bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative teaching of metabolic modeling and flux analysis with interactive python modules
Authors: Kaste Joshua A. M. , Green Antwan , Shachar‐Hill Yair
Published: August 2023

The modeling of rates of biochemical reactions—fluxes—in metabolic networks is widely used for both basic biological research and biotechnological applications. A number of different modeling methods have been developed to estimate and predict fluxes, including kinetic and constraint‐based (Metabolic Flux Analysis and flux balance analysis) approaches. Although different resources exist for teaching these methods individually, to‐date no resources have been developed to teach these approaches in an integrative way that equips learners with an understanding of each modeling paradigm, how they relate to one another, and the information that can be gleaned from each. We have developed a series of modeling simulations in Python to teach kinetic modeling, metabolic control analysis, 13C‐metabolic flux analysis, and flux balance analysis. These simulations are presented in a series of interactive notebooks with guided lesson plans and associated lecture notes. Learners assimilate key principles using models of simple metabolic networks by running simulations, generating and using data, and making and validating predictions about the effects of modifying model parameters. We used these simulations as the hands‐on computer laboratory component of a four‐day metabolic modeling workshop and participant survey results showed improvements in learners' self‐assessed competence and confidence in understanding and applying metabolic modeling techniques after having attended the workshop. The resources provided can be incorporated in their entirety or individually into courses and workshops on bioengineering and metabolic modeling at the undergraduate, graduate, or postgraduate level.
Metabolomics study of the hepatoprotective effect of total flavonoids of Mallotus apelta leaf in carbon tetrachloride‐induced liver fibrosis in rats
Authors: Ye Yong , Zhang Bo , Mai Wanting , Tan Yanjun , Feng Zhongwen , Huang Qiujie
Published: August 2023

Mallotus apelta leaf, recorded in the quality standard of Yao Medicinal Material in Guangxi Zhuang autonomous region, is commonly used in the treatment of liver diseases. Total flavonoids of M. apelta leaf (TFM) had good anti‐fibrosis activity, but the anti‐fibrosis mechanism of TFM is still unclear. Nuclear magnetic resonance technology was used to study the dynamic changes of urine metabolites in CCl4‐induced liver fibrosis before and after TFM treatment. Ingenuity Path Analysis (IPA) was used to find potential target genes for TFM to improve liver fibrosis and verify the expression of target genes by real‐time fluorescent quantitative PCR and Western blotting. TFM can significantly reduce serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) levels, improve liver steatosis and reduce inflammation; in urine metabolomics, a total of seven potential biomarkers were found, mainly involving two metabolic pathways; IPA analysis showed that TNF may be a potential target for TFM to improve liver fibrosis induced by CCl4 in rats. This study found that TNF may be a potential target gene for TFM treatment of liver fibrosis, and shows that the anti‐fibrosis mechanism of TFM could improve liver fibrosis by regulating the tricarboxylic acid cycle and subtaurine metabolism.
Development and validation of an HPLC–MS/MS method to quantify the KRAS inhibitor adagrasib in mouse plasma and tissue‐related matrices
Authors: Retmana Irene A. , Loos Nancy H. C. , Schinkel Alfred H. , Beijnen Jos H. , Sparidans Rolf W.
Published: August 2023

We developed and validated an assay utilizing a liquid chromatography–tandem mass spectrometry technique to quantify the KRAS inhibitor adagrasib in mouse plasma and seven tissue‐related matrices. The straightforward protein precipitation technique was selected to extract adagrasib and the internal standard salinomycin from the matrices. Gradient elution of acetonitrile and water modified with 0.5% (v/v) ammonium hydroxide and 0.02% (v/v) acetic acid on a C18 column at a flow rate of 0.6 ml/min was applied to separate the analytes. Both adagrasib and salinomycin were detected with a triple quadrupole mass spectrometer with positive electrospray ionization in a selected reaction monitoring mode. A linear calibration range of 2–2,000 ng/ml of adagrasib was demonstrated during the validation. In addition, the reported precision values (intra‐ and inter‐day) were between 3.5 and 14.9%, while the accuracy values were 85.5–111.0% for all tested levels in all investigated matrices. Adagrasib in mouse plasma was reported to have good stability at room temperature, while adagrasib in tissue‐related matrices was stable on ice for up to 4 h (matrix dependent). Finally, this method was successfully applied to determine the pharmacokinetic profile and tissue distribution of adagrasib in wild‐type mice.
Use of patient‐derived tumor organoid platform to predict the benefit of postoperative adjuvant chemotherapy for poor responders to neoadjuvant chemoradiotherapy in locally advanced rectal cancer
Authors: Xue Weisong , Wang Ting , Yao Jiaxin , Wu Wei , Chen Dexin , Yan Botao , Dong Xiaoyu , Tang Yuting , Zeng Yunli , He Yueyu , Cao Peihua , Shao Fangyuan , Huang Wenhua , Deng Chuxia , Yan Jun
Published: August 2023

Postoperative adjuvant chemotherapy (AC) for poor responders to neoadjuvant chemoradiotherapy (nCRT) remains debatable among patients with locally advanced rectal cancer (LARC), necessitating biomarkers to accurately predict the benefits of AC. This study aimed to develop a patient‐derived tumor organoid (PDTO) platform to predict the benefit of AC in LARC patients showing poor nCRT response. PDTOs were established using irradiated rectal cancer specimens with poor nCRT responses, and their sensitivity to chemotherapy regimens was tested. The half‐maximal inhibitory concentration (IC50) value for the PDTO drug test was defined based on the clinical outcomes, and the accuracy of the PDTO prognostic predictions was calculated. Predictive models were developed and validated using the PDTO drug test results. Between October 2018 and December 2021, 86 PDTOs were successfully constructed from 138 specimens (success rate 62.3%). The optimal IC50 cut‐off value for the organoid drug test was 39.31 μmol/L, with a sensitivity of 84.75%, a specificity of 85.19%, and an accuracy of 84.88%. Multivariate Cox regression analysis revealed that the PDTO drug test was an independent predictor of prognosis. A nomogram based on the PDTO drug test was developed, showing good prognostic ability in predicting the 2‐year and 3‐year disease‐free survivals (AUC of 0.826 [95% CI, 0.721–0.931] and 0.902 [95% CI, 0.823–0.982], respectively) and overall survivals (AUC of 0.859 [95% CI, 0.745–0.973] and 0.885 [95% CI, 0.792–0.978], respectively). The PDTO drug test can predict the benefit of postoperative AC in poor responders with LARC to nCRT.
Sternal foramina: An imaging study
Authors: Ma De‐Ting , Wang Jun‐Xia , Wang Zhao‐Hua , Cui Xue
Published: August 2023

To investigate the computed tomography (CT) image characteristics, adjacent tissues, and related measurement indices of the sternal foramina and provide an anatomical basis for the safety of minimally invasive sternum surgery. The data from 2500 thoracic multi‐slice computed tomography (MSCT) cases from January 2020 to June 2021 were analyzed retrospectively. The number and location of the sternal foramina and adjacent tissues (mediastinal adipose tissue, lung, pericardium) were observed. The size of the sternal foramina, CT value of the tissue inside the foramina, subcutaneous adipose tissue thickness, distance from skin to lung, distance from skin to the pericardium, and manubrio‐foraminal distance were measured. Sex differences were compared for each indicator performed. The incidence of sternal foramina was 4.44% (111/2500), with 83 males and 28 females. All sternal foramina were located at the mesosternum's fourth to sixth costal cartilage level. The transverse diameter of the sternal foramina was (0.60 ± 0.29) cm, and the vertical diameter was (0.68 ± 0.39) cm, which was greater in males than females (p > 0.01). The CT value of the tissue in the sternal foramina was (−77.05 ± 32.26) Hu, and there was no statistical difference between male and female patients (t = −1.780, p = 0.078). The adjacent tissues of the sternal foramina were only adjacent to adipose tissue in 41 cases (36.94%), pericardium in 18 patients (16.22%), lung tissue in 37 cases (33.33%), and both kinds of tissue in 15 cases (13.51%). The sternal foramina were not adjacent to the left lung in the female patients. In the sternal foramina region, the thickness of subcutaneous adipose tissue was (1.13 ± 0.51) cm, the distance from skin to lung was (1.86 ± 0.57) cm, the distance from skin to pericardium was (3.07 ± 0.72) cm, the manubrio‐foraminal distance was (12.68 ± 1.31) cm, which was significantly greater in males than in females (p < 0.05). The sternal foramina are closely related to the heart and lungs. The size and location of sternal foramina, the thickness of subcutaneous adipose tissue, and the distance from skin to heart and lung are all crucial factors in evaluating the safety of sternal puncture biopsy.
Accuracy analysis of traditional acupoint location and the coincidence of cutaneous arterial perforators and acupoints
Authors: Guo Chunxia , Zhang Yongguang , Ding Zhiwei , Han Rong , Jiao Xuwen , Hu Jinlian
Published: August 2023

Several reports have shown a coincidence relationship between perforators and acupoints. However, there have been few previous reports of objective experimental methods to verify the reliability of the accuracy of acupoint location (APL) with nearby perforators. This research aimed to determine the internal agreement of the APL of five acupuncturists and to analyze the coincidence rate of acupoints with nearby perforators. Three two healthy volunteers were recruited with the inclusion and exclusion criteria. Three TCM clinical physicians determined acupoints in areas of the lower limb of participants. Two microsurgeons sketched corresponding regions based on the most common skin flap operation sites, located bone markers, and drew the skin flap axis. Doppler ultrasound was used to mark the perforator point and the distances measured for both points. There is no significant difference in the distance between the acupoints and perforators localization in different groups, and there are significant differences between the angle formed by acupoints and penetrators in all groups. All the points located by the traditional Chinese medicine (TCM) therapists are distributed around the dot. The distance between the coordinate point (A‐B) of 溫溜 Wēnliū (LI7) localization is the largest, reaching 16.6 mm. The accuracy of the acupoint location of each physician is limited by the clinical experience of physicians, and the difference among them is significant. There is a certain correspondence between the location of acupoints and perforators, which needs further studies to confirm.
The efficacy and safety of immune checkpoint inhibitors for patients with EGFR‐mutated non‐small cell lung cancer who progressed on EGFR tyrosine‐kinase inhibitor therapy: A systematic review and network meta‐analysis
Authors: Wang Zhen , Zhou Fang , Xu Shan , Wang Kang , Ding Huan
Published: August 2023

Background

Non‐small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)‐mutated who progressed on EGFR tyrosine‐kinase inhibitor (EGFR‐TKI) therapy have limited therapeutic options. There is still no consensus on the role of immune checkpoint inhibitors (ICIs) in NSCLC with EGFR mutations.

Methods

We did a network meta‐analysis (NMA) with a systematic literature search on PubMed, Embase, Web of Science, and The Cochrane Library. We included all phase II and III randomized controlled trials (RCTs), non‐randomized controlled trials (Non‐RCTs), and retrospective studies. Progression‐free survival (PFS) and overall survival (OS) were assessed through hazard ratios (HR). Objective response rate (ORR) and adverse events (AEs) were assessed through odds ratio (OR) and relative risk (RR), respectively. R software was used to compare the outcomes of different treatments by Bayesian NMA.

Findings

We identified 1835 published results and 17 studies were included ultimately. A total of 2085 patients were included and accepted the following six treatments: ICIs plus chemotherapy (ICIs+Chemo), chemotherapy (Chemo), ICIs monotherapy (ICIs), ICIs plus chemotherapy and antiangiogenic therapy (ICIs+Chemo+Antiangio), antiangiogenic therapy plus chemotherapy (Antiangio+Chemo), ICIs plus antiangiogenic therapy (ICIs+Antiangio). ICIs+Chemo+Antiangio was associated with longer PFS and OS, as well as higher ORR (surface under the cumulative ranking curve [SUCRA], 96%, 90%, 91%). ICIs conferred the safety profile in terms of any‐grade AEs, grade greater than or equal to 3 AEs and any grade leading to treatment discontinuation occurred AEs (SUCRA, 99%, 68%, 94%).

Interpretation

ICIs+Chemo+Antiangio brings the greatest survival benefit in NSCLC patients with EGFR mutations who progressed on EGFR‐TKI therapy, even for whom with baseline brain metastases. Compared with chemotherapy, ICIs has a low incidence of AEs and a benefit in OS.
Phytochemical Profiling by UPLC‐ESI‐QTOF‐MS of Kalaharia uncinata (Schinz) Moldenke, Widely Used in Traditional Medicine in DR Congo
Authors: Kibungu Kembelo Pathy , Tuenter Emmy , Vanhove Wouter , Belesi Katula Honoré , Van Damme Patrick , Pieters Luc
Published: August 2023

Kalaharia uncinata (Schinz) Moldenke, is a tropical erect bushy shrub or subshrub of the Lamiaceae family. It is an endemic plant species of Southern Africa, widely used in the pharmacopoeia against upper respiratory tract infections. A previously conducted ethnobotanical survey revealed that it is believed to contain bioactive substances. However, no relevant phytochemical information was available. This study aimed to perform a phytochemical characterization of K. uncinata and also to discuss the potential bioactivity of the identified phytochemical constituents based on documented data. Ultra‐performance liquid chromatography with electrospray ionization quadrupole time‐of‐flight mass spectrometry (UPLC‐ESI‐QTOF‐MS) was used for profiling and identification of the main phytochemical constituents from leaf extracts (MeOH 90 %, DCM, AcOEt, BuOH, hexane and residue) of K.uncinata. Twenty‐four constituents, representing mainly flavonoids (14), followed by phenylethanoid glycosides (7), phenolic acids (2), and an iridoid glycoside (1) were tentatively identified. Most of the identified compounds are documented to have antiviral and anti‐inflammatory properties, which could possibly be the rationale behind the use of K. uncinata against upper respiratory tract infections.
Nickel‐Catalyzed Cross‐Electrophile Coupling of Triazine Esters with Aryl Bromides
Authors: Liu Xiang , He Cai‐Yu , Yin Hao‐Nan , Miao Chengping , Chu Xue‐Qiang , Rao Weidong , Xu Hao , Zhou Xiaocong , Shen Zhi‐Liang
Published: August 2023

Comprehensive Summary

Cross‐electrophile coupling of triazine esters with aryl bromides could be facilely accomplished by employing nickel as catalyst, magnesium as metal mediator, and lithium chloride as additive. The reactions proceeded efficiently in THF at room temperature through C—O bond activation to afford an array of structurally different diaryl ketones in moderate to good yields with wide functional group tolerance. Control experiments showed that nickel, magnesium, lithium chloride, and THF are all indispensable for the good performance of the coupling reaction. Preliminary mechanistic exploration indicated that in situ formed arylmagnesium reagent by the insertion of magnesium into aryl bromide might serve as the key intermediate of the cross‐coupling. The method which avoids the utilization of moisture‐labile and relatively difficult‐to‐obtain organometallics is step‐economical, cost‐efficient, and operationally simple, potentially serving as an attractive alternative to documented methods.
Perspectives of patients undergoing neoadjuvant chemotherapy for breast cancer during the COVID‐19 pandemic
Authors: Gaughan Alice A. , MacEwan Sarah R. , Rush Laura J. , Gatti‐Mays Margaret E. , Pariser Ashley C. , McAlearney Ann Scheck
Published: August 2023

Background

The COVID‐19 pandemic resulted in a lapse in routine health care and cancer screenings for many individuals. This study sought to improve our understanding of the impact of the COVID‐19 pandemic on women being treated for breast cancer, both in general, and specifically related to their diagnosis.

Methods

Semi‐structured interviews were conducted between August 2021 and February 2022 with women who were receiving neoadjuvant chemotherapy for early‐stage breast cancer at the Stefanie Spielman Comprehensive Breast Center in Columbus, Ohio. Interviews were recorded and transcribed verbatim. Transcripts were coded using deductive dominant thematic analysis and inductive coding that allowed for categorization of data as well as identification of emergent themes.

Results

Data collected from our 19 interviews revealed that the COVID‐19 pandemic posed important challenges for breast cancer patients including fear of COVID‐19 infection and feelings of isolation. Most interviewees noted they had been vaccinated against COVID‐19 because of a desire to protect themselves and others from getting sick. Some women also expressed concerns about having delayed their screening mammograms due to the pandemic. Several patients described unexpected positive aspects of the pandemic such as being able to spend more time with family and having the ability to continue working because of the option to work from home during their cancer treatment.

Conclusions

Our findings provide important insight about the impact of COVID‐19 on breast cancer patients. We highlight the positives that have been reported because of the pandemic, as well as the need to address delayed breast cancer screening.
Patient Centric Microsampling to Support Paxlovid Clinical Development: Bridging and Implementation
Authors: Wan Katty , Kavetska Olga , Damle Bharat , Shi Haihong , Cox Donna S. , Oladoyinbo Olayide , Chan Phylinda , Singh Ravi Shankar P. , Craft Susan , Berthier Erwin , Corrigan Brian
Published: August 2023

Nirmatrelvir is a potent and selective severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) main protease inhibitor. Nirmatrelvir co‐packaged with ritonavir (as PAXLOVID) received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) on December 22, 2021, as an oral treatment for coronavirus disease 2019 (COVID‐19) and subsequent new drug application approval on May 25, 2023. Pharmacokinetic (PK) capillary blood sampling at‐home using Tasso‐M20 micro‐volumetric sampling device was implemented in the program, including three phase II/III outpatient and several clinical pharmacology studies supporting the EUA. The at‐home sampling complemented venous blood sampling procedures to enrich the PK dataset, to decrease the need for patients' site visit for PK sampling, and to allow different sampling approaches for flexibility and convenience. To demonstrate concordance/equivalence, bridging between venous plasma and Tasso dried blood results was conducted by comparing concentrations and derived PK parameters from both sampling approaches. In addition, a two‐compartment population PK model was utilized to bridge the plasma and Tasso data by estimating the PK parameters using blood‐to‐plasma ratio as a slope parameter. Operational challenges were successfully managed to implement at‐home PK sampling in global phase II/III trials. Sample quality was generally very good with less than 3% samples deemed as “not usable” from over 800 samples collected in all the studies. Experience gained from sites and patients will guide future broader implementations.
Systematic Sampling of the Female Reproductive System for Molecular Characterization
Authors: Fisher Stephen A. , Grijalva Marielena , Guo Rong , Johnston Sarah A. , Laurent Louise C. , Nguyen Hieu , Renz John , Rosario Jean G. , Rudich Steven , Gregory Brian D. , Kim Junhyong , O'Neill Kathleen
Published: August 2023

As part of the National Institutes of Health Human BioMolecular Atlas Program to develop a global platform to map the 37 trillion cells in the adult human body, we are generating a comprehensive molecular characterization of the female reproductive system. Data gathered from multiple single‐cell/single‐nucleus and spatial molecular assays will be used to build a 3D molecular atlas. Herein, we describe our multistep protocol, beginning with an optimized organ procurement workflow that maintains functional characteristics of the uterus, ovaries, and fallopian tubes by perfusing these organs with preservation solution. We have also developed a structured tissue sampling procedure that retains information on individual‐level anatomic, physiologic, and individual diversity of the female reproductive system, toward full exploration of the function and structure of female reproductive cells. © 2023 Wiley Periodicals LLC.

Basic Protocol 1: Preparation and preservation of the female reproductive system (ovaries, fallopian tubes, and uterus) prior to procurement

Basic Protocol 2: Removal of the female reproductive system en bloc

Basic Protocol 3: Postsurgical dissection of ovaries

Basic Protocol 4: Postsurgical dissection of fallopian tubes

Basic Protocol 5: Postsurgical dissection of cervix

Basic Protocol 6: Postsurgical dissection of uterine body

Support Protocol 1: OCT‐embedded tissue protocol

Support Protocol 2: Tissue fixation protocol

Support Protocol 3: Snap‐frozen tissue protocol

Basic Protocol 7: Tissue slice preparation for Visium analysis

Support Protocol 4: Hematoxylin and eosin staining for 10X Visium imaging

Basic Protocol 8: Manual tissue dissociation for Multiome analysis

Basic Protocol 9: Tissue dissociation for Multiome analysis using S2 Singulator
Physiological contributors to yield in advanced cotton breeding lines
Authors: Virk Gurpreet , Snider John L. , Chee Peng , Virk Simerjeet , Parkash Ved , Kaur Navneet , Jones Donald
Published: August 2023

Cotton (Gossypium hirsutumL.) yield can be expressed as the product of intercepted photosynthetically active radiation (IPAR), radiation use efficiency (RUE), and harvest index (HI). Studies comparing genetic diversity in functional yield drivers for the progeny of elite breeding lines are limited or non‐existent. A field study was conducted during the 2020 and 2021 growing seasons to characterize crop development and to evaluate yield and underlying yield drivers in 16 advanced breeding lines (F7generation). Significant breeding line differences existed for lint yield, cutout date, reproductive, vegetative, and total biomass, RUE, and HI but not for IPAR. The lint yield for the lowest yielding lines was 24% lower than the highest yielding line with a lint yield of 1706 kg ha−1. Differences in RUE were not associated with single‐leaf photosynthetic rates. HI positively contributed to lint yield gain for most lines evaluated, whereas RUE was negatively correlated with lint yield for the majority of breeding lines evaluated. However, in the two highest‐yielding lines, two different strategies of yield maximization were identified. One line exhibited the earliest cutout date, reduced biomass production, low RUE, and the highest HI values, whereas the other line had the latest cutout date and produced the highest total biomass, highest RUE, and a low to intermediate HI. Breeding lines used in the current study achieved high yields by differentially manipulating underlying physiological components such as RUE, biomass accumulation, or dry matter allocation to fiber. Our work provides future direction for efforts aimed at maximizing yield through the selection for functional yield drivers.
Unraveling the dangerous duet between cancer cell plasticity and drug resistance
Authors: Chatterjee Namrata , Pulipaka Bhavana , Subbalakshmi Ayalur Raghu , Jolly Mohit Kumar , Nair Radhika
Published: August 2023

Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognized as one of the major contributors to intratumoral heterogeneity, a critical factor underlying the progression of malignant tumors, which is known to modify tumor response and induce resistance against various modes of therapy, thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like mitogen‐activated protein kinase pathway, phosphoinositide‐3‐kinase, signal transducer and activator of transcription 3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. This review will explore the current understanding we have in breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease.
A new high voltage gain DC‐DC converter based on active switched‐inductor technique
Authors: Imanlou Arash , Seifi Najmi Ebrahim , Babaei Ebrahim
Published: August 2023

This article proposes a brand‐new high voltage gain step‐up DC‐DC converter through the amalgamation of active switched‐inductors (A‐SL) and a coupled‐inductor (CL) unit. This topology stands out due to its capacity to achieve noteworthy high voltage amplification employing a lesser amount of components when put in contrast to other comparable topologies. The voltage stress across the switches is low, which enables the utilization of low‐voltage rating switches to elevate efficiency. Moreover, the division of the input current between the switches of the converter enables the power dissipation to be diminished. The CL is utilized in a way that if the turn ratio of its windings is lessened, the voltage boost will be augmented. Furthermore, the leakage energy is recycled through the output diode; therefore, problems such as voltage spikes across the switches do not occur. Moreover, the output diode turns off naturally without reverse recovery problems. The switching pattern of the converter is simple, and both switches are driven simultaneously, and the converter can be controlled using a simple controller in a closed‐loop control method. In addition, the duty cycle range has no limitations. The operation principle and the steady‐state analysis of the proffered converter are discussed in detail for CCM and DCM. The design considerations and efficiency analysis are provided, followed by small‐signal modeling and controller design. Moreover, to evaluate the performance of the proffered converter among other topologies, a comparison study is conducted in terms of voltage gain, total device count, and voltage tension on the power switches and diodes. Finally, a 200–300 W, 28/400 V lab‐based prototype is implemented and tested to validate the analysis.
Allosteric modulation of SHP2: Quest from known to unknown
Authors: Wang Ning , Zhu Shilin , Lv Dan , Wang Yajun , Khawar Muhammad B. , Sun Haibo
Published: August 2023

Src homology‐2 domain‐containing protein tyrosine phosphatase‐2 (SHP2) is a key regulatory factor in the cell cycle and its activating mutations play an important role in the development of various cancers, making it an important target for antitumor drugs. Due to the highly conserved amino acid sequence and positively charged nature of the active site of SHP2, it is difficult to discover inhibitors with high affinity for the catalytic site of SHP2 and sufficient cell permeability, making it considered an “undruggable” target. However, the discovery of allosteric regulation mechanisms provides new opportunities for transforming undruggable targets into druggable ones. Given the limitations of orthosteric inhibitors, SHP2 allosteric inhibitors have become a more selective and safer research direction. In this review, we elucidate the oncogenic mechanism of SHP2 and summarize the discovery methods of SHP2 allosteric inhibitors, providing new strategies for the design and improvement of SHP2 allosteric inhibitors.
Efficacy, safety, and tolerability of nivasorexant in adults with binge‐eating disorder: A randomized, Phase II proof of concept trial
Authors: McElroy Susan L. , Coloma Preciosa M. , Berger Benjamin , Guerdjikova Anna I. , Joyce J. Mark , Liebowitz Michael R. , Pain Scott , Rabasa Cristina
Published: August 2023

Objective

This Phase II, placebo‐controlled, double‐blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge‐eating disorder (BED).

Methods

Adults meeting the DSM‐5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale‐Brown Obsessive‐Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD‐17). Key safety outcomes included treatment‐emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue).

Results

Sixty‐eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: −2.93) and nivasorexant (LSM: −2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): −.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo.

Discussion

In this proof‐of‐concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED.

Public Significance

The results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin‐1 receptor in BED.
metanetwork: A R package dedicated to handling and representing trophic metanetworks
Authors: Ohlmann Marc , Garnier Jimmy , Vuillon Laurent
Published: August 2023

Trophic networks describe interactions between species at a given location and time. Due to environmental changes, anthropogenic perturbations or sampling effects, trophic networks may vary in space and time. The collection of network time series or networks in different sites thus constitutes a metanetwork. We present here the R packagemetanetwork, which will ease the representation, the exploration and analysis of trophic metanetwork data sets that are increasingly available. Our main methodological advance consists in suitable layout algorithm for trophic networks, which is based on trophic levels and dimension reduction in a graph diffusion kernel. In particular, it highlights relevant features of trophic networks (trophic levels, energetic channels). In addition, we developed tools to handle, compare visually and quantitatively and aggregate those networks. Static and dynamic visualisation functions have been developed to represent large networks. We apply our package workflow to several trophic network data sets.
Effects of drought, disturbance, and biotic neighborhood on experimental tree seedling performance
Authors: Ramage Benjamin S. , Johnson Daniel J. , Chan David M.
Published: August 2023

Forest biodiversity is likely maintained by a complex suite of interacting drivers that vary in importance across both space and time. Contributing factors include disturbance, interannual variation in abiotic variables, and biotic neighborhood effects. To probe ongoing uncertainties and potential interactions, we investigated tree seedling performance in a temperate mid‐Atlantic forest ecosystem. We planted seedlings of five native tree species in mapped study plots, half of which were subjected to disturbance, and then monitored seedling survival, height growth, and foliar condition. The final year of data collection encompassed a drought, enabling comparison between intervals varying in water availability. Seedling performance was analyzed as a function of canopy cover and biotic neighborhood (conspecific and heterospecific abundance), including interactions, with separate generalized linear mixed models fit for each interval. All species exhibited: (a) pronounced declines in height growth during the drought year, (b) detrimental effects of adult conspecifics, and (c) beneficial effects of canopy openness. However, despite these consistencies, there was considerable variation across species in terms of the relevant predictors for each response variable in each interval. Our results suggest that drought may strengthen or reveal conspecific inhibition in some instances while weakening it or obscuring it in others, and that some forms of conspecific inhibition may manifest only under particular canopy conditions (although given the inconsistency of our findings, we are not convinced that conspecific inhibition is critical for diversity maintenance in our study system). Overall, our work reveals a complex forest ecosystem that appears simultaneously and interactively governed by biotic neighborhood structure (e.g., conspecific and/or heterospecific abundance), local habitat conditions (e.g., canopy cover), and interannual variability (e.g., drought).
Semiconductor piezoresistance prediction model for mechanical sensor design
Authors: Nakanishi Ryo , Morikawa Ryo , Kawai Masashi , Nakahara Takumi , Toriyama Toshiyuki
Published: August 2023

This paper addresses semiconductor piezoresistive materials selection in MEMS engineering design. From the practical engineering point of view, it is important to understand piezoresistance properties of semiconductors even if less accuracy under feasibility design phase. However, piezoresistance is frequently analyzed based on first principle electronic band structure simulations by sophisticate physicists. Practical engineers not familiar with this simulation cannot directly apply useful information derived from the result of simulation. This paper provides practical prediction method for piezoresistance based on electronic band parameters obtained from the state‐of‐the‐art solid‐state physics. It is demonstrated that the crucial parameters which control the p‐type shear piezoresistance coefficient π44 in diamond and zinc‐blend single crystals are the inverse of square of bond length in unit cell atom, the square root of valence light hole mass, and the shear elastic compliance coefficient S44.
Fundamental evaluation of direct‐cooling technology for in‐wheel drive system
Authors: Suto Tetsuya , Ito Makoto , Takahashi Akeshi , Iwano Ryuichiro , Hara Takafumi
Published: August 2023

We are developing a small and lightweight direct‐drive system toward the realization of in‐wheel electric vehicles (EVs). To increase the power density of the motor, we developed a direct‐cooling motor that immersed the core, coils, and magnets in cooling oil and improved cooling efficiency. Moreover, we performed measurements of frictional loss, measurement of pressure drop, and a continuous heat‐run test on the test bench. The results demonstrated that direct cooling is effective and continuous operation can be achieved. Additionally, it was found that the coil temperature can be controlled by the flow rate of the cooling oil. In this paper, we report on the concept of direct cooling and the measurement results.
GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development
Authors: Ni Duan , Tan Jian , Robert Remy , Taitz Jemma , Ge Anjie , Potier‐Villette Camille , Reyes Julen Gabirel Araneta , Spiteri Alanna , Wishart Claire , Mackay Charles , Piccio Laura , King Nicholas Jonathan Cole , Macia Laurence
Published: August 2023

Regulatory T cells (Treg) maintain immune homeostasis due to their anti‐inflammatory functions. They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short‐chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G‐protein‐coupled‐receptors like GPR109A. In this study, we identified a novel role for GPR109A in thymic Treg development. We found that Gpr109a−/− mice had increased Treg under basal conditions in multiple organs compared with WT mice. GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single‐cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from Gpr109a−/− mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express Gpr109a in the WT displayed increased Aire expression and also enhanced signaling related to mTEC functionality. Increased thymic Treg in Gpr109a−/− mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and possibly the gut microbiota, on thymic Treg development via its regulation of mTECs.
Levamisole suppresses activation and proliferation of human T cells by the induction of a p53‐dependent DNA damage response
Authors: Khan Gerarda H. , Veltkamp Floor , Scheper Mirte , Hoebe Ron A. , Claessen Nike , Butter Loes , Bouts Antonia H.M. , Florquin Sandrine , Guikema Jeroen E. J. ,   LEARNS Consortium
Published: August 2023

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse‐free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T‐cell activation‐associated cytokines such as IL‐2, TNF‐α, and IFN‐γ were reduced upon LMS treatment, whereas IL‐4 and IL‐13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas‐mediated apoptosis. LMS treatment resulted in a mid‐S phase cell cycle arrest accompanied by γH2AX‐foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53‐dependent DNA damage response.
Lymphocyte pathway analysis using naturally lymphocyte‐deficient fish
Authors: Zhang Gaoqun , Swann Jeremy B. , Felder Marius , O'Meara Connor , Boehm Thomas
Published: August 2023

Comparative phylogenetic analyses are of potential value to establish the essential components of genetic networks underlying physiological traits. For species that naturally lack particular lymphocyte lineages, we show here that this strategy readily distinguishes trait‐specific actors from pleiotropic components of the genetic network governing lymphocyte differentiation. Previously, three of the four members of the DNA polymerase X family have been implicated in the junctional diversification process during the somatic assembly of antigen receptors. Our phylogenetic analysis indicates that the presence of terminal deoxynucleotidyl transferase is strictly associated with the facility of V(D)J recombination, whereas PolL and PolM genes are retained even in species lacking Rag‐mediated somatic diversification of antigen receptor genes.
Design and Synthesis of Rigid‐Featured Tertiary Amine‐Derived C2‐Symmetric Chiral Furan‐N,N′‐dioxide Ligands
Authors: Chen Zi‐Yue , Hu Pan , Wang Xi‐Rui , Xu Ke‐Lan , Wang Yu‐Heng , Tian You‐Ping , Zhou Ying , Liu Xiong‐Li
Published: August 2023

To expand the chemical space of chiral N‐oxides and chiral furan‐containing ligands, herein we designed and synthesized a new class of rigid‐featured tertiary amine‐derived C2‐symmetric chiral furan‐N,N′‐dioxide (Fu‐2NO) ligands from optically pure l‐prolinamides/hydroxylprolinamides in operationally simple two steps and up to 57 % overall yield. The newly developed rigid‐featured chiral Fu‐2NO ligands possesses two pyrroloimidazolone‐based N‐oxides as non‐flat chiral walls, and afforded the opportunity for fine‐tuning the ligand electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom. More importantly, The Fu‐2NO ligands can tolerate air and moisture such that no special handling is needed for their storage, and can be applied in the Ni(II)‐catalyzed asymmetric Friedel‐Crafts alkylation reaction of indole.
PPh3‐Mediated Nucleophilic Sulfonation of Sulfonyl Chlorides with Arynes: Access to Manifold Aryl Sulfones
Authors: Yue Hui‐Qi , Li Qi‐Wei , Shi Da‐Wei , Yang Rui‐Jia , Han Liang‐Liang , Yang Bin
Published: August 2023

Sulfonyl chlorides are a class of cheap and readily available basic chemicals, which have routinely served as electrophilic reagents in their chemical transformations. Herein, we disclose a novel PPh3‐mediated nucleophilic sulfonation method of sulfonyl chlorides with arynes. Different from the classical P(III)‐mediated reductive deoxygenation reaction of sulfonyl chlorides, the valence state of the sulfur atom has not been changed. This protocol exhibits broad functional group tolerance and provides a direct approach to a variety of aryl and alkyl sulfones.
Fabrication of a Robust and Porous MnO2 Electrode as the Cathode for High‐Performance Aqueous Zinc‐Ion Batteries
Authors: Nie Nantian , Wang Fuliang , Yao Wenhao
Published: August 2023

Due to their excellent qualities (cheaper raw materials, convenient fabrication method, and high level of safety) of aqueous Zn–MnO2 batteries, they have aroused interest as potential replacements for lithium‐ion batteries. However, the sluggish electron/ion‐transfer rate of MnO2 cathodes hinders their further application as energy‐storage devices. Hence, a simple preparation method is proposed for MnO2 cathodes with porous structures that can effectively reduce the difficulty of electron/ion migration inside an electrode. In addition, the filamentous poly(1,1‐difluoroethylene) generated during the preparation process can act as a supporting structure in the cathode, which maintains the structural stability of the MnO2 cathode, even enduring long‐term charge/discharge cycles. Thus, this cathode has great Zn2+‐storage performance: a high specific capacity of 313 mAh g−1 at 0.1 A g−1 and an impressive rate capability of 106.4 mAh g−1 at an ultrahigh current density of 5 A g−1. In particular, the cathode exhibited superior cycling stability with 69.7% capacity retention after 800 cycles at 3 A g−1. In addition, this cathode presents excellent comprehensive performance of energy conservation. In this method, a versatile approach may be provided for producing cathodes with superior performance in aqueous zinc‐ion batteries systems.
Polymorphism of glucocorticoid receptor gene (rs41423247) in functional seizures (psychogenic nonepileptic seizures/attacks)
Authors: Firouzabadi Negar , Asadi‐Pooya Ali A. , Alimoradi Nahid , Simani Leila , Asadollahi Marjan
Published: August 2023

Objective

We investigated the association between the glucocorticoid receptor (GR) gene, also known as the nuclear receptor subfamily 3, group C, member 1 (NR3C1), rs41423247 polymorphism, and functional seizures (psychogenic nonepileptic seizures/attacks) in a case–control study. We hypothesized that the tested polymorphism has significant associations with functional seizures (psychogenic nonepileptic seizures/attacks) independent from comorbid depression.

Methods

Seventy patients with functional seizures (psychogenic nonepileptic seizures/attacks), 70 with major depressive disorder (MDD), and 70 healthy controls (HCs) were studied. Their DNAs were analyzed for NR3C1 rs41423247 polymorphism.

Results

Genotype and allele frequencies of rs41423247 were different between the three groups. G allele carriers were more frequent in patients with functional seizures (psychogenic nonepileptic seizures/attacks) and those with MDD compared to HCs (p = 0.0001). However no significant difference was observed with respect to allele distributions between functional seizures (psychogenic nonepileptic seizures/attacks) and MDD groups (p = 0.391). CC genotype was less often associated with functional seizures (psychogenic nonepileptic seizures/attacks) versus HC: Codominant model; p = 0.001, OR = 0.11, 95% CI = 0.05–0.24, and −2loglilkelihood = 231.7. In comparison between functional seizures (psychogenic nonepileptic seizures/attacks) group and other (MDD + HC) groups, we observed a significant association between CG genotype and functional seizures (psychogenic nonepileptic seizures/attacks) (Codominant model; p = 0.001, OR = 5.63, 95% CI = 2.60–12.40 and −2loglikelihood = 245.99).

Significance

Patients with functional seizures (psychogenic nonepileptic seizures/attacks) and those with MDD were significantly more often G allele carriers in rs41423247 compared with HCs. We observed a significant association between CG genotype and functional seizures (psychogenic nonepileptic seizures/attacks). However, we could not exclude the possibility of confounding effects of depression. Future genetic studies of patients with functional seizures (psychogenic nonepileptic seizures/attacks) should include a comparison group with depression in addition to a comparison group of HCs.
Forecasting the different influencing factors of household food waste behavior in China under the COVID‐19 pandemic
Authors: Shen Xiangdong , Wang Junbin , Wang Li , Jiao Chunlan
Published: August 2023

At present, both developed and developing countries around the world are facing a serious problem of household food waste. The current state of food waste cannot be ignored, especially during the COVID‐19 pandemic. This study examined the effects of psychological level factors, cultural level factors, and situational level factors on household food waste behavior in China. Besides, the factors affecting household food waste behavior were identified and evaluated using the extended theory of planned behavior (TPB) model. In this study, participants (N = 337) completed a questionnaire assessing their household food waste behavior. We found that COVID‐19 food supply restriction, budget constraints, attitude, subjective norm, and perceived behavioral control have a positive significant impact on residents' intention to reduce food waste. The result unveiled that perceived health risks, herd mentality, status display face consciousness, and other‐oriented face consciousness have a negative significant impact on residents' intention to reduce food waste. We tested the mediating effect of intention to reduce food waste between antecedent variables and household food waste behavior. The study adds to the academic literature and practical implication on Chinese household food waste behavior by combining numerous factors on a single model, grounded in the TPB.