bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

ABSTRACT
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

ABSTRACT
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

Abstract

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

Abstract
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

Abstract
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

Abstract
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.