CC).

Methods

We first compared GJB2 expression between CC and normal tissues using public databases and immunohistochemistry (IHC). Based on The Cancer Genome Atlas data (TCGA cohort, n = 304) and tissue microarray samples (OBC cohort, n = 111), we explored the prognostic value of GJB2 for CC patients using bioinformatics analysis and IHC scoring. To explore the biological significance of GJB2, Gene set enrichment analysis (GSEA) and Gene Ontology (GO) were performed. The impact of GJB2 on the immune microenvironment was analyzed by CIBERSORTx and ESTIMATE algorithms. We finally investigated the relationship between GJB2 and drug sensitivity based on the Genomics of Drug Sensitivity in Cancer (GDSC).

Results

The expression of GJB2 was significantly increased in CC over normal tissues. Both the TCGA and OBC cohort found that patients with high GJB2 expression had shorter overall survival (OS) time, and high GJB2 expression was the independent risk factor for prognosis (TCGA: HR, 2.566; 95% CI, 1.066–6.180; p = 0.036; OBC: HR, 2.198; 95% CI, 1.019–4.741; p = 0.045). GJB2 was correlated with patient clinical factors such as tumor size and differentiation grade. The p53 signaling pathway and toll-like receptor pathway may be regulated by GJB2. The abundance of various immune cells was significantly different between the low and high GJB2 expression groups. The ImmuneScore was significantly increased in the high GJB2 expression group. In addition, the expression level of GJB2 was positively correlated with the natural log of the half-maximal inhibitory concentration (LN_IC50) value of cisplatin/paclitaxel (Spearman r = 0.238/0.153, p < 0.001).

Conclusion

GJB2 can serve as a potential prognostic marker of poor survival and a therapeutic target in CC. Moreover, GJB2 may affect the immune microenvironment and is correlated with chemoresistance.
Case Report: Sustained complete remission on combination therapy with olaparib and pembrolizumab in BRCA2-mutated and PD-L1-positive metastatic cholangiocarcinoma after platinum derivate
Authors: Zhou Taotao , Mahn Robert , Möhring Christian , Sadeghlar Farsaneh , Meyer Carsten , Toma Marieta , Kreppel Barbara , Essler Markus , Glowka Tim , Matthaei Hanno , Kalff Jörg C. , Strassburg Christian P. , Gonzalez-Carmona Maria A.
Published: July 2022

Cholangiocarcinoma (CCA) still has a poor prognosis and remains a major therapeutic challenge. When curative resection is not possible, palliative systemic chemotherapy with gemcitabine and platinum derivate as first line followed by a 5-FU doublet combination as second line is the standard therapy. Recently, targeted therapy and immunotherapy have rapidly emerged as personalized therapeutic approaches requiring previous tumor sequencing and molecular profiling. BRCA mutations are well-characterized targets for poly (ADP-ribose) polymerase inhibitors (PARPi). However, BRCA gene mutations in CCA are rare and few data of PARPi in the treatment of CCA are available. Immunotherapy with programmed death receptor-1 (PD-1) has been shown to be effective in combination with chemotherapy or in PD-L1-positive CCA. However, data from immunotherapy combined with targeted therapy, including PARPi, are lacking. In this report, we present the case of a male patient with PD-L1-positive and BRCA2-mutated metastatic intrahepatic cholangiocarcinoma, who was treated with a combined therapy with PARP (PARPi), olaparib, and a PD-1 antibody, pembrolizumab, as second-line therapy after gemcitabine/platinum derivate failure. Combined therapy was able to induce a long-lasting complete remission for over 15 months. The combined therapy was feasible and well tolerated. Only mild anemia and immune-related thyroiditis were observed, which were easily manageable and did not result in discontinuation of olaparib and pembrolizumab.

Conclusion

The presented case showed substantial clinical activity of a combination with olaparib/pembrolizumab in advanced BRCA2-mutated CCA. Thus, identifying targetable molecular signatures and combinations of targeted therapies with immunotherapy reveals a promising strategy to effectively treat patients with cholangiocarcinoma and should be considered after failure of standard chemotherapy.
Current and Future Frontiers of Molecularly Defined Oligodendrogliomas
Authors: Rincon-Torroella Jordina , Rakovec Maureen , Materi Josh , Raj Divyaansh , Vivas-Buitrago Tito , Ferres Abel , Reyes Serpa William , Redmond Kristin J. , Holdhoff Matthias , Bettegowda Chetan , González Sánchez José Juan
Published: July 2022

Oligodendrogliomas are a subtype of adult diffuse glioma characterized by their better responsiveness to systemic chemotherapy than other high-grade glial tumors. The World Health Organization (WHO) 2021 brain tumor classification highlighted defining molecular markers, including 1p19q codeletion and IDH mutations which have become key in diagnosing and treating oligodendrogliomas. The management for patients with oligodendrogliomas includes observation or surgical resection potentially followed by radiation and chemotherapy with PCV (Procarbazine, Lomustine, and Vincristine) or Temozolomide. However, most of the available research about oligodendrogliomas includes a mix of histologically and molecularly diagnosed tumors. Even data driving our current management guidelines are based on post-hoc subgroup analyses of the 1p19q codeleted population in landmark prospective trials. Therefore, the optimal treatment paradigm for molecularly defined oligodendrogliomas is incompletely understood. Many questions remain open, such as the optimal timing of radiation and chemotherapy, the response to different chemotherapeutic agents, or what genetic factors influence responsiveness to these agents. Ultimately, oligodendrogliomas are still incurable and new therapies, such as targeting IDH mutations, are necessary. In this opinion piece, we present relevant literature in the field, discuss current challenges, and propose some studies that we think are necessary to answer these critical questions.
A Review on Nanocarrier Mediated Treatment and Management of Triple Negative Breast Cancer: A Saudi Arabian Scenario
Authors: Nahvi Insha , Belkahla Sana , Biswas Supratim , Chakraborty Suparna
Published: July 2022

People have continued to be petrified by the devastating effects of cancer for decades and thus a pursuit for developing anticancer agents have seen an ever-increasing trend in the past few decades. Globally, breast cancer is the most common malignancy in women and the second most common cause of cancer-related deaths. In Saudi Arabia, breast cancer is the most common type of cancer among women, constituting almost 14.2% of the total cancer burden. Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which is a pathologically diverse disease of higher grade characterized by the absence of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) expressions. Despite the considerable advancements achieved in the therapeutic management of cancer, TNBC remains an unbeatable challenge, which requires immediate attention as it lacks conventional targets for treatment, leading to a poor clinical prognosis. The present research goals are directed toward the development and implementation of treatment regimens with enhanced bioavailability, targetability, minimized systemic toxicity, and improved outcomes of treatment options. The present treatment and management scenario of TNBC continues to provoke oncologists as well as nanomedical scientists to develop novel and efficient nanotherapies. Lately, scientific endeavors have addressed the importance of enhanced availability and targeted cellular uptake with minimal toxicity, which are achieved by the application of nano drug-carriers. This review intends to summarize the incidence rates of TNBC patients, the importance of nanotherapeutic options for patients suffering from TNBC, the identification of promising molecular targets, and challenges associated with the development of targeted nanotherapeutics with special reference to the Saudi Arabian context.
A mobile health + health coaching application for the management of chronic non-cancer pain in older adults: Results from a pilot randomized controlled study
Authors: Kaul Usha , Scher Clara , Henderson Charles R. , Kim Patricia , Dyhrberg Mette , Rudin Vanessa , Lytle Millie , Bundy Nicole , Reid M. Carrington
Published: July 2022

Introduction

The rapid growth of mobile health (mHealth) devices holds substantial potential for improving care and care outcomes in aging adults with chronic non-cancer pain (CNCP), however, research evaluating these devices in older adults remains limited.

Objective

To ascertain the feasibility and preliminary efficacy of an mHealth intervention (Mymee) that combines symptom, diet, and behavior tracking via a smartphone application with data analytics to detect associations between symptoms and lifestyle factors along with weekly health coaching sessions to mitigate CNCP in adults 55 years of age and older.

Methods

Participants (N = 31) in this pilot study were recruited from one primary care practice in New York City and randomized to an intervention [app + up to 12 health coaching sessions (scheduled approximately once weekly) + usual care] or a control (app + usual care) arm. Feasibility measures included recruitment (proportion of eligible persons who enrolled) and retention rates (proportion of subjects completing a follow-up assessment) as well as adherence with the weekly coaching sessions and logging daily data on the app. Efficacy outcomes (e.g., pain intensity, self-efficacy, disability, anxiety) were assessed at baseline and follow-up (~16 weeks after baseline). Descriptive statistics were obtained and general linear mixed models used for primary analyses.

Results

Participants had a mean (standard deviation) age of 67.32 (9.17) and were mostly female (61%). Feasibility outcomes were mixed as evidenced by recruitment and retention rates of 74% and 65%, respectively. The mean number of weekly coaching sessions attended by intervention participants was 6.05 (SD = 5.35), while the average number of days logging data on the app was 44.82 (34.02). We found a consistent trend in favor of the intervention, where pain intensity, affect, and quality of life measures improved considerably more among intervention (vs. control) participants. Finally, the proportion of participants with GAD-7 scores at follow up decreased by 0.35 to 0, whereas controls did not change, a significant effect in favor of the intervention (p = 0.02).

Conclusions

This study supports the need for future research that seeks to enhance feasibility outcomes and confirm the efficacy of the Mymee intervention among aging adults with CNCP.
Efficacy and safety of 12 immunosuppressive agents for idiopathic membranous nephropathy in adults: A pairwise and network meta-analysis
Authors: Liu Jiarong , Li Xiang , Huang Tianlun , Xu Gaosi
Published: July 2022

Background: Immunosuppressants have been applied in the remedy of idiopathic membranous nephropathy (IMN) extensively. Nevertheless, the efficacy and safety of immunosuppressants do not have final conclusion. Thus, a pairwise and network meta-analysis (NMA) was carried out to seek the most recommended therapeutic schedule for patients with IMN.

Methods: Randomized controlled trials (RCTs) including cyclophosphamide (CTX), mycophenolate mofetil (MMF), tacrolimus-combined mycophenolate mofetil (TAC + MMF), cyclosporine (CsA), tacrolimus (TAC), leflunomide (LEF), chlorambucil (CH), azathioprine (AZA), adrenocorticotropic hormone (ACTH), non-immunosuppressive therapies (CON), steroids (STE), mizoribine (MZB), and rituximab (RIT) for patients with IMN were checked. Risk ratios (RRs) and standard mean difference (SMD) were reckoned to assess dichotomous variable quantities and continuous variable quantities, respectively. Total remission (TR) and 24-h urine total protein (24-h UTP) were compared using pairwise and NMA. Then interventions were ranked on the basis of the surface under the cumulative ranking curve (SUCRA).

Results: Our study finally included 51 RCTs and 12 different immunosuppressants. Compared with the CON group, most regimens demonstrated better therapeutic effect in TR, with RR of 2.1 (95% CI) (1.5–2.9) for TAC, 1.9 (1.3–2.8) for RIT, 2.5 (1.2–5.2) for TAC + MMF, 1.9 (1.4–2.7) for CH, 1.8 (1.4–2.4) for CTX, 2.2 (1.0–4.7) for ACTH, 1.6 (1.2–2.1) for CsA, 1.6 (1.0–2.5) for LEF, and 1.6 (1.1–2.2) for MMF. In terms of 24-h UTP, TAC (SMD, −2.3 (95% CI −3.5 to −1.1)), CTX (SMD, −1.7 (95% CI −2.8 to −0.59)), RIT (SMD, −1.8 (95% CI −3.5 to −0.11)), CH (SMD, −2.4 (95% CI −4.3 to −0.49)), AZA (SMD, −−4.2 (95% CI −7.7 to −0.68)), and CsA (SMD, −1.7 (95% CI −3 to −0.49)) were significantly superior than the CON group. As for adverse effects (AEs), infections, nausea, emesia, myelosuppression, and glucose intolerance were the collective adverse events for most immunosuppressants.

Conclusion: This study indicates that TAC + MMF performed the best in terms of TR, and TAC shows the best effectiveness on 24-h UTP compared with other regimens. On the contrary, there seems to be little advantage on STE alone, LEF, AZA, and MZB in treating patients with IMN compared with CON.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021287013]
Prenatal Exposure to Gabapentin Alters the Development of Ventral Midbrain Dopaminergic Neurons
Authors: Alsanie Walaa F. , Abdelrahman Sherin , Alhomrani Majid , Gaber Ahmed , Habeeballah Hamza , Alkhatabi Heba A. , Felimban Raed I. , Hauser Charlotte A. E. , Tayeb Hossam H. , Alamri Abdulhakeem S. , Raafat Bassem M. , Anwar Sirajudheen , Alswat Khaled A. , Althobaiti Yusuf S. , Asiri Yousif A.
Published: July 2022

Background: Gabapentin is widely prescribed as an off-label drug for the treatment of various diseases, including drug and alcohol addiction. Approximately 83–95% of the usage of gabapentin is off-label, accounting for more than 90% of its sales in the market, which indicates an alarming situation of drug abuse. Such misuse of gabapentin has serious negative consequences. The safety of the use of gabapentin in pregnant women has always been a serious issue, as gabapentin can cross placental barriers. The impact of gabapentin on brain development in the fetus is not sufficiently investigated, which poses difficulties in clinical decisions regarding prescriptions.

Methods: The consequences effect of prenatal gabapentin exposure on the development of ventral midbrain dopaminergic neurons were investigated using three-dimensional neuronal cell cultures. Time-mated Swiss mice were used to isolate embryos. The ventral third of the midbrain was removed and used to enrich the dopaminergic population in 3D cell cultures that were subsequently exposed to gabapentin. The effects of gabapentin on the viability, ATP release, morphogenesis and genes expression of ventral midbrain dopaminergic neurons were investigated.

Results: Gabapentin treatment at the therapeutic level interfered with the neurogenesis and morphogenesis of vmDA neurons in the fetal brain by causing changes in morphology and alterations in the expression of key developmental genes, such as Nurr1, Chl1, En1, Bdnf, Drd2, and Pitx3. The TH + total neurite length and dominant neurite length were significantly altered. We also found that gabapentin could halt the metabolic state of these neuronal cells by blocking the generation of ATP.

Conclusion: Our findings clearly indicate that gabapentin hampers the morphogenesis and development of dopaminergic neurons. This implies that the use of gabapentin could lead to serious complications in child-bearing women. Therefore, caution must be exercised in clinical decisions regarding the prescription of gabapentin in pregnant women.
Combinatorial Strategies With PD-1/PD-L1 Immune Checkpoint Blockade for Breast Cancer Therapy: Mechanisms and Clinical Outcomes
Authors: Zheng Dan , Hou Xiaolin , Yu Jing , He Xiujing
Published: July 2022

As an emerging antitumor strategy, immune checkpoint therapy is one of the most promising anticancer therapies due to its long response duration. Antibodies against the programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) axis have been extensively applied to various cancers and have demonstrated unprecedented efficacy. Nevertheless, a poor response to monotherapy with anti-PD-1/PD-L1 has been observed in metastatic breast cancer. Combination therapy with other standard treatments is expected to overcome this limitation of PD-1/PD-L1 blockade in the treatment of breast cancer. In the present review, we first illustrate the biological functions of PD-1/PD-L1 and their role in maintaining immune homeostasis as well as protecting against immune-mediated tissue damage in a variety of microenvironments. Several combination therapy strategies for the combination of PD-1/PD-L1 blockade with standard treatment modalities have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including chemotherapy, radiotherapy, targeted therapy, antiangiogenic therapy, and other immunotherapies. The corresponding clinical trials provide valuable estimates of treatment effects. Notably, several combination options significantly improve the response and efficacy of PD-1/PD-L1 blockade. This review provides a PD-1/PD-L1 clinical trial landscape survey in breast cancer to guide the development of more effective and less toxic combination therapies.
Brucea javanica Oil Emulsion Promotes Autophagy in Ovarian Cancer Cells Through the miR-8485/LAMTOR3/mTOR/ATG13 Signaling Axis
Authors: Wang Yihan , Chen Bocen , Xiao Man , Wang Xiaoli , Peng Yunhua
Published: July 2022

Background: Ovarian cancer is a common malignant tumor of the female reproductive tract, with the highest mortality rate. At present, no effective approaches to improve the survival rate exist. B. javanica Oil Emulsion (BJOE), an extract from B. javanica (L.) Merr. [Simaroubaceae], exhibits antitumor effects and can increase the sensitivity of radiotherapy and chemotherapy in many types of cancers. MiR-8485, a discovered miRNA, has been shown to be involved in the occurrence and development of tumors. The purpose of this study was to investigate the effect of BJOE on the regulation of mammalian rapamycin target protein (mTOR) autophagy signal pathway and related autophagy factors on ovarian cancer cells through miR-8485.

Methods: The main chemical constituents of BJOE were determined by UHPLC-MS/MS. Detection of miR-8485 expression in ovarian cancer cells treated with BJOE by quantitative reverse transcription polymerase chain reaction (qRT-PCR). CCK8 experiment and flow cytometry were used to observe the effects of BJOE and overexpression of miR-8485 on cell proliferation and apoptosis. Then, monodansylcadaverine (MDC) fluorescence staining was used to observe the changes of autophagy vesicles before and after the effect of BJOE and overexpressed miR-8485 on cancer cells. Next, the binding sites between miR8485 and mammalian rapamycin target protein activator 3 (LAMTOR3) were detected by double luciferase reporter assay. Furthermore, qRT-PCR and Western blot experiments were used to explore the changes of autophagy-related factors LAMTOR3, mTOR and autophagy-related 13 (ATG13), and microtubule associated protein 1 light chain 3 beta (LC3-Ⅱ) after BJOE and overexpression of miR-8485, in addition to autophagy inhibitor (3-MA) for rescue experiment verification.

Results: The qRT-PCR results showed that the expression of miR-8485 increased after BJOE treatment in the SKOV3 cell. The CCK8 assay and flow cytometry analysis revealed that both BJOE and miR-8485 overexpression inhibited the proliferation and promoted the apoptosis of the SKOV3 cell. MDC fluorescence staining showed that BJOE and miR-8485 overexpression led to a significant increase in autophagy vesicles in the SKOV3 cell. Double luciferase reporter assay confirmed the existence of binding sites between miR8485 and LAMTOR3. The results of qRT-PCR and Western blot showed that BJOE and overexpressed miR-8485 downregulated the expression of LAMTOR3 and mTOR and up-regulated the expression of ATG13 and LC3-Ⅱ.

Conclusion: 1) MiR-8485 may be the key factor of BJOE in promoting autophagy and apoptosis and inhibiting cell proliferation of ovarian cancer cells; 2) BJOE may play an antitumor role by regulating LAMTOR3/mTOR/ATG13 signaling axis through miR-8485 to promote autophagy in ovarian cancer cells.
Development and Validation of a UHPLC–MS/MS Method for Quantitation of Almonertinib in Rat Plasma: Application to an in vivo Interaction Study Between Paxlovid and Almonertinib
Authors: Tang Peng-fei , Bao Su-su , Gao Nan-yong , Shao Chuan-feng , Xie Wei-fei , Wu Xue-meng , Zhao Le-ping , Xiao Zhong-xiang
Published: July 2022

Almonertinib was approved for the first-line treatment of advanced NSCLC patients with EGFR-TKI-sensitive genetic mutations by National Medical Products Administration (NMPA) in 2021.The purpose of this study was to establish and validate a fast, accurate, stable and facile ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of almonertinib in rat plasma, it was employed to explore the effect of Paxlovid on the pharmacokinetics of almonertinib in rats. Zanubrutinib was used as an internal standard (IS), and the plasma samples were prepared by the protein precipitation method using acetonitrile. Chromatographic separation was carried out on a Shimadzu LC-20AT ultra-performance liquid chromatography system using a Shim-pack velox C18 (2.1× 50 mm, 2.7 μM) column. The mobile phase consisted of methanol and 0.1% formic acid-water. Mass spectrum analysis was executed using Shimadzu 8040 Triple quadrupole mass spectrometry. The precursor and product ions of the analyte and internal standard were detected in multiple reaction monitoring (MRM) mode. The typical fragment ions were m/z 526.20 → 72.10 for almonertinib and m/z 472.15 → 290.00 for zanubrutinib (IS). The method was validated to have good linearity for quantifying almonertinib in rat plasma from 0.1–1000 ng/ml (R2 = 0.999), and the LLOQ was 0.1 ng/ml. The validity of this method was sufficiently verified for selectivity, specificity, extraction recovery, matrix effect, accuracy, precision and stability. The validated UHPLC–MS/MS method was successfully applied to the drug interaction study of almonertinib with Paxlovid in rats. Paxlovid significantly inhibits the metabolism of almonertinib and increased the exposure of almonertinib. This study can help us to understand the metabolic profile of almonertinib better, and further human trials should be conducted to validate the results.
Theoretical study of vortex beam generation based on geometric coordinate transformation
Authors: Li Yanke , Xie Yuqing , Liu Sheng , Li Peng , Wei Bingyan , Zhao Jianlin
Published: July 2022

By performing a conformal optical mapping of an input beam from Cartesian to log-polar coordinates, we propose a method to generate vortex beam. By tilting the incident beam, a phase gradient is attached and evolves into a vortex phase due to the optical transformation. Thus, the topological charge of the generated vortex beam is continuously adjustable. With this method, vortex beams with integer and fractional orders are generated. The purity of the generated vortex beam is theoretically analyzed, as well as the possible effects of phase misalignment on the output vortex. The continuously tunable vortex beam achieved by this method is expected to be used in information processing and optical routing in optical communications.
Impact of the Addition of a Centrifugal Pump in a Preterm Miniature Pig Model of the Artificial Placenta
Authors: Charest-Pekeski Alex J. , Cho Steven K. S. , Aujla Tanroop , Sun Liqun , Floh Alejandro A. , McVey Mark J. , Sheta Ayman , Estrada Marvin , Crawford-Lean Lynn , Foreman Celeste , Mroczek Dariusz , Belik Jaques , Saini Brahmdeep S. , Lim Jessie Mei , Moir Olivia J. , Lee Fu-Tsuen , Quinn Megan , Darby Jack R. T. , Seed Mike , Morrison Janna L. , Haller Christoph
Published: July 2022

The recent demonstration of normal development of preterm sheep in an artificial extrauterine environment has renewed interest in artificial placenta (AP) systems as a potential treatment strategy for extremely preterm human infants. However, the feasibility of translating this technology to the human preterm infant remains unknown. Here we report the support of 13 preterm fetal pigs delivered at 102 ± 4 days (d) gestation, weighing 616 ± 139 g with a circuit consisting of an oxygenator and a centrifugal pump, comparing these results with our previously reported pumpless circuit (n = 12; 98 ± 4 days; 743 ± 350 g). The umbilical vessels were cannulated, and fetuses were supported for 46.4 ± 46.8 h using the pumped AP versus 11 ± 13 h on the pumpless AP circuit. Upon initiation of AP support on the pumped system, we observed supraphysiologic circuit flows, tachycardia, and hypertension, while animals maintained on a pumpless AP circuit exhibited subphysiologic flows. On the pumped AP circuit, there was a progressive decline in umbilical vein (UV) flow and oxygen delivery. We conclude that the addition of a centrifugal pump to the AP circuit improves survival of preterm pigs by augmenting UV flow through the reduction of right ventricular afterload. However, we continued to observe the development of heart failure within a matter of days.
Post-Hatch Performance of Broilers Following Hypoxic Exposure During Incubation Under Suboptimal Environmental Temperature
Authors: Haron A. , Shinder D. , Ruzal M. , Druyan S.
Published: July 2022

The modern broiler is selected to exploit its full genetic potential, to sustain a rapid growth rate, and to lower the feed conversion rate (FCR). Recently reported reductions in FCR have been associated with augmented tissue formation at the expense of physiological functions such as thermoregulation. In turn, modern broilers exhibit a relatively low capability to balance energy expenditure under suboptimal ambient temperature. Hypoxic conditions at late incubation stages play a role in reforming metabolic plasticity. This work examined the effect of exposure to 12-h hypoxia (12H; 17% O2) for three consecutive days (from E16 through E18), or continuous hypoxia exposure for 48 h (48H), from E16 through E17, as compared to standard incubation (21% O2) on post-hatch performance of broilers maintained under suboptimal ambient temperatures (cold, hot, and diurnal cyclic ambient temperature). 12H chicks kept under hot ambient temperature had significantly lower body temperature (Tb) as compared to the control chicks. On day 42, both 12H and 48H chicks grown in the cyclic temperature room had significantly lower Tbs than controls. In parallel, from week 4, onward, 12H chicks had a significantly lower FCR than controls, and the 48H chicks demonstrated a lower FCR from week 5 and on. 12H and 48H broilers maintained under diurnal cyclic ambient temperature, exhibited significantly greater relative breast muscle weight, and a similar pattern was found in hypoxic broilers raised under standard and hot ambient temperatures. Hypoxic manipulation affects and create an adaptive bias in allocating metabolic energy between maintenance and growth, thus resulting in improved broiler performance, thermoregulation, and rearing under suboptimal environmental temperature.