bluuebunny/crossref_metadata_2025 huggingface dataset:
CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells
Authors: Horvath Riley M. , Brumme Zabrina L. , Sadowski Ivan
Published: September 2023

Latent HIV-1 provirus represents the barrier toward a cure for infection and is dependent upon the host RNA Polymerase (Pol) II machinery for reemergence. Here, we find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency-reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to the HIV-1 LTR. Furthermore, HIV-1 expression in response to several latency reversal agents was impaired upon disruption of
CDK8
by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Additionally, treatment of CD4
+
peripheral blood mononuclear cells isolated from people living with HIV-1 and who are receiving antiretroviral therapy with Senexin A inhibited induction of viral replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases, CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression.

IMPORTANCE

A cure for HIV-1 infection will require novel therapies that can force elimination of cells that contain copies of the virus genome inserted into the cell chromosome, but which is shut off, or silenced. These are known as latently-infected cells, which represent the main reason why current treatment for HIV/AIDS cannot cure the infection because the virus in these cells is unaffected by current drugs. Our results indicate that chemical inhibitors of Cdk8 also inhibit the expression of latent HIV provirus. Cdk8 is an important enzyme that regulates the expression of genes in response to signals to which cells need to respond and which is produced by a gene that is frequently mutated in cancers. Our observations indicate that Cdk8 inhibitors may be employed in novel therapies to prevent expression from latent provirus, which might eventually enable infected individuals to cease treatment with antiretroviral drugs.
Understanding the causal relationships of attention-deficit/hyperactivity disorder with mental disorders and suicide attempt: a network Mendelian randomisation study
Authors: Meisinger Christa , Freuer Dennis
Published: September 2023

Background

Attention-deficit/hyperactivity disorder (ADHD) is a lifespan neurodevelopmental condition resulting from complex interactions between genetic and environmental risk factors. There is evidence that ADHD is associated with other mental disorders, but it remains unclear whether and in what way a causal relationship exists.

Objective

To investigate the direct and indirect causal paths between ADHD and seven common mental disorders.

Methods

Two-sample network Mendelian randomisation analysis was performed to identify psychiatric disorders causally related to ADHD. Total and direct effects were estimated in an univariable and multivariable setting, respectively. Robustness of results was ensured in three ways: a range of pleiotropy-robust methods, an iterative approach identifying and excluding outliers, and use of up to two genome-wide association studies per outcome to replicate results and calculate subsequently pooled meta-estimates.

Results

Genetic liability to ADHD was independently associated with the risk of anorexia nervosa (OR 1.28 (95% CI 1.11 to 1.47); p=0.001). A bidirectional association was found with major depressive disorder (OR 1.09 (95% CI 1.03 to 1.15); p=0.003 in the forward direction and OR 1.76 (95% CI 1.50 to 2.06); p=4×10−12in the reverse direction). Moreover, after adjustment for major depression disorder, a direct association with both suicide attempt (OR 1.30 (95% CI 1.16 to 1.547); p=2×10−5) and post-traumatic stress disorder (OR 1.18 (95% CI 1.05 to 1.33); p=0.007) was observed. There was no evidence of a relationship with anxiety, bipolar disorder or schizophrenia.

Conclusions

This study suggests that ADHD is an independent risk factor for a number of common psychiatric disorders.

Clinical implications

The risk of comorbid psychiatric disorders in individuals with ADHD needs to be considered both in diagnosis and treatment.
Maternal and child nutrition programme of investigation within the 100 Million Brazilian Cohort: study protocol
Authors: Carrilho Thais Rangel Bousquet , Silva Natanael de Jesus , Paixão Enny Santos , Falcão Ila Rocha , Fiaccone Rosemeire Leovigildo , Rodrigues Laura Cunha , Katikireddi Srinivasa Vittal , Leyland Alastair H , Dundas Ruth , Pearce Anna , Velasquez-Melendez Gustavo , Kac Gilberto , Silva Rita de Cássia Ribeiro , Barreto Mauricio L
Published: September 2023

Introduction

There is a limited understanding of the early nutrition and pregnancy determinants of short-term and long-term maternal and child health in ethnically diverse and socioeconomically vulnerable populations within low-income and middle-income countries. This investigation programme aims to: (1) describe maternal weight trajectories throughout the life course; (2) describe child weight, height and body mass index (BMI) trajectories; (3) create and validate models to predict childhood obesity at 5 years of age; (4) estimate the effects of prepregnancy BMI, gestational weight gain (GWG) and maternal weight trajectories on adverse maternal and neonatal outcomes and child growth trajectories; (5) estimate the effects of prepregnancy BMI, GWG, maternal weight and interpregnancy BMI changes on maternal and child outcomes in the subsequent pregnancy; and (6) estimate the effects of maternal food consumption and infant feeding practices on child nutritional status and growth trajectories.

Methods and analysis

Linked data from four different Brazilian databases will be used: the 100 Million Brazilian Cohort, the Live Births Information System, the Mortality Information System and the Food and Nutrition Surveillance System. To analyse trajectories, latent-growth, superimposition by translation and rotation and broken stick models will be used. To create prediction models for childhood obesity, machine learning techniques will be applied. For the association between the selected exposure and outcomes variables, generalised linear models will be considered. Directed acyclic graphs will be constructed to identify potential confounders for each analysis investigating potential causal relationships.

Ethics and dissemination

This protocol was approved by the Research Ethics Committees of the authors’ institutions. The linkage will be carried out in a secure environment. After the linkage, the data will be de-identified, and pre-authorised researchers will access the data set via a virtual private network connection. Results will be reported in open-access journals and disseminated to policymakers and the broader public.
Genetic research and the collective good: participants as leaders to reconcile individual and public interests
Authors: Galasso Ilaria , Geiger Susi
Published: September 2023

This paper problematises the notions of public or common good as weighed against individual sovereignty in the context of medical research by focusing on genetic research. We propose the notion of collective good as the good of the particular collective in which the research was conducted. We conducted documentary and interview-based research with participant representatives and research leaders concerned with participant involvement in leading genetic research projects and around two recent genetic data controversies: the case of the UK Wellcome Sanger Institute, accused of planning unauthorised commercialisation of African DNA samples, and the case of the company Genuity Science, which planned genetic research on brain tumour samples in Ireland with no explicit patient consent. We advocate for greater specificity in circumscribing the collective to which genetic research relates and for greater efforts in including representatives of this collective as research coleaders in order to enable a more inclusive framing of the good arising from such research. Such community-based participant cogovernance and coleadership in genetic research is vital especially when minorities or vulnerable groups are involved, and it centrally requires community capacity building to help collectives articulate their own notions of the collective good.
Four problems for the pregnancy rescue case
Authors: Gillham Alex
Published: September 2023

The pregnancy rescue case (PRC) is supposed to show that when forced between preventing a fetus from being killed and preventing someone from remaining unwillingly pregnant, we are morally required to do the former. If this is true, then Hendricks argues that the typical abortion is morally wrong. I pose four problems for PRC and how Hendricks uses it here. First, one might simply deny the intuition Hendricks takes PRC to pump for reasons having to do with the moral status of the fetus. Second, even if it is true that we should prevent the fetus from being killed in PRC, this might not tell us much about the moral permissibility of abortion in typical cases because there are important differences between PRC and the typical abortion. Third, I propose some modifications to PRC that would better isolate whether fetal personhood does any work to pump the target intuition. Fourth, I argue that PRC only succeeds if we presuppose that Thomson’s defence is unsound, but presupposing this comes at too high a cost.
Direct Versus Indirect Revascularization for Moyamoya: a Large Multicenter Study
Authors: El Naamani Kareem , Chen Ching-Jen , Jabre Roland , Saad Hassan , Grossberg Jonathan A , Dmytriw Adam A , Patel Aman B , Khorasanizadeh Mirhojjat , Ogilvy Christopher S , Thomas Ajith , Monteiro Andre , Siddiqui Adnan , Cortez Gustavo M , Hanel Ricardo A , Porto Guilherme , Spiotta Alejandro M , Piscopo Anthony J , Hasan David M , Ghorbani Mohammad , Weinberg Joshua , Nimjee Shahid M , Bekelis Kimon , Salem Mohamed M , Burkhardt Jan-Karl , Zetchi Akli , Matouk Charles , Howard Brian M , Lai Rosalind , Du Rose , Abbas Rawad , Sioutas Georgios S , Amllay Abdelaziz , Munoz Alfredo , Atallah Elias , Herial Nabeel A , Tjoumakaris Stavropoula I , Gooch Michael Reid , Rosenwasser Robert H , Jabbour Pascal
Published: September 2023

Background

Moyamoya is a chronic occlusive cerebrovascular disease of unknown etiology causing neovascularization of the lenticulostriate collaterals at the base of the brain. Although revascularization surgery is the most effective treatment for moyamoya, there is still no consensus on the best surgical treatment modality as different studies provide different outcomes.

Objective

In this large case series, we compare the outcomes of direct (DR) and indirect revascularisation (IR) and compare our results to the literature in order to reflect on the best revascularization modality for moyamoya.

Methods

We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational studies in Epidemiology guidelines of moyamoya affected hemispheres treated with DR and IR surgeries across 13 academic institutions predominantly in North America. All patients who underwent surgical revascularization of their moyamoya-affected hemispheres were included in the study. The primary outcome of the study was the rate of symptomatic strokes.

Results

The rates of symptomatic strokes across 515 disease-affected hemispheres were comparable between the two cohorts (11.6% in the DR cohort vs 9.6% in the IR cohort, OR 1.238 (95% CI 0.651 to 2.354), p=0.514). The rate of total perioperative strokes was slightly higher in the DR cohort (6.1% for DR vs 2.0% for IR, OR 3.129 (95% CI 0.991 to 9.875), p=0.052). The rate of total follow-up strokes was slightly higher in the IR cohort (8.1% vs 6.6%, OR 0.799 (95% CI 0.374 to 1.709) p=0.563).

Conclusion

Since both modalities showed comparable rates of overall total strokes, both modalities of revascularization can be performed depending on the patient’s risk assessment.
A new computational approach for velocity components analysis of a solid particle in an incompressible fluid flow
Authors: Vahidi J. , Akbari H. , Ghasemi S. E.
Published: September 2023

In this work, the dynamic motion of a particle in an incompressible Newtonian fluid flow is investigated analytically. The shear and rotation effects on the lift and drag forces of the particle are considered for this problem. Also, the equations governing the motion of a particle are solved using the Temimi–Ansari technique. Analytical solutions for the horizontal and vertical velocities of this particle are obtained and analyzed in terms of time. The corresponding analytical findings are verified in comparison with numerical solutions. The obtained results showed very good accuracy of the solutions and the efficiency of this method in the whole time domain by employing the Padé approximation.
Dynamic Multi-Swarm Competitive Fireworks Algorithm for Global Optimization and Engineering Constraint Problems
Authors: Lei Ke , Wu Yonghong
Published: September 2023

As a novel intelligent algorithm, fireworks algorithm (FWA) is applied to deal with different types of optimization problems. Since FWA’s search processes are relatively simple, it is inefficient. In this paper, a dynamic multi-swarm competitive fireworks algorithm (DMCFWA) is developed to enhance the search capability of FWA. Firstly, based on the scaling coefficient updated by utilizing the fitness value of the optimal firework, the dynamic explosion amplitude strategy is proposed to improve the search capability of the best firework. Secondly, utilizing the location information of the fireworks, an improved search method is designed to enhance the local search capability of firework swarms. Thirdly, a multi-swarm independent selection technique and a restart operation are adopted to boost its abilities of global exploration and local exploitation. Finally, to reduce the computational cost of FWA, a new initialization method is used and a new model for calculating the spark number is embedded in DMCFWA. By adopting these strategies, DMCFWA easily implements and does well in exploitation and exploration. CEC2017 test suite and four engineering constraint problems are used to demonstrate the performance of DMCFWA. Experimental results show that DMCFWA performs more effectively and stably than its competitors.
An Integral-Generalized Finite Difference Method for Interface Problems in Solid Mechanics
Authors: Ci Huiling , Wang Wei , Shi Lu , Bai Bing , Wang Lei , Liu Jianfeng , Jia Yun
Published: September 2023

Interface problems exist widely in various engineering problems and their high-precision simulation is of great importance. A new computational approach for dealing with interface problems is proposed based on the recently developed integral-generalized finite difference (IGFD) scheme. In this method, the research domain is divided into several subdomains by interfaces, and discretization schemes are established independently in each subdomain. A new cross-subdomain integration scheme is introduced to connect these subdomains. Several two-dimensional elasticity models containing material interfaces are studied to test the effectiveness of the proposed method. The results show that the recently proposed approach without the help of discontinuous functions or auxiliary equations that are commonly used in other numerical methods (e.g., extended finite element method and boundary element method) enables obtaining high accuracy and efficiency in interface problems. The proposed method has great potential in the application of material interface problems in solid mechanics and, furthermore, weak discontinuity problems in various fields.
Improved Robust Control of a New Morphing Quadrotor UAV Subject to Aerial Configuration Change
Authors: Derrouaoui Saddam Hocine , Bouzid Yasser , Belmouhoub Amina , Guiatni Mohamed
Published: September 2023

Over these last years, morphing Unmanned Aerial Vehicles (UAVs) control became one of the critical problems, which has not been properly solved by the researchers. This is due to their particular and complex features compared to the ordinary ones as: morphology change, flight transition, model asymmetry, geometric variation, different dynamics, over-actuation and high nonlinearity. To deal with such challenges, this paper addresses the control of a new over-actuated morphing drone that changes its arms in different orientations to form various morphology and configuration models. First, the present system is divided into two principal parts: an attitude subsystem and a position subsystem. Furthermore, an improved Adaptive Nonsingular Fast Terminal Sliding Mode Controller (ANFTSMC) is proposed to stabilize the attitude loop. While the position loop is controlled by Integral Backstepping Controller (IBC) using Lyapunov theory. Second, with the aim to better adjust the control gains, a recent metaheuristic technique based on the Whale Optimization Algorithm (WOA) is adopted. At last, a comparative study with the standard control algorithms is accomplished to evaluate the effectiveness and robustness of the proposed methods.
Development and validation of rapidPrakritianalysis tool for a standard clinical approach
Authors: Doddoli Gururaj , Doddoli Suchitra , Shete Sanjay , Verma Anita
Published: September 2023

Background: A specific prakriti is formed for each person by tridosha at the moment when sperm and ovum unite within the uterus. The prakriti evaluation is of vital relevance for research and standardization of therapeutic practice. The current accessible prakriti assessment tools are not destined to be applied in clinical settings, which necessitates the adoption of simple and flexible ones. Hence, this study was conducted to develop a precise, less-technical instrument for prakriti analysis that is quick to assess and exhibit long-term use in healthcare system. Materials and Methods: The content validity of prakriti analysis tool was assessed by panel of 17 skilled ayurvedic physicians. The prakriti analysis tool was developed on the basis of ayurvedic classic texts. A total of 30 items were included in the tool and each item was rated as (i) not essential, (ii) useful but not essential and (iii) essential. The content validity ratio (CVR) was determined by applying Lawshe formula. The CVR calculation was done for all the 30 items of prakriti analysis tool. The items with CVR ≤ 0.45 were excluded from the final scale. To quantify the content validity of tool, content validity index (CVI) at the levels of item (I-CVI) and average-based scale (S-CVI/Ave) were also estimated. Results: The results showed that CVR for item number 4, 7, 9, 10, 16 27, 29 and 30 was less than 0.45. Therefore, from the final prakriti tool these items were removed. In this way the final prakriti analysis tool contains 22 items with CVR ≥ 0.45 which is satisfactory. Further, item level content validity was computed for all the 22 items which ranged from 0.76 to 1. The S-CVI/Ave was also excellent which is equivalent to 0.90. Conclusion: The findings of study infer that prakriti analysis tool is consistent, reliable and worthy of being used on a broad scale to assess greater diversity among healthy volunteers and patients.
Lessons Learnt from a Multimodal Learning Analytics Deployment In-the-Wild
Authors: Martinez-Maldonado Roberto , Echeverria Vanessa , Fernandez-Nieto Gloria , Yan Lixiang , Zhao Linxuan , Alfredo Riordan , Li Xinyu , Dix Samantha , Jaggard Hollie , Wotherspoon Rosie , Osborne Abra , Shum Simon Buckingham , Gašević Dragan
Published: September 2023

Multimodal Learning Analytics (MMLA) innovations make use of rapidly evolving sensing and artificial intelligence algorithms to collect rich data about learning activities that unfold in physical spaces. The analysis of these data is opening exciting new avenues for both studying and supporting learning. Yet, practical and logistical challenges commonly appear while deploying MMLA innovations “in-the-wild”. These can span from technical issues related to enhancing the learning space with sensing capabilities, to the increased complexity of teachers’ tasks. These practicalities have been rarely investigated. This article addresses this gap by presenting a set of lessons learnt from a 2-year human-centred MMLA in-the-wild study conducted with 399 students and 17 educators in the context of nursing education. The lessons learnt were synthesised into topics related to (i) technological/physical aspects of the deployment; (ii) multimodal data and interfaces; (iii) the design process; (iv) participation, ethics and privacy; and (v) sustainability of the deployment.
Extending Silver Nanowire Modified Electrodes to Industrial Zinc Electrolyte for Copper Ion Detection
Authors: Xiao Ni , Chen Yinan , Tan Wen , Ku Jiangang , Wang Qiang , Chen Hang , Weng Wei , Zhong Shuiping
Published: September 2023

Real-time and rapid determination of trace copper ion (Cu2+) in the electrolyte of zinc smelting process is urgently needed. However, the complicated composition of the electrolyte, especially the extremely high-concentration of zinc ion (Zn2+) may cause severe interference to the detection of Cu2+. This work describes a facile electrochemical sensor for Cu2+ determination in the electrolyte of zinc smelting plants based on a fluorine-doped tin oxide (FTO) electrode with silver nanowires (AgNWs) and Nafion modification. The AgNWs/Nafion-FTO electrode showed good detection ability with the linear detection range of 0.2−2 mg l−1 Cu2+ in 45 g l−1 Zn2+ solution using differential pulse anodic stripping voltammetry (DPASV) technique. With DPASV technique, Cu2+ can be first reduced and pre-concentrated on the working electrode surface at −0.6 V vs Ag/AgCl for 500 s, after which the deposited Cu metal is oxidized around 0 V vs Ag/AgCl during the stripping step. It has been proved by transmission electron microscopy (TEM) and X-ray photoelectron spectra (XPS) that trace Cu2+ can be adsorbed and reduced on AgNWs in solutions with Zn/Cu ratio up to (2.25−22.5) × 104. The results extend AgNWs modified electrode to the industrial solution, providing a new strategy for detection of trace metal ions in industrial solutions.
Evidence for Correlation between Novel Autoantibody against Phospholipid Named Neoself Anti-β2-GPI/HLA-DR Antibody and Complement Consumption in Infertile Patients
Authors: Matsumi Hirotaka
Published: September 2023

Impaired implantation is one of the causes of infertility. It occurs under vital inflammatory status due to immune hyperactivation. In the innate immune system, the inflammatory response to pathogenic stimuli is initiated by complement activation. Minimal vasculitis associated with complement consumption in infertile patients may be an underlying mechanism for impaired implantation. Antiphospholipid antibodies regulate the inflammatory response. Recently, a novel autoantibody (neoself antibody) against a complex of β2-GPI and HLA class II molecules (β2-GPI/HLA-DR) has been reported to be an independent autoantibody associated with aPLs. This study investigated the relationship between neoself antibodies and complement consumption in infertile patients with impaired implantation. It was found that decreased C4 levels were strongly related to the increased neoself antibody titers in the serum among those patients whose antibody titers were not as high. On the contrary, serum levels of CH50 and CRP are not correlated with them. These results suggest that neoself antibodies might indicate low-grade inflammation, which causes endometrial vasculitis in impaired implantation of infertile patients.
Complete Resection of a Torcular Herophili Hemangiopericytoma without Sinus Reconstruction: A Case Report and Review of the Literature
Authors: Safi Salah-Edine , Godfrain Julie , Rooijakkers Herbert , Collignon Frederic
Published: September 2023

A 78-year-old woman presented to the emergency department with mild headaches and a sudden onset of blurred vision. Computerized tomography scan and magnetic resonance imaging showed what was described at first as a meningioma invading and occluding the torcular Herophili, the posterior third of the superior sagittal sinus and the proximal part of the right transverse sinus. Gross total resection of the tumor was performed without reconstructing dural sinuses. The patient was discharged home without new neurological deficit. Histopathology was in favor of a hemangiopericytoma Grade II World Health Organization (WHO). Total body positron emission tomography [18F]fluorodeoxyglucose found no secondary location. Radiotherapy was planned post-operatively.
Point-of-Care Ultrasound for Mimicker Lesions of Incarcerated Inguinal Hernia
Authors: Hosokawa Takahiro , Yoshizawa Shinsuke , Deie Kyoichi , Ohashi Kensuke , Kawashima Hiroshi
Published: September 2023

Inguinal hernia is the most common surgical disease in pediatric patients, and urgent intervention such as manual reduction is needed for incarcerated inguinal hernia. Torsion of undescended testes, inguinal herniated ovarian torsion, and purulent lymphadenitis are mimickers of this condition. If these mimicker lesions are misdiagnosed as incarcerated inguinal hernia, manual reduction usually fails, and edematous and erythematous changes may occur in these mimicker lesions due to manual reduction. For physicians in the emergency department, prompt decisions and familiarity with the sonographic appearance of different contents within an inguinal hernia are important to accurately diagnose these mimickers. In this case series, we present sonographic images of a typical case of incarcerated inguinal hernia (an 11-month-old male with right incarcerated inguinal hernia) and three cases of mimicker lesions (a 7-month-old female with herniated ovarian torsion, a 7-year-old boy with undescended testicular torsion, and a 2-month-old male with purulent lymphadenitis). The incidence of incarcerated inguinal hernia is reported to be higher in males (80%), on the right side (60%), and in infants and toddlers. This information is important for diagnosing mimicker lesions. In addition, to prevent manual reduction in mimicker diseases, point-of-care ultrasound before manual reduction in suspected cases of incarcerated inguinal hernia is important.
Multiobjective Mission Planning for Multiple Geosynchronous Spacecraft Refueling
Authors: Kong Linjie , Zhou Yang
Published: September 2023

This paper studies the multiple geosynchronous spacecraft refueling problem (MGSRP) with multiple servicing spacecraft (Ssc) and fuel depots (FDs). In the mission scenario, multiple Ssc and FDs are parked in the geosynchronous Earth orbit (GEO) initially. Ssc start from FDs and maneuver to visit and refuel multiple GEO targets with known demands. These capacitated Ssc are expected to rendezvous with fuel-deficient GEO targets and FDs for the purpose of delivering the fuel stored in FDs to GEO targets. The objective is to find a set of Pareto-optimal solutions with minimum fuel cost and mission duration. The MGSRP is a much more complex variant of multidepot vehicle routing problems mixing discrete and continuous variables. A two-nested optimization model is built. We propose a new multiobjective hybrid particle swarm optimization to solve the outer-loop problem, and the design variables are the refueling sequence, task assignment, time distribution, and locations of FDs. In the inner-loop problem, branch and bound method is used to find the optimal decision variable for a given outer-loop solution. Finally, numerical simulations are presented to illustrate the effectiveness and validity of the proposed approach.
Video Laryngoscope Assistance in Button Battery Retrieval
Authors: Ren Sandy , Lopes Heitor , Masters Neil
Published: September 2023

Foreign body ingestion remains a common cause of pediatric emergency surgery with button battery ingestion of particular concern. Newer, higher power lithium batteries can cause catastrophic damage of the gastrointestinal tract through erosion of mucosa into surrounding structures. Prompt diagnosis and treatment are paramount. We present a case of an 11-month-old with a button battery lodged in the proximal esophagus. The extraction was difficult and only made possible with the assistance of a video laryngoscope. We make the case for more routine usage of video laryngoscopy for removal of foreign bodies in the upper esophagus.
High-Fidelity Monte Carlo Analysis of Highly-Localized Fission Power Peaking near a Flux Trap in an MTR Core
Authors: Abuzlf Hadi , Castagna Christian , Makmal Tzach , Aviv Ofer , Yungrais Zohar , Gabrieli Guy , Steinitz Uri , Neder Izhar , Gilad Erez
Published: September 2023

In this study, a high-fidelity Monte Carlo model was utilized to investigate the localized behavior of the power peaking factor in a reactor core. The model considered the effect of water gaps, also known as flux traps, on the local power peaking. The model, developed using the Serpent code, employs a fine spatial mesh to accurately describe the fission power and burnup distribution. The results obtained from the model were validated through comparison with experimental measurements of the power distribution obtained from the IRR1 facility. The study found that the local accumulation of thermal flux caused by enhanced neutron moderation in the flux trap leads to a highly localized increase in power density, affecting the power peaking factor. The quantification of this effect was a key finding of the study. The results obtained from the study were highly dependent on the model’s fidelity, with significant differences being observed between the power peaking factor calculated on a fine mesh as opposed to that calculated at the plate or assembly scale. Furthermore, the experimental validation of the model enabled the prediction of the power peaking factor in other regions within the fuel assembly, which are not accessible to measurement instrumentation, with a high degree of confidence. The study’s findings may be useful for optimizing reactor design and operation and assessing the safety margins in reactors with similar characteristics.
Transparent and Interpretable State of Health Forecasting of Lithium-Ion Batteries with Deep Learning and Saliency Maps
Authors: von Bülow Friedrich , Hahn Yannik , Meyes Richard , Meisen Tobias
Published: September 2023

Batteries are the most expensive component of battery electric vehicles (BEVs), but they degrade over time and battery operation. State of health (SOH) forecasting models learn how battery operation over long-time periods of weeks or months influences battery aging. Currently, existing methods for SOH forecasting of lithium-ion batteries based on deep neural network (DNN) models lack explainability of their forecasts due to their inherent black box character. However, the explainability of forecasts is essential to build user trust into the forecasting models. In this work, we address this problem from two perspectives: First, we compared four machine learning (ML) models like decision tree and random forest, which are inherently transparent, to two new DNN architectures with a more inherent black box character. Second, we proposed a new method using Gaussian-filtered saliency maps to visualize battery operational states that are relevant to DNN models. This method is applied to the best DNN models previously trained. We used an extensive data corpus consisting of five public data sets with different operational conditions, battery types, and aging trajectories. Furthermore, we show that the Gaussian-filtered saliency maps meaningfully visualize battery operational states that are consistent with findings from controlled laboratory aging experiments. Thus, this work was able to add transparency and interpretability to the SOH forecasting results of two state-of-the-art DNNs, while maintaining their superior performance compared to transparent ML models, while mitigating their inherent black box character.
Supplementary Figure 9 from AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors
Authors: Weng Weining , Meng Tao , Pu Junyi , Ma Linjie , Shen Yi , Wang Zhaohui , Pan Rong , Wang Mingqiao , Chen Caiwei , Wang Lijun , Zhang Jianjian , Zhou Biao , Shao Siyuan , Qian Yu , Liu Shuhui , Hu Wenhao , Meng Xun
Published: September 2023

Organoids homogeneity and pharmacodynamics of AMT-562 in organoids.
Figure S2 from S-531011, a Novel Anti-Human CCR8 Antibody, Induces Potent Antitumor Responses through Depletion of Tumor-Infiltrating CCR8-Expressing Regulatory T Cells
Authors: Nagira Yoji , Nagira Morio , Nagai Ryohei , Nogami Wataru , Hirata Michinari , Ueyama Azumi , Yoshida Tetsuya , Yoshikawa Mai , Shinonome Satomi , Yoshida Hiroshi , Haruna Miya , Miwa Hiroto , Chatani Natsumi , Ohkura Naganari , Wada Hisashi , Tanaka Hidekazu
Published: September 2023

Generation of humanized CCR8 KI mice
Supplementary Figure 5 from AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors
Authors: Weng Weining , Meng Tao , Pu Junyi , Ma Linjie , Shen Yi , Wang Zhaohui , Pan Rong , Wang Mingqiao , Chen Caiwei , Wang Lijun , Zhang Jianjian , Zhou Biao , Shao Siyuan , Qian Yu , Liu Shuhui , Hu Wenhao , Meng Xun
Published: September 2023

Pathology of AMT-562 in comparison with AMT-562-T1000.
Figure 3 from Upregulation of Somatostatin Receptor Type 2 Improves 177Lu-DOTATATE Therapy in Receptor-Deficient Pancreatic Neuroendocrine Tumor Model
Authors: Sharma Rupali , Earla Bhargav , Baidoo Kwamena E. , Zeiger Martha A. , Madigan James P. , Escorcia Freddy E. , Sadowski Samira M.
Published: September 2023

HDACis upregulate SSTR2 surface expression in three NET cell lines. A and B, SSTR2 surface expression in BON-1 cells was determined by flow cytometry analysis. Cells treated with both VPA at 4 mmol/L (P = 0.0103) and CI-994 at 2.5 μmol/L (P = 0.0416) and 10 μmol/L (P = 0.0205) for 72 hours showed a significant increase in SSTR2 expression. C, QGP-1 cells treated with VPA at 4 mmol/L for 72 hours (P = 0.0366) had a significant increase in SSTR2 expression. D, Cells treated with CI-994 had no significant increase in SSTR2 expression. E, QGP-1 cells treated with CI-994 at 2.5 μmol/L (P = 0.0159) and 5 μmol/L (P = 0.0174) for 5 days showed a significant increase in SSTR2 expression. F, GOT-1 cells treated with CI-994 at 5 μmol/L (P = 0.0051) and 10 μmol/L (P < 0.0001) for 72 hours had a significant increase in SSTR2 expression. Data are expressed as mean ± SEM, (n = 3). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.
Supplementary table 2 from FOXN Transcription Factors: Regulation and Significant Role in Cancer
Authors: Song Jiali , Li Longshan , Fang Yang , Lin Yue , Wu Luojia , Wan Wei , Wei Gen , Hua Fuzhou , Ying Jun
Published: September 2023

Supplementary table 2
Table S4 from Pan-Cancer Pharmacogenomic Analysis of Patient-Derived Tumor Cells Using Clinically Relevant Drug Exposures
Authors: Chang Stephen H. , Ice Ryan J. , Chen Michelle , Sidorov Maxim , Woo Rinette W.L. , Rodriguez-Brotons Aida , Jian Damon , Kim Han Kyul , Kim Angela , Stone David E. , Nazarian Ari , Oh Alyssia , Tranah Gregory J. , Nosrati Mehdi , de Semir David , Dar Altaf A. , Desprez Pierre-Yves , Kashani-Sabet Mohammed , Soroceanu Liliana , McAllister Sean D.
Published: September 2023

Supplementary Table 4 LOBICO PDXC % sens vs insens
Supplementary Data Figure S2 from Pan-Cancer Pharmacogenomic Analysis of Patient-Derived Tumor Cells Using Clinically Relevant Drug Exposures
Authors: Chang Stephen H. , Ice Ryan J. , Chen Michelle , Sidorov Maxim , Woo Rinette W.L. , Rodriguez-Brotons Aida , Jian Damon , Kim Han Kyul , Kim Angela , Stone David E. , Nazarian Ari , Oh Alyssia , Tranah Gregory J. , Nosrati Mehdi , de Semir David , Dar Altaf A. , Desprez Pierre-Yves , Kashani-Sabet Mohammed , Soroceanu Liliana , McAllister Sean D.
Published: September 2023

Figure S2
Data from AMT-562, a Novel HER3-targeting Antibody–Drug Conjugate, Demonstrates a Potential to Broaden Therapeutic Opportunities for HER3-expressing Tumors
Authors: Weng Weining , Meng Tao , Pu Junyi , Ma Linjie , Shen Yi , Wang Zhaohui , Pan Rong , Wang Mingqiao , Chen Caiwei , Wang Lijun , Zhang Jianjian , Zhou Biao , Shao Siyuan , Qian Yu , Liu Shuhui , Hu Wenhao , Meng Xun
Published: September 2023

Abstract
HER3 is a unique member of the EGFR family of tyrosine kinases, which is broadly expressed in several cancers, including breast, lung, pancreatic, colorectal, gastric, prostate, and bladder cancers and is often associated with poor patient outcomes and therapeutic resistance. U3-1402/Patritumab-GGFG-DXd is the first successful HER3-targeting antibody–drug conjugate (ADC) with clinical efficacy in non–small cell lung cancer. However, over 60% of patients are nonresponsive to U3-1402 due to low target expression levels and responses tend to be in patients with higher target expression levels. U3-1402 is also ineffective in more challenging tumor types such as colorectal cancer. AMT-562 was generated by a novel anti-HER3 antibody Ab562 and a modified self-immolative PABC spacer (T800) to conjugate exatecan. Exatecan showed higher cytotoxic potency than its derivative DXd. Ab562 was selected because of its moderate affinity for minimizing potential toxicity and improving tumor penetration purposes. Both alone or in combination therapies, AMT-562 showed potent and durable antitumor response in low HER3 expression xenograft and heterogeneous patient-derived xenograft/organoid models, including digestive system and lung tumors representing of unmet needs. Combination therapies pairing AMT-562 with therapeutic antibodies, inhibitors of CHEK1, KRAS, and tyrosine kinase inhibitor showed higher synergistic efficacy than Patritumab-GGFG-DXd. Pharmacokinetic and safety profiles of AMT-562 were favorable and the highest dose lacking severe toxicity was 30 mg/kg in cynomolgus monkeys. AMT-562 has potential to be a superior HER3-targeting ADC with a higher therapeutic window that can overcome resistance to generate higher percentage and more durable responses in U3-1402–insensitive tumors.
Supplementary Tables 3-5 from A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy
Authors: Pei Shanshan , Shelton Ian T. , Gillen Austin E. , Stevens Brett M. , Gasparetto Maura , Wang Yanan , Liu Lina , Liu Jun , Brunetti Tonya M. , Engel Krysta , Staggs Sarah , Showers William , Sheth Anagha Inguva , Amaya Maria L. , Minhajuddin Mohammad , Winters Amanda , Patel Sweta B. , Tolison Hunter , Krug Anna E. , Young Tracy N. , Schowinsky Jeffrey , McMahon Christine M. , Smith Clayton A. , Pollyea Daniel A. , Jordan Craig T.
Published: September 2023

List of commonly mutated genes in AML, Clinical information of VEN/AZA relapsed AML patients, CITE-seq and flow antibodies
Supplementary Table 7 from A Novel Type of Monocytic Leukemia Stem Cell Revealed by the Clinical Use of Venetoclax-Based Therapy
Authors: Pei Shanshan , Shelton Ian T. , Gillen Austin E. , Stevens Brett M. , Gasparetto Maura , Wang Yanan , Liu Lina , Liu Jun , Brunetti Tonya M. , Engel Krysta , Staggs Sarah , Showers William , Sheth Anagha Inguva , Amaya Maria L. , Minhajuddin Mohammad , Winters Amanda , Patel Sweta B. , Tolison Hunter , Krug Anna E. , Young Tracy N. , Schowinsky Jeffrey , McMahon Christine M. , Smith Clayton A. , Pollyea Daniel A. , Jordan Craig T.
Published: September 2023

LSC gene expression signatures
Supplementary Excel S4 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2023

Supplementary Excel S4 shows the list of SNA-pull down glycoproteins detected via glycoproteiomics analysis
Supplementary Excel S2 from Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer
Authors: Dashzeveg Nurmaa K. , Jia Yuzhi , Zhang Youbin , Gerratana Lorenzo , Patel Priyam , Shajahan Asif , Dandar Tsogbadrakh , Ramos Erika K. , Almubarak Hannah F. , Adorno-Cruz Valery , Taftaf Rokana , Schuster Emma J. , Scholten David , Sokolowski Michael T. , Reduzzi Carolina , El-Shennawy Lamiaa , Hoffmann Andrew D. , Manai Maroua , Zhang Qiang , D'Amico Paolo , Azadi Parastoo , Colley Karen J. , Platanias Leonidas C. , Shah Ami N. , Gradishar William J. , Cristofanilli Massimo , Muller William A. , Cobb Brian A. , Liu Huiping
Published: September 2023

Supplementary Excel S2 shows SNA binding on patient CTCs analyzed by flow cytometry.
Supplementary References from RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations
Authors: Subbiah Vivek , Sahai Vaibhav , Maglic Dejan , Bruderek Kamil , Touré B. Barry , Zhao Songping , Valverde Roberto , O'Hearn Patrick J. , Moustakas Demetri T. , Schönherr Heike , Gerami-Moayed Nastaran , Taylor Alexander M. , Hudson Brandi M. , Houde Damian J. , Pal Debjani , Foster Lindsey , Gunaydin Hakan , Ayaz Pelin , Sharon Dina A. , Goyal Lipika , Schram Alison M. , Kamath Suneel , Sherwin Cori Ann , Schmidt-Kittler Oleg , Jen Kai Yu , Ricard Fabien , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Casaletto Jessica B.
Published: September 2023

three references cited in supplementary data
Supplementary Figure S2 from RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across FGFR2 Alterations and Resistance Mutations
Authors: Subbiah Vivek , Sahai Vaibhav , Maglic Dejan , Bruderek Kamil , Touré B. Barry , Zhao Songping , Valverde Roberto , O'Hearn Patrick J. , Moustakas Demetri T. , Schönherr Heike , Gerami-Moayed Nastaran , Taylor Alexander M. , Hudson Brandi M. , Houde Damian J. , Pal Debjani , Foster Lindsey , Gunaydin Hakan , Ayaz Pelin , Sharon Dina A. , Goyal Lipika , Schram Alison M. , Kamath Suneel , Sherwin Cori Ann , Schmidt-Kittler Oleg , Jen Kai Yu , Ricard Fabien , Wolf Beni B. , Shaw David E. , Bergstrom Donald A. , Watters James , Casaletto Jessica B.
Published: September 2023

Supplementary Figure 2. Treatment with RLY-4008 is well-tolerated and leads to dose-dependent inhibition of FGFR2 and tumor regression in multiple FGFR2-altered tumor models.
Supplementary Figure 2 from Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer
Authors: Facchinetti Francesco , Hollebecque Antoine , Braye Floriane , Vasseur Damien , Pradat Yoann , Bahleda Rastislav , Pobel Cédric , Bigot Ludovic , Déas Olivier , Florez Arango Juan David , Guaitoli Giorgia , Mizuta Hayato , Combarel David , Tselikas Lambros , Michiels Stefan , Nikolaev Sergey I. , Scoazec Jean-Yves , Ponce-Aix Santiago , Besse Benjamin , Olaussen Ken A. , Loriot Yohann , Friboulet Luc
Published: September 2023

Documentation of the allelic status in cis of FGFR3 S249C and V553L mutations from MR406 tissue biopsy.
Figure 1 from Resistance to Selective FGFR Inhibitors in FGFR-Driven Urothelial Cancer
Authors: Facchinetti Francesco , Hollebecque Antoine , Braye Floriane , Vasseur Damien , Pradat Yoann , Bahleda Rastislav , Pobel Cédric , Bigot Ludovic , Déas Olivier , Florez Arango Juan David , Guaitoli Giorgia , Mizuta Hayato , Combarel David , Tselikas Lambros , Michiels Stefan , Nikolaev Sergey I. , Scoazec Jean-Yves , Ponce-Aix Santiago , Besse Benjamin , Olaussen Ken A. , Loriot Yohann , Friboulet Luc
Published: September 2023

Mutational landscape of urothelial cancers included in MATCH-R or MOSCATO studies, with WES ± RNA-seq performed. CNV, copy-number variation; INDEL, insertion/deletion; mut/Mb, mutations per megabase; SNP, single-nucleotide polymorphism; TMB, tumor mutation burden.
Data from FH Variant Pathogenicity Promotes Purine Salvage Pathway Dependence in Kidney Cancer
Authors: Wilde Blake R. , Chakraborty Nishma , Matulionis Nedas , Hernandez Stephanie , Ueno Daiki , Gee Michayla E. , Esplin Edward D. , Ouyang Karen , Nykamp Keith , Shuch Brian , Christofk Heather R.
Published: September 2023

Abstract
Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive, which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest the pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.
Significance:
This study functionally characterizes patient-associated FH variants with unknown significance for pathogenicity. This study also reveals nucleotide salvage pathways as a targetable feature of FH-deficient cancers, which are shown to be sensitive to the purine salvage pathway inhibitor 6-mercaptopurine. This presents a new rapidly translatable treatment strategy for FH-deficient cancers.

This article is featured in Selected Articles from This Issue, p. 1949
Data from A novel type of monocytic leukemia stem cell revealed by the clinical use of venetoclax-based therapy
Authors: Pei Shanshan , Shelton Ian T. , Gillen Austin E. , Stevens Brett M. , Gasparetto Maura , Wang Yanan , Liu Lina , Liu Jun , Brunetti Tonya M. , Engel Krysta , Staggs Sarah , Showers William , Sheth Anagha Inguva. , Amaya Maria L. , Minhajuddin Mohammad , Winters Amanda , Patel Sweta B. , Tolison Hunter , Krug Anna E. , Young Tracy N. , Schowinsky Jeffrey , McMahon Christine M. , Smith Clayton A. , Pollyea Daniel A. , Jordan Craig T.
Published: September 2023

Abstract
The BCL-2 inhibitor venetoclax has recently emerged as an important component of acute myeloid leukemia (AML) therapy. Notably, use of this agent has revealed a previously unrecognized form of pathogenesis characterized by monocytic disease progression. We demonstrate that this form of disease arises from a fundamentally different type of leukemia stem cell (LSC), which we designate as monocytic LSC (m-LSC), that is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC). The m-LSC is distinguished by a unique immunophenotype (CD34-, CD4+, CD11b-, CD14-, CD36-), unique transcriptional state, reliance on purine metabolism, and selective sensitivity to cladribine. Critically, in some instances m-LSC and p-LSC subtypes can co-reside in the same AML patient and simultaneously contribute to overall tumor biology. Thus, our findings demonstrate that LSC heterogeneity has direct clinical significance and highlights the need to distinguish and target m-LSCs as a means to improve clinical outcomes with venetoclax-based regimens.