bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of divertor heat flux distribution with an island divertor configuration on the J-TEXT tokamak
Authors: YANG 杨 Yutong 雨桐 , LIANG 梁 Yunfeng 云峰 , YAN 严 Wei 伟 , SHU 舒 Shuangbao 双宝 , HUA 华 Jiankun 建坤 , ZHOU 周 Song 松 , YANG 杨 Qinghu 庆虎 , GUO 郭 Jinlong 金龙 , JIN 金 Ziyang 子阳 , (谢伟) Wei XIE , Team the J-TEXT
Published: July 2024

On J-TEXT, the temporal evolution of heat flux distribution on the high-field side (HFS) divertor plate has been measured by an infrared (IR) camera during the plasma operation with an island divertor configuration. In experiments, the island divertor configuration is an edge magnetic island chain structure surrounded by stochastic layers, which can be induced by resonant magnetic perturbations (RMPs). The experimental results show that the heat flux distribution on the HFS target plate depends significantly on the edge magnetic topology. Furthermore, the impact of hydrogen fueling using supersonic molecular beam injection (SMBI) on the divertor heat flux distributions is studied on J-TEXT with an island divertor configuration. It has been observed that power detachment can be achieved when the radiation front approaches the last closed flux surface (LCFS) after each SMBI pulse. This result may provide a method of access for divertor detachment on a fusion device with a three-dimensional (3D) boundary magnetic structure.
A novel SiC VD-MOSFET with optimized P-type shielding structure in JFET region for improved short circuit robustness
Authors: Guo Zhijia , Zhai Dongyuan , Lu Jiwu , Tu Chunming
Published: July 2024

This paper investigates the short-circuit characteristics of Silicon Carbide (SiC) Vertical Double-Implanted Metal-Oxide-Semiconductor Field-Effect Transistor (VD-MOSFET) utilizing TCAD tools. Expanding upon the conventional VD-MOSFET structure, a novel 900 V SiC VD-MOSFET with two P-type shielding layers introduced in JFET region (PW-MOSFET), is proposed and designed. In contrast to the traditional VD-MOSFET, PW-MOSFET not only significantly improves short-circuit (SC) reliability but also optimizes static performance. Simulation results reveal that PW-MOSFET demonstrates notably superior SC performance at a DC link voltage of 600 V compared to the traditional VDMOSFET, with a 63% increase in Short-Circuit Withstand Time (SCWT) and a 25% enhancement in Baliga Figure of Merit (FOM). The key factor contributing to this performance enhancement is attributed to the advantageous role of the P-type shielding layers, facilitating adjustments in the current flow path, thereby suppressing saturation current and enhancing the reliability of short-circuit events. Furthermore, the issue of increased characteristic on-state resistance (Ron,sp) resulting from the introduction of the P-type shielding layers is addressed by augmenting the doping concentration in the JFET region.
SAMP Rao algorithm based minimization of the roughness of milled surface of Ti-6Al-4V
Authors: Sahu Neelesh Kumar , Patel Ruchi , Verma Ashok Kumar , Khaparkar Shailesh
Published: July 2024

In order to solve optimization problems including machining responses as objectives, this study suggests a parameter-less method called the self-adaptive multi population (SAMP) Rao algorithm that does not rely on metaphors. When machining titanium alloys, achieving a good surface quality is a difficult process. In the current study, an effort has been made to reduce surface roughness during milling Ti-6Al-4V. Response surface methodology (RSM) was used in the experiment design to create a model for surface roughness using cutting parameters as variables. The developed model was tested in additional tests in addition to the primary experiments. It was shown that cutter speed and feed rate had the biggest effects on milled roughness, whereas depth of cut had very little of an impact. The model’s quality is demonstrated by the correlation coefficient (R2) 98%, which indicates that the model can explain 98% of the data. Later, a response surface-based desirability technique was used to minimize roughness of milled surface. The outcome of the proposed algorithm is compared with RSM optimizer. It has been noted that the outcomes achieved with the SAMP approach are more advantageous than RSM approach and found 18% minimum value of roughness of milled surface. Main reason to get better result in case of SAMP Rao algorithm is that it is based on the iterative search process with random values of cutting parameters with in defined range. SAMP Rao Algorithm provides cutting settings of 133.5 m min−1, 0.13 mm/tooth feed rate, and 2.06 mm of milling depth along with a minimal roughness of milled surface of 0.37 μm.
Automating the discovery of partial differential equations in dynamical systems
Authors: Li Weizhen , Carvalho Rui
Published: July 2024

Identifying partial differential equations (PDEs) from data is crucial for understanding the governing mechanisms of natural phenomena, yet it remains a challenging task. We present an extension to the ARGOS framework, ARGOS-RAL, which leverages sparse regression with the recurrent adaptive lasso to identify PDEs from limited prior knowledge automatically. Our method automates calculating partial derivatives, constructing a candidate library, and estimating a sparse model. We rigorously evaluate the performance of ARGOS-RAL in identifying canonical PDEs under various noise levels and sample sizes, demonstrating its robustness in handling noisy and non-uniformly distributed data. We also test the algorithm’s performance on datasets consisting solely of random noise to simulate scenarios with severely compromised data quality. Our results show that ARGOS-RAL effectively and reliably identifies the underlying PDEs from data, outperforming the sequential threshold ridge regression method in most cases. We highlight the potential of combining statistical methods, machine learning, and dynamical systems theory to automatically discover governing equations from collected data, streamlining the scientific modeling process.
On the cohomology of 𝑝-adic analytic spaces, I: The basic comparison theorem
Authors: Colmez Pierre , Nizioł Wiesława
Published: July 2024

The purpose of this paper is to prove a basic

p
p

-adic comparison theorem for smooth rigid analytic and dagger varieties over the algebraic closure

C
C

of a

p
p

-adic field:

p
p

-adic pro-étale cohomology, in a stable range, can be expressed as a filtered Frobenius eigenspace of de Rham cohomology (over

B

dR

+

{\mathbf B}^+_{\operatorname {dR} }

). The key computation is the passage from absolute crystalline cohomology to Hyodo–Kato cohomology and the construction of the related Hyodo–Kato isomorphism. We also “geometrize” our comparison theorem by turning

p
p

-adic pro-étale and syntomic cohomologies into sheaves on the category

P
e
r
f

C

{\mathrm {Perf}}_C

of perfectoid spaces over

C
C

and the period morphisms into maps between such sheaves (this geometrization will be crucial in our study of the

C

s
t

C_{\mathrm {st}}

-conjecture in the sequel to this paper and in the formulation of duality for geometric

p
p

-adic pro-étale cohomology).
Introduction: Nobody Understands Quantum Mechanics
Authors: Stuckey W M , Silberstein Michael , McDevitt Timothy
Published: July 2024

Chapter 1 points out that the mystery of entanglement has led Physics Nobel Laureates to claim “nobody understands quantum mechanics.” The Chapter goes on to introduce: the EPR and EPR–Bell paradoxes, various attempts to resolve them, our proposed resolution whereby the relativity principle (no preferred reference frame, NPRF) justifies the Planck postulate (NPRF + h) exactly like the relativity principle justifies the light postulate (NPRF + c), the Planck postulate as a result of Information Invariance & Continuity from quantum information theory, the importance of the relativity principle, subjective versus objective spacetime models of reality, spacelike and timelike relations in spacetime, and four experiments leading to our Poincaré symmetric ontology.
The Mystery: Mermin’s Device
Authors: Stuckey W M , Silberstein Michael , McDevitt Timothy
Published: July 2024

Chapter 2 reviews Mermin’s presentation of the mystery of entanglement for the general reader with its simple Bell inequality violation by QM. Chapter 2 goes on to introduce spin angular momentum, the Planck-Einstein relation, and Mermin’s challenge, i.e., Mermin’s call for an explanation of entanglement for the general reader that does not violate local causality or statistical independence.
A Precedent: Special Relativity
Authors: Stuckey W M , Silberstein Michael , McDevitt Timothy
Published: July 2024

Chapter 4 briefly reviews the history of special relativity, including FitzGerald–Lorentz (or length) contraction, the light postulate, aether theory, emission theory, the speed of light from Maxwell’s equations, the Michelson–Morley experiment, and wave interference.
Einstein’s Principle or Reichenbach’s?
Authors: Stuckey W M , Silberstein Michael , McDevitt Timothy
Published: July 2024

Chapter 5 presents the constructive bias associated with Newtonian mechanics. Since Newtonian mechanics follows from QM (h goes to zero) and SR (c goes to infinity), which are both principle theories based on NPRF, we argue the constructive bias is ill-founded. In QM the constructive bias is reflected by Reichenbach’s Principle applied to the Bell state correlations, i.e., Bell state correlations should be explained causally. Zigzag or co-causation as an alternative associated with all-at-once retrocausality using colliders is introduced and dismissed using an analogy with SR.
Schrodinger’s Cat and Wigner’s Friend
Authors: Stuckey W M , Silberstein Michael , McDevitt Timothy
Published: July 2024

In Sub-Chapter 9D we present Schrödingerös Cat and Wigner’s Friend showing how the assumptions leading to the absurdity or contradiction are nonstarters on our view. Whenever one does measure a variable for some quantum, the outcome will become part of the self-consistent, shared information between observers satisfying intersubjective agreement on the model. The new scientific worldview given by our constraint-based, principle account of quantum mechanics guarantees it.
Line-field confocal optical coherence tomography for the differential diagnosis of porokeratosis from clinical mimickers: a preliminary study
Authors: Tognetti Linda , Cappilli Simone , Falcinelli Francesca , Soglia Simone , Lacarrubba Francesco , Maione Vincenzo , Ricci Costantino , Suppa Mariano , Venturini Marina , Cinotti Elisa , Di Stefani Alessandro , Perrot Jean Luc , Rubegni Pietro
Published: July 2024

Background

Porokeratosis variants are relatively rare and can be clinically misdiagnosed with several common papulokeratotic mimickers. Line-field confocal optical coherence tomography (LC-OCT) is a new technology able to explore the skin in vivo up to a depth of 500 µm.

Objectives

To investigate the role of LC-OCT in the diagnosis of many porokeratosis variants in a preliminary study.

Method

In total, 130 LC-OCT images were obtained from 98 patients, 45 affected by a porokeratosis variant (69 images) and 53 with a mimicker condition (61 images).

Results

We found almost perfect interobserver agreement for LC-OCT image interpretation and perfect correspondence with the findings from histological slides. In addition, a series of morphological in vivo and three-dimensional features related to the cornoid lamella were detected by LC-OCT that were not visible from the histology.

Conclusions

This device can be proposed to assist with rapid bedside noninvasive differentiation of porokeratosis variants from their mimickers, possibly sparing incisional biopsy in patients where the diagnosis is uncertain.
Aging and chronic kidney disease: epidemiology, therapy, management and the role of immunity
Authors: Tang Yukun , Jiang Jipin , Zhao Yuanyuan , Du Dunfeng
Published: July 2024

Chronic kidney disease (CKD) is now an unquestionable progressive condition that affects more than 10% of the general population worldwide, and has emerged as one of the most important causes of global mortality. It is clear that the prevalence of CKD among the aging population is significantly elevated. It involves a broad range of complex and poorly understood concerns in older adults such as frailty, malnutrition, sarcopenia, and even cognitive and mental dysfunction. In kidneys, renal function such as glomerular filtration, urine concentration and dilution, and homeostasis of sodium and potassium, can be influenced by the aging process. In addition, it is worth noting that CKD and end-stage kidney disease patients often have accompanying activation of immune system and inflammation, involving both the innate and adaptive immune system. Based on this background, in this review article we attempt to summarize the epidemiological characteristics of CKD in the aging population, discuss the immunological mechanisms in aging-related CKD, and furnish the reader with processes for the therapy and management of elderly patients with CKD.
Cardiac remodelling during pregnancy in women with congenital heart disease and systemic left ventricle
Authors: Egbe Alexander C , Miranda William R , Jain C Charles , Burchill Luke J , Young Kathleen A , Rose Carl H , Karnakoti Snigdha , Ahmed Marwan H , Connolly Heidi M
Published: July 2024

Aims

Women with congenital heart disease (CHD) are at risk of pregnancy-related adverse outcomes (PRAO). The purpose of this study was to assess temporal changes in cardiac structure and function (cardiac remodelling) during pregnancy, and the association with PRAO in women with CHD.

Methods and results

Retrospective study of pregnant women with CHD and serial echocardiograms (2003–2021). Cardiac structure and function were assessed at pre-specified time points: prepregnancy, early pregnancy, late pregnancy, and postnatal period. PRAO was defined as the composite of maternal cardiovascular, obstetric, and neonatal complications. The study comprised 81 women with CHD (age, 29 ± 5 years). Compared to the baseline echocardiogram, there was a relative increase in right ventricular systolic pressure (RVSP) (relative change 13 ± 5%, P < 0.001, in early pregnancy; and 18 ± 5%, P < 0.001, in late pregnancy). There was a relative decrease in right ventricle free wall strain (RVFWS) (relative change −11 ± 3%, P < 0.001, in late pregnancy; and −11 ± 4%, P = 0.003, in postnatal period), and a relative decrease in RVFWS/RVSP (relative change, −10 ± 5%, P = 0.02 in early pregnancy, −26 ± 7%, P < 0.001, in late pregnancy, and −14 ± 5%, P < 0.001, in postnatal period). Baseline right ventricular to pulmonary arterial (RV–PA) coupling, and temporal change in RV–PA coupling were associated with PRAO, after adjustment for maternal age and severity of cardiovascular disease.

Conclusion

Women with CHD had a temporal decrease in RV systolic function and RV–PA coupling, and these changes were associated with PRAO. Further studies are required to delineate the aetiology of deterioration in RV–PA coupling during pregnancy, and the long-term implications of right heart dysfunction observed in the postnatal period.
Association of PCSK9 inhibitors with mortality: insights from a retrospective cohort analysis
Authors: Huang Chi-Hsien , Wang Shiow-Ing , Fan Frank S , Lu Hsueh-Ju , Wei James Cheng-Chung
Published: July 2024

Aims

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in reducing cardiovascular events, but their impact on all-cause mortality and medical utilization compared to statins is unclear. This study investigated PCSK9 inhibitor use and its impact on mortality and medical utilization vs. statins, using TriNetX database data with up to 9 years of follow-up.

Methods and results

This retrospective cohort study analysed TriNetX data spanning 1 July 2015, to 31 December 2023, including 79 194 PCSK9 inhibitor users (alirocumab, evolocumab, inclisiran) and 5 437 513 statin users with hyperlipidaemia. The primary outcomes were all-cause mortality and medical utilization, including hospital inpatient services, emergency department visits, critical care, and mechanical ventilation. Propensity score matching showed that PCSK9 inhibitor use was associated with a 28.3% lower risk of all-cause mortality [adjusted hazard ratio (aHR) 0.717, 95% confidence interval (CI): 0.673–0.763] and significant reductions in medical utilization (hospital inpatient services usage: aHR 0.692, 95% CI: 0.664–0.721; emergency department services: aHR 0.756, 95% CI: 0.726–0.788; critical care services: aHR 0.619, 95% CI: 0.578–0.664; and mechanical ventilation: aHR 0.537, 95% CI: 0.484–0.596) compared to statins. These findings were consistent across various demographics and clinical subgroups. The sensitivity analyses supported the robustness of the findings.

Conclusion

PCSK9 inhibitors significantly reduced all-cause mortality and medical utilization compared to statins, suggesting their important role in dyslipidaemia management, particularly for statin-naïve or intolerant patients. Further research, including randomized controlled trials, is needed to confirm these findings and explore the underlying mechanisms.
Segmentation-free measurement of locomotor frequency in Caenorhabditis elegans using image invariants
Authors: Ji Hongfei , Chen Dian , Fang-Yen Christopher
Published: July 2024

An animal's locomotor rate is an important indicator of its motility. In studies of the nematode Caenorhabditis elegans (C. elegans), assays of the frequency of body bending waves have often been used to discern the effects of mutations, drugs, or aging. Traditional manual methods for measuring locomotor frequency are low in throughput and subject to human error. Most current automated methods depend on image segmentation, which requires high image quality and is prone to errors. Here, we describe an algorithm for automated estimation of C. elegans locomotor frequency using image invariants, i.e. shape-based parameters that are independent of object translation, rotation, and scaling. For each video frame, the method calculates a combination of 8 Hu's moment invariants and a set of maximally stable extremal regions (MSER) invariants. The algorithm then calculates the locomotor frequency by computing the autocorrelation of the time sequence of the invariant ensemble. Results of our method show excellent agreement with manual or segmentation-based results over a wide range of frequencies. We show that compared to a segmentation-based method that analyzes a worm's shape and a method based on video covariance, our technique is more robust to low image quality and background noise. We demonstrate the system's capabilities by testing the effects of serotonin and serotonin pathway mutations on C. elegans locomotor frequency.
Report on the Academic Round Table, 30 April 2024, New York City: Freedom of Online Communication Across Transatlantic Borders
Authors: Ollig Christian
Published: July 2024

The Alexander von Humboldt Institute for Internet and Society (HIIG), the Leibniz Institute for Media Research | Hans Bredow Institute (HBI), the Columbia Global Freedom of Expression and the UNESCO Chair on Freedom of Communication and Information co-hosted an academic workshop in New York City on 30 April 2024. European and US experts examined the current state of freedom of expression on digital platforms on both sides of the Atlantic. The round table took place as part of the Year of Science 2024 in Germany. To celebrate the 75th anniversary of the German Basic Law (‘Grundgesetz’), this Year of Science has ‘Freedom’ as its central theme. This provided an excellent opportunity to examine the various understandings of freedom as it relates to communication rights and free speech between the US and Europe. The full extent of mutual learning opportunities remains untapped, and the practical implications are vast.
Enricommender: Business Intelligence for User Interface Design
Authors: Ciarrone Alexis , Leiva Luis A , Dubiel Mateusz
Published: July 2024

Graphical user interface (GUI) browsing and retrieval tools are becoming essential to interaction design research and practice. These tools allow GUI designers to browse large amounts of data and recover inspiring or relevant designs for their task. Unfortunately, data-driven market analysis or business intelligence (BI) applied to GUIs have mostly been left aside. To address this research gap, we elicit designers’ needs and responses regarding the development of Enricommender, a high-fidelity prototype of a market analysis recommender and reporting system. We identify and discuss key design challenges, as reported by more than 200 real-world designers, as well as their workflows and overall expectations towards such a BI system. Ultimately, this article sets the foundation for developing future GUI-oriented BI applications.

RESEARCH HIGHLIGHTS Insights about ideation and design of graphical user interfaces. Elicited preferences and current practices from 200 real-world designers. A business intelligence prototype for comparative analysis and design recommendations.
Raman spectroscopy as an alternative rapid microbial bioburden test method for continuous, automated detection of contamination in biopharmaceutical drug substance manufacturing
Authors: Masucci Erin M , Hauschild James E , Gisler Helena M , Lester Erin M , Balss Karin M
Published: July 2024

Aims

To investigate an in-line Raman method capable of detecting accidental microbial contamination in pharmaceutical vessels, such as bioreactors producing monoclonal antibodies via cell culture.

Methods and results

The Raman method consists of a multivariate model built from Raman spectra collected in-line during reduced-scale bioreactor batches producing a monoclonal antibody, as well as a reduced-scale process with intentional spiking of representative compendial method microorganisms (n = 4). The orthogonal partial least squares regression discriminant analysis model (OPLS-DA) area under the curve (AUC), specificity and sensitivity were 0.96, 0.99, and 0.95, respectively. Furthermore, the model successfully detected contamination in an accidentally contaminated manufacturing-scale batch. In all cases, the time to detection (TTD) for Raman was superior compared to offline, traditional microbiological culturing.

Conclusions

The Raman OPLS-DA method met acceptance criteria for equivalent decision making to be considered a viable alternative to the compendial method for in-process bioburden testing. The in-line method is automated, non-destructive, and provides a continuous assessment of bioburden compared to an offline compendial method, which is manual, results in loss of product, and in practice is only collected once daily and requires 3–5 days for enumeration.
Prevalence and characteristics of postoperative and nonoperative chronic hypoparathyroidism in Japan: a nationwide retrospective analysis
Authors: Hasegawa Miyuki , Sakakibara Yuko , Takeuchi Yasuhiro , Sugitani Iwao , Ozono Keiichi , Castriota Felicia , Ayodele Olulade , Sakaguchi Motonobu
Published: July 2024

Hypoparathyroidism is a rare endocrine disorder characterized by low serum calcium and elevated serum phosphorus levels. Patients who do not recover parathyroid function after surgeries or have nonsurgical causes involving congenital and metabolic diseases, require long-term use of active vitamin D and calcium supplementation as conventional therapy in Japan. This study aimed to estimate prevalence of chronic hypoparathyroidism and investigate its disease etiology, patient characteristics, and treatment in Japan, using a health insurance claim database. Individuals who were available in the 4-yr observation period spanning 2015–2018 (2015–2017 for look-back and 2018 for prevalence estimation) were eligible for the denominator. Chronic hypoparathyroidism was defined as individuals who had both a record of prescription of conventional therapy for hypoparathyroidism in 2018 and a record of relevant surgery, radiotherapy, or disease at least 6 mo apart. Among the denominator (N = 2 241 717), 509 patients with chronic hypoparathyroidism were identified (mean age of 49 yr). The standardized prevalence of chronic hypoparathyroidism in 2018 was 38.3 (95% CI: 33.4–43.6) per 100 000 individuals, with 37.0 (32.2–42.3) and 1.2 (0.8–2.0) per 100 000 for postoperative and nonoperative causes, respectively. Six percent of the patients had chronic kidney disease as a comorbidity. Chronic hypoparathyroidism had heterogenous causes, with thyroid malignancy and 22q11.2 deletion syndrome being the most common postoperative and nonoperative causes, respectively. The mean duration of prescribed vitamin D and calcium was 963 and 629 d, respectively, during the 4-yr period. The prevalence of chronic hypoparathyroidism was similar but slightly higher than estimates reported for the United States and Europe, which may be due to the differences in study designs and high healthcare accessibility in Japan. Our study suggests that there is a nonnegligible number of patients, ~48 500 patients, with chronic hypoparathyroidism in Japan.
Cycles in Epilepsy
Authors: Baud Maxime O. , Rao Vikram R. , Bernard Christophe , Karoly Philippa J.
Published: July 2024

Epilepsy is among the most dynamic disorders in neurology. A canonical view holds that seizures, the characteristic sign of epilepsy, occur at random, but for centuries humans have looked for patterns of temporal organization in seizure occurrence. Observations that seizures are cyclical date back to antiquity, but recent technological advances have, for the first time, enabled cycles of seizure occurrence to be quantitatively characterized with direct brain recordings. Chronic recordings of brain activity in humans and in animals have yielded converging evidence for the existence of cycles of epileptic brain activity that operate over diverse timescales: daily (circadian), multiday (multidien), and yearly (circannual). This chapter reviews this evidence, synthesizing data from historical observational studies, modern implanted devices, electronic seizure diaries, and laboratory-based animal neurophysiology. The chapter discusses advances in our understanding of the mechanistic underpinnings of these cycles and highlights the knowledge gaps that remain. The potential clinical applications of a knowledge of cycles in epilepsy, including seizure forecasting and chronotherapy, are discussed in the context of the emerging concept of seizure risk. In essence, this review addresses the broad question of why seizures occur when they occur.
Genetic and Imaging Biomarkers of Epileptogenesis
Authors: Koepp Matthias J. , Balestrini Simona , Dedeurwaerdere Stefanie , Theodore William H.
Published: July 2024

A biomarker is a measurable characteristic or indicator of normal biologic or pathogenic processes. Biomarkers are needed to (1) identify individuals who have the highest risk of developing epilepsy after an epileptogenic insult (susceptibility/risk biomarkers), (2) improve early diagnosis, possibly even during the presymptomatic latency period following an insult (diagnostic biomarkers), (3) characterize the disease course (prognostic biomarkers), and (4) assess disease severity or response to treatment (predictive biomarkers/surrogate endpoints). Attempts to harmonize the methodologies and procedures of biomarker data collection and analysis will increase the statistical power of preclinical and clinical studies. A strategic roadmap is needed for proposing research priorities in biomarker discovery for epileptogenesis, regulatory issues, and optimization of the use of resources, similar to those devised for cancer and Alzheimer disease research. This chapter will discuss potential genetic and molecular imaging biomarkers, with examples for each, emphasizing susceptibility/risk, diagnosis, prognosis, and predictive markers. In the future, pathophysiological knowledge on epileptogenesis will need to be translated from experimental and animal studies into clinical research to provide more insights into the development and progression of symptomatic epilepsy.
Mechanisms of Depression in the Epileptic Brain
Authors: Jones Nigel C. , Maguire Jamie
Published: July 2024

Psychiatric illnesses, including depression and anxiety, are highly comorbid with epilepsy. Although the bidirectional relationship between depression and epilepsy has been acknowledged since at least 400 BCE, the incidence and impact of comorbid epilepsy and depression have only been brought to light over the past 20 years, and the mechanisms mediating this comorbidity are just beginning to be explored. This chapter will provide a comprehensive overview of what we know as a field regarding the comorbidity of depression and epilepsy. It will also provide a current assessment of potential mechanisms contributing to this comorbidity.
Genetic and Cellular Mechanisms Underlying SUDEP Risk
Authors: Noebels Jeffrey L.
Published: July 2024

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality among young adults with refractory seizures. A sharp increase in clinical and forensic awareness over the last decade has accelerated the search to identify predictive risk biomarkers, clarify underlying cellular mechanisms, and develop effective interventions. In monitored nocturnal cases, available evidence points to a consistent pattern of postictal bradycardia with rapid collapse of brainstem cardiorespiratory pacemaking within minutes following termination of a generalized tonic-clonic seizure. Single gene discovery leading to SUDEP phenotypes in humans and mouse models now promises to speed the validation of candidate SUDEP genetic biomarkers and pinpoint malignant cellular excitability defects. The diverse biology and shared expression in brainstem pathways delineate distinct survival trajectories and molecular targets to mitigate SUDEP risk. Conditional deletion models confirm that SUDEP is a neurogenic, not cardiogenic, event and that brainstem involvement is both necessary and sufficient. SUDEP gene mutations lower the threshold for spreading depolarization (SD), a slow, self-regenerative pathological wave that silences neurons in critical brainstem networks. SD can occur independently of seizures, but can also be tightly coupled to their co-occurrence, offering molecular insight into a latent excitability threshold mechanism, a “second hit” that can explain why only some tonic-clonic seizures are lethal. While the role of brainstem SD awaits human confirmation, gene mutations that lower SD threshold in mice are found in clinical populations with elevated SUDEP risk. More research on modulating brainstem SD threshold could lead to lifesaving interventions in individuals at risk.
Animal Models of Pharmacoresistant Epilepsy
Authors: Guignet Michelle , Steve White H.
Published: July 2024

Recognizing the pressing need for better treatment options for pharmacoresistant patients with epilepsy, collaborative efforts among the NINDS Epilepsy Therapy Screening Program, the pharmaceutical industry, and academia have focused on the inclusion of therapy-resistant animal models for the screening and characterization of novel compounds that offer more effective seizure control for a difficult-to-treat population. This chapter discusses the role of the 6 Hz psychomotor seizure model, the lamotrigine- and phenytoin-resistant kindled rodent models of focal epilepsy, and the post–status epilepticus models of spontaneous recurring seizures in the antiseizure drug discovery process. While each of these models reproduces some aspects of the pathological, behavioral, and pharmacological characteristics of pharmacoresistant seizures in humans, their clinical validity has yet to be established. However, the approval of cenobamate (CBM) in 2019, an ASD with remarkable clinical efficacy (~20% seizure freedom) and profound preclinical efficacy in the 6 Hz test, opens the door to reevaluate these animal seizure models with renewed hope and optimism. While it would have been premature to speculate on the predictive clinical efficacy of CBM based on only the 6 Hz test, it does provide hope that existing animal models can identify new drugs and potentially change the landscape for pharmacoresistance in the future.
Excitatory Transmission in Status Epilepticus
Authors: Joshi Suchitra , Kapur Jaideep
Published: July 2024

Prolonged, self-sustaining seizures that can cause neuronal injury and respiratory compromise are called status epilepticus (SE). SE is a dynamic condition where drug responsiveness, electroencephalography, active neuronal circuits, and synapses change over time, which has prompted division into early, established, and refractory stages. As SE evolves, the neuronal circuits generating seizures also change dynamically, engaging more structures. We review the role of excitatory transmission in generating and sustaining SE. Organophosphates precipitate SE by enhancing glutamate release from the presynaptic terminals. GABAergic inhibition fails in the early stages of SE, especially in the hippocampus, and then the glutamatergic transmission is potentiated during established SE. AMPA receptor-mediated excitation increases due to the insertion of the GluA1 subunit into synaptic receptors. NMDA receptor-mediated excitation is enhanced, and blocking this receptor can prevent reduced GABAergic inhibition and enhanced glutamatergic transmission. These studies form the basis for clinical trials to treat SE with NMDA receptor antagonist ketamine and AMPA receptor antagonist perampanel.
The H i covering fraction of Lyman Limit Systems in FIRE haloes
Authors: Tortora Lucas , Feldmann Robert , Bernardini Mauro , Faucher-Giguère Claude-André
Published: July 2024

Atomic hydrogen (H i) serves a crucial role in connecting galactic-scale properties such as star formation with the large-scale structure of the Universe. While recent numerical simulations have successfully matched the observed covering fraction of H i near Lyman Break Galaxies (LBGs) and in the foreground of luminous quasars at redshifts $z \lesssim 3$, the low-mass end remains as-of-yet unexplored in observational and computational surveys. We employ a cosmological, hydrodynamical simulation (FIREbox) supplemented with zoom-in simulations (MassiveFIRE) from the Feedback In Realistic Environments (FIRE) project to investigate the H i covering fraction of Lyman Limit Systems ($N_{{\text{H}}\, \rm{{\small I}}} \gtrsim 10^{17.2}$ cm$^{-2}$) across a wide range of redshifts ($z=0-6$) and halo masses ($10^8-10^{13} \, \,\mathrm{ M}_{\odot }$ at $z=0$, $10^8-10^{11}\, \,\mathrm{ M}_{\odot }$ at $z=6$) in the absence of feedback from active galactic nuclei. We find that the covering fraction inside haloes exhibits a strong increase with redshift, with only a weak dependence on halo mass for higher mass haloes. For massive haloes ($M_{\mathrm{vir}} \sim 10^{11}-10^{12} \,\mathrm{ M}_{\odot }$), the radial profiles showcase scale-invariance and remain independent of mass. The radial dependence is well captured by a fitting function. The covering fractions in our simulations are in good agreement with measurements of the covering fraction in LBGs. Our comprehensive analysis unveils a complex dependence with redshift and halo mass for haloes with $M_{\mathrm{vir}} \lesssim 10^{10} \,\mathrm{ M}_{\odot }$ that future observations aim to constrain, providing key insights into the physics of structure formation and gas assembly.
radiosed – I. Bayesian inference of radio SEDs from inhomogeneous surveys
Authors: Kerrison Emily F , Allison James R , Moss Vanessa A , Sadler Elaine M , Rees Glen A
Published: July 2024

We present here radiosed, a Bayesian inference framework tailored to modelling and classifying broad-band radio spectral energy distributions (SEDs) using only data from publicly released, large-area surveys. We outline the functionality of radiosed, with its focus on broad-band radio emissions that can trace kiloparsec-scale absorption within both the radio jets and the circumgalactic medium of active galactic nuclei (AGN). In particular, we discuss the capability of radiosed to advance our understanding of AGN physics and composition within youngest and most compact sources, for which high-resolution imaging is often unavailable. These young radio AGN typically manifest as peaked spectrum sources that, before radiosed, were difficult to identify owing to the large, broad-band frequency coverage typically required, and yet they provide an invaluable environment for understanding AGN evolution and feedback. We discuss the implementation details of radiosed, and we validate our approach against both synthetic and observational data. Since the surveys used are drawn from multiple epochs of observation, we also consider the output from radiosed in the context of AGN variability. Finally, we show that radiosed recovers the expected SED shapes for a selection of well-characterized radio sources from the literature, and we discuss avenues for further study of these and other sources using radio SED fitting as a starting point. The scalability and modularity of this framework make it an exciting tool for multiwavelength astronomers as next-generation telescopes begin several all-sky surveys. Accordingly, we make the code for radiosed, which is written in python, available on GitHub.
Results from a phase I study of 4-
l
-[131I]iodo-phenylalanine ([131I]IPA) with external radiation therapy in patients with recurrent glioblastoma (IPAX-1)
Authors: Pichler Josef , Traub-Weidinger Tatjana , Spiegl Kurt , Imamovic Larisa , Braat Arthur J A T , Snijders Tom J , Verhoeff Joost J C , Flamen Patrick , Tauchmanova Libuse , Hayward Colin , Kluge Andreas
Published: July 2024

Background

Glioblastoma (GBM), the most common malignant brain tumor, is associated with devastating outcomes. IPAX-1 was a multicenter, open-label, single-arm phase I study to evaluate carrier-added 4-L-[131I]iodo-phenylalanine ([131I]IPA) plus external radiation therapy (XRT) in recurrent GBM.

Methods

A total of 10 adults with recurrent GBM who had received first-line debulking surgery plus radio-chemotherapy, were randomized to a single-dose regimen (1f; 131I-IPA 2 GBq before XRT); a fractionated parallel dose regimen (3f-p; 3 131I-IPA 670 MBq fractions, in parallel with second-line XRT), or a fractionated sequential dose regimen (3f-s; 3 131I-IPA 670 MBq fractions before and after XRT). Metabolic tumor responses were determined using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography, while single-photon emission computed tomography was used to guide [131I]IPA tumor dosimetry.

Results

All dose regimens were well tolerated. Organ-absorbed radiation doses in red marrow (0.38 Gy) and kidney (1.28 Gy) confirmed no radiation-based toxicity. Stable disease was observed in 4 of the 9 patients at 3 months post-treatment (3-month follow-up [FU], 1 patient did not reach protocol-mandated end of study), yielding a response rate of 44.4%. At the 3-month FU, 6 patients demonstrated metabolic stable disease. Median progression-free survival was 4.3 months (95% confidence interval [CI]: 3.3–4.5), while median overall survival was 13 months (95% CI: 7.1–27).

Conclusions

Single or fractionated doses of [131I]IPA plus XRT were associated with acceptable tolerability and specific tumor targeting in patients with recurrent GBM, warranting further investigation.
Altering cold-regulated gene expression decouples the salicylic acid–growth trade-off in Arabidopsis
Authors: Ortega María A , Celoy Rhodesia M , Chacon Francisco , Yuan Yinan , Xue Liang-Jiao , Pandey Saurabh P , Drowns MaKenzie R , Kvitko Brian H , Tsai Chung-Jui
Published: July 2024

In Arabidopsis (Arabidopsis thaliana), overproduction of salicylic acid (SA) increases disease resistance and abiotic stress tolerance but penalizes growth. This growth–defense trade-off has hindered the adoption of SA-based disease management strategies in agriculture. However, investigation of how SA inhibits plant growth has been challenging because many SA-hyperaccumulating Arabidopsis mutants have developmental defects due to the pleiotropic effects of the underlying genes. Here, we heterologously expressed a bacterial SA synthase gene in Arabidopsis and observed that elevated SA levels decreased plant growth and reduced the expression of cold-regulated (COR) genes in a dose-dependent manner. Growth suppression was exacerbated at below-ambient temperatures. Severing the SA-responsiveness of individual COR genes was sufficient to overcome the growth inhibition caused by elevated SA at ambient and below-ambient temperatures while preserving disease- and abiotic-stress-related benefits. Our results show the potential of decoupling SA-mediated growth and defense trade-offs for improving crop productivity.
Neuropeptide Y receptor activation preserves inner retinal integrity through PI3K/Akt signaling in a glaucoma mouse model
Authors: Palanivel Viswanthram , Gupta Vivek , Chitranshi Nitin , Tietz Ole , Vander Wall Roshana , Blades Reuben , Maha Thananthirige Kanishka Pushpitha , Salkar Akanksha , Shen Chao , Mirzaei Mehdi , Gupta Veer , Graham Stuart L , Basavarajappa Devaraj
Published: July 2024

Neuropeptide Y (NPY), an endogenous peptide composed of 36 amino acids, has been investigated as a potential therapeutic agent for neurodegenerative diseases due to its neuroprotective attributes. This study investigated the neuroprotective effects of NPY in a mouse model of glaucoma characterized by elevated intraocular pressure (IOP) and progressive retinal ganglion cell degeneration. Elevated IOP in mice was induced through intracameral microbead injections, accompanied by intravitreal administration of NPY peptide. The results demonstrated that NPY treatment preserved both the structural and functional integrity of the inner retina and mitigated axonal damage and degenerative changes in the optic nerve under high IOP conditions. Further, NPY treatment effectively reduced inflammatory glial cell activation, as evidenced by decreased expression of glial fibrillary acidic protein and Iba-1. Notably, endogenous NPY expression and its receptors (NPY-Y1R and NPY-Y4R) levels were negatively affected in the retina under elevated IOP conditions. NPY treatment restored these changes to a significant extent. Molecular analysis revealed that NPY mediates its protective effects through the mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling pathways. These findings highlight the therapeutic potential of NPY in glaucoma treatment, underscoring its capacity to preserve retinal health, modulate receptor expression under stress, reduce neuroinflammation, and impart protection against axonal impairment.
Delineating the shape of COat Protein complex-II coated membrane bud
Authors: Paul Sanjoy , Audhya Anjon , Cui Qiang
Published: July 2024

Curvature-generating proteins that direct membrane trafficking assemble on the surface of lipid bilayers to bud transport intermediates, which move protein and lipid cargoes from one cellular compartment to another. However, it remains unclear what controls the overall shape of the membrane bud once curvature induction has begun. In vitro experiments showed that excessive concentrations of the COPII protein Sar1 promoted the formation of membrane tubules from synthetic vesicles, while COPII-coated transport intermediates in cells are generally more spherical or lobed in shape. To understand the origin of these morphological differences, we employ atomistic, coarse-grained (CG), and continuum mesoscopic simulations of membranes in the presence of multiple curvature-generating proteins. We first characterize the membrane-bending ability of amphipathic peptides derived from the amino terminus of Sar1, as a function of interpeptide angle and concentration using an atomistic bicelle simulation protocol. Then, we employ CG simulations to reveal that Sec23 and Sec24 control the relative spacing between Sar1 protomers and form the inner-coat unit through an attachment with Sar1. Finally, using dynamical triangulated surface simulations based on the Helfrich Hamiltonian, we demonstrate that the uniform distribution of spacer molecules among curvature-generating proteins is crucial to the spherical budding of the membrane. Overall, our analyses suggest a new role for Sec23, Sec24, and cargo proteins in COPII-mediated membrane budding process in which they act as spacers to preserve a dispersed arrangement of Sar1 protomers and help determine the overall shape of the membrane bud.
A Tale of Three Spectra: Basic Symptoms in Clinical-High-Risk of Psychosis Vary Across Autism Spectrum Disorder, Schizotypal Personality Disorder, and Borderline Personality Disorder
Authors: Martin James C , Clark Scott R , Hartmann Simon , Schubert K Oliver
Published: July 2024

Background and Hypothesis

The clinical-high-risk (CHR) approach was developed to prevent psychosis through the detection of psychosis risk. CHR services are transdiagnostic in nature, therefore the appropriate management of comorbidity is a central part of care. Differential diagnosis is particularly challenging across 3 common comorbidities, schizotypal personality disorder (SPD), autism spectrum disorder (ASD), and borderline personality disorder (BPD). Phenomenological research indicates a disturbance of “basic self” may differentiate between these commonly comorbid disorders and can be captured by Huber’s basic symptoms (BS) concept. We investigated whether BS vary across these disorders and may inform differential diagnosis in young person’s meeting CHR criteria.

Study Design

A total of 685 participants meeting CHR criteria from the NAPLS-3 cohort completed the COGDIS items of the schizophrenia proneness instrument, a measure of BS, as well as the structured interview for DSM-5 (SCID-5). A logistic regression model was used to investigate the variation of COGDIS across SPD, ASD, and BPD, while controlling for age and SIPs positive severity.

Study Results

Meeting COGDIS criteria was positively associated with SPD (OR = 1.72, CI = [1.31–2.28], P = .001) but not ASD nor BPD.

Conclusions

Our results indicate that “basic self-disturbance” as indicated by COGDIS differs across SPD, ASD, and BPD. COGDIS may be useful to inform the management of comorbidities in CHR services, by providing insight into subtle subjective experiences that may benefit from disorder-specific interventions.