bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-capillary pulmonary hypertension in heart failure: impact of current definition in the PH-HF multicentre study
Authors: Fauvel Charles , Damy Thibaud , Berthelot Emmanuelle , Bauer Fabrice , Eicher Jean-Christophe , de Groote Pascal , Trochu Jean-Noël , Picard François , Renard Sébastien , Bouvaist Hélène , Logeart Damien , Roubille François , Sitbon Olivier , Lamblin Nicolas
Published: July 2024

Background and Aims

Based on retrospective studies, the 2022 European guidelines changed the definition of post-capillary pulmonary hypertension (pcPH) in heart failure (HF) by lowering the level of mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR). However, the impact of this definition and its prognostic value has never been evaluated prospectively.

Methods

Stable left HF patients with the need for right heart catheterization were enrolled from 2010 to 2018 and prospectively followed up in this multicentre study. The impact of the successive pcPH definitions on pcPH prevalence and subgroup [i.e. isolated (IpcPH) vs. combined pcPH (CpcPH)] was evaluated. Multivariable Cox regression analysis was used to assess the prognostic value of mPAP and PVR on all-cause death or hospitalization for HF (primary outcome).

Results

Included were 662 HF patients were (median age 63 years, 60% male). Lowering mPAP from 25 to 20 mmHg resulted in +10% increase in pcPH prevalence, whereas lowering PVR from 3 to 2 resulted in +60% increase in CpcPH prevalence (with significant net reclassification improvement for the primary outcome). In multivariable analysis, both mPAP and PVR remained associated with the primary outcome [hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.00–1.03, P = .01; HR 1.07, 95% CI 1.00–1.14, P = .03]. The best PVR threshold associated with the primary outcome was around 2.2 WU. Using the 2022 definition, pcPH patients had worse survival compared with HF patients without pcPH (log-rank, P = .02) as well as CpcPH compared with IpcPH (log-rank, P = .003).

Conclusions

This study is the first emphasizing the impact of the new pcPH definition on CpcPH prevalence and validating the prognostic value of mPAP > 20 mmHg and PVR > 2 WU among HF patients.
Expression regulation of type III secretion system 2 in Vibrio parahaemolyticus by catabolite activator protein
Authors: Tanabe Tomotaka , Tsukamoto Mitsuki , Shioda Mahiro , Nagaoka Kenjiro , Funahashi Tatsuya
Published: July 2024

Vibrio parahaemolyticus has two sets of type III secretion systems that are major pathogenic factors: T3SS1 (cytotoxicity) and T3SS2 (enterotoxicity). V. parahaemolyticus mainly colonizes the distal small intestine after oral infection and may be exposed to carbon-limiting stress due to the lack of readily available carbohydrates in this environment. Catabolite activator protein (CAP), a transcription factor involved in carbon-limiting metabolism in many Gram-negative bacteria, is well known to be involved in the regulation of the expression of many virulence factors. In this study, we determined the effects of CAP on the expression of T3SSs in this bacterium. Based on a lactate dehydrogenase-based cytotoxicity assay, CAP was found to have a greater contribution to the expression of T3SS2-dependent cytotoxicity than to that of T3SS1. Reverse transcription quantitative PCR revealed decreased expression of many T3SS2-related genes, including vpa1348, in the cap gene deletion mutant compared to the parent strain. CAP was demonstrated to bind near the T-rich elements within the vpa1348 promoter region in an electrophoretic mobility shift assay and DNase I footprinting. CAP also enhanced the expression of vpa1348 in a β-galactosidase reporter assay. Collectively, these results suggest that CAP is involved in T3SS2-mediated virulence by regulating the expression of vpa1348 in V. parahaemolyticus.
Adaptive genetic mechanisms in mammalian Parp1 locus
Authors: Karpova Yaroslava , Tulin Alexei V
Published: July 2024

Poly(ADP-ribose) polymerase 1 (PARP1) is a highly conserved nuclear protein in multicellular organisms that by modulating chromatin opening facilitates gene expression during development. All reported Parp1 null knockout mouse strains are viable with no developmental anomalies. It was believed that functional redundancy with other PARP family members, mainly PARP2, explains such a controversy. However, while PARP2 has similar catalytic domain to PARP1, it lacks other domains, making the absence of developmental problems in Parp1 mice knockouts unlikely. Contrary to prior assumptions, in our analysis of the best-investigated Parp1 knockout mouse strain, we identified persistent mRNA expression, albeit at reduced levels. Transcript analysis revealed an alternatively spliced Parp1 variant lacking exon 2. Subsequent protein analysis confirmed the existence of a truncated PARP1 protein in knockout mice. The decreased level of poly(ADP-ribose) (pADPr) was detected in Parp1 knockout embryonic stem (ES) cells with western blotting analysis, but immunofluorescence staining did not detect any difference in distribution or level of pADPr in nuclei of knockout ES cells. pADPr level in double Parp1 Parg mutant ES cells greatly exceeded its amount in normal and even in hypomorph Parg mutant ES cells, suggesting the presence of functionally active PARP1. Therefore, our findings challenge the conventional understanding of PARP1 depletion effects.
Scarcity of fixed carbon transfer in a model microbial phototroph–heterotroph interaction
Authors: Dupuis Sunnyjoy , Lingappa Usha F , Mayali Xavier , Sindermann Eve S , Chastain Jordan L , Weber Peter K , Stuart Rhona , Merchant Sabeeha S
Published: July 2024

Although the green alga Chlamydomonas reinhardtii has long served as a reference organism, few studies have interrogated its role as a primary producer in microbial interactions. Here, we quantitatively investigated C. reinhardtii’s capacity to support a heterotrophic microbe using the established coculture system with Mesorhizobium japonicum, a vitamin B12-producing α-proteobacterium. Using stable isotope probing and nanoscale secondary ion mass spectrometry (nanoSIMS), we tracked the flow of photosynthetic fixed carbon and consequent bacterial biomass synthesis under continuous and diurnal light with single-cell resolution. We found that more 13C fixed by the alga was taken up by bacterial cells under continuous light, invalidating the hypothesis that the alga’s fermentative degradation of starch reserves during the night would boost M. japonicum heterotrophy. 15NH4 assimilation rates and changes in cell size revealed that M. japonicum cells reduced new biomass synthesis in coculture with the alga but continued to divide—a hallmark of nutrient limitation often referred to as reductive division. Despite this sign of starvation, the bacterium still synthesized vitamin B12 and supported the growth of a B12-dependent C. reinhardtii mutant. Finally, we showed that bacterial proliferation could be supported solely by the algal lysis that occurred in coculture, highlighting the role of necromass in carbon cycling. Collectively, these results reveal the scarcity of fixed carbon in this microbial trophic relationship (particularly under environmentally relevant light regimes), demonstrate B12 exchange even during bacterial starvation, and underscore the importance of quantitative approaches for assessing metabolic coupling in algal–bacterial interactions.
On farm precision feeding of gestating sows based on energy and amino acids on farrowing performances and feeding behavior over 3 consecutive gestations
Authors: Ribas Clément , Quiniou Nathalie , Gaillard Charlotte
Published: July 2024

Gestating sows are often fed a single diet throughout their gestation cycle, leading to situations of nutrients deficiency or excess at the individual level. The purpose of this study was to characterize, over 3 consecutive cycles, the impact of a precision feeding (PF), i.e., dietary supplies adjusted at individual level in terms of quantity (energy intake) and quality (standardized ileal digestible (SID) lysine (Lys) intake), on gestating sows’ productive performance, feeding behavior, environmental outputs, and health status compared with sows fed a conventional feeding (CF, i.e., fixed SID Lys intake). At the start of the trial, 2 batches of 20 Landrace × Large White gestating sows were allocated to one of the 2 feeding strategies (PF vs. CF), based on their parity (1, 2, or 3 and more), body weight, and backfat thickness (BT) 3 days after insemination. The PF strategy consisted in mixing with automatic feeders 2 iso-energetic diets (9.8 MJ/kg of net energy with 3.3 and 8.5 g SID Lys/kg, respectively) in variable proportions at individual and daily levels, whereas for the CF strategy these proportions remained constant throughout gestation (73% and 27%, respectively, resulting in an SID Lys concentration of 4.7 g/kg). Sows were followed over 3 consecutive gestations and the sows remained allocated to the same strategy throughout the study. Some sows were culled before the end of the study and were replaced by other sows who therefore performed only 1 or 2 gestations during the study. Thus, 106 gestations and lactations from 51 sows were fully studied and their data analyzed. The PF strategy allowed the sows to reach more closely the expected BT values at farrowing across cycles than the CF strategy (P < 0.001). The PF sows consumed 16% less SID Lys per gestation than the CF sows (P < 0.001), resulting in a 4% improvement in N efficiency (P < 0.001), with no impact on performance at farrowing (P > 0.10). The sows consumed their daily ration in a single visit whatever the feeding strategy (P = 0.41), but CF sows spent more time in the feeder in cycles 2 and 3 (P < 0.001). Thus, compared to the CF strategy implemented by farmers, the individual and daily nutritional supplies implemented with the PF strategy were more efficient in enabling sows to achieve body condition objectives at farrowing over the long term, also with a reduced SID Lys intake and an improved N efficiency without negative impact on farrowing performances.
Negative dietary cation and anion difference supplementation of twin-bearing Merino ewes grazing pasture in late gestation did not affect lamb growth or survival
Authors: Munn Amy Laurel , van Wettere William H E J , Swinbourne Alyce Marie , Lean Ian John , Weaver Alice Caroline
Published: July 2024

Each year in Australia, 53% of lamb mortalities are attributed to dystocia, with subclinical maternal calcium deficiencies likely contributing to dystocia rates. A negative dietary cation and anion difference (DCAD) diet has increased circulating calcium in sheep. Therefore, this study aimed to investigate the effects of supplementing twin-bearing, grazing ewes with a negative DCAD partial mixed ration (PMR) during late gestation on ewe calcium and magnesium concentrations and subsequent lamb growth and survival. On day 120 of gestation (dG), blood samples were collected from 115 twin-bearing Merino ewes and analyzed for glucose, ketone bodies, pH, ionized calcium, and serum calcium and magnesium. On dG 130, ewes were moved into lambing paddocks and placed in the following 2 treatment groups; ewes receiving a positive DCAD PMR (DCAD = 287 mEq/kg DM; n = 58) and ewes receiving a negative DCAD PMR (DCAD = −125 mEq/kg DM; n = 57) fed as a PMR. On dG 140, a blood and urine sample were collected. The urine was tested for pH. Pasture samples were taken on dG 133 and 149 and tested for DCAD and mineral content. When a lamb was 6 to 18 h old, survival, vigor score, liveweight (LW), rectal temperature, blood glucose, and body morphology were recorded. At 10 d of age, lamb LW and survival were recorded and a milk sample was collected from ewes. At 44 d of age, lamb LW and survival were recorded. The DCAD of the pastures across the 6 paddocks ranged from 598 to 893 mEq/kg DM. There were no differences in lamb survival, weight, or viability at any timepoint (P > 0.05). There were no differences in mineral status, metabolic state, or acid–base balance between the positive and negative DCAD-supplemented ewes (P > 0.05) during supplementation (dG 140). Supplementing a negative DCAD diet to ewes grazing pasture during late gestation did not improve lamb survival. The blood and urine pH of the negative DCAD-supplemented ewes indicated a mild metabolic acidosis was not reached due to the high DCAD of the pastures. Further research needs to take careful consideration of the DCAD of pasture when designing a negative DCAD supplement in order for it to be effective.
Effects of maternal inflammation on growth performance, carcass characteristics, and meat quality of offspring pigs
Authors: Johnson Danielle C , Bryan Erin E , Burris Elli S , Dilger Ryan N , Harsh Bailey N , Dilger Anna C
Published: July 2024

The objective of this research was to determine the effects of mid-gestational maternal inflammation on performance, carcass characteristics, and meat quality of offspring. Pregnant gilts were administered either lipopolysaccharide (LPS; n = 7) or saline (CON, n = 7) from days 70 to 84 of gestation. Gilts assigned to the LPS treatment were administered an intravenous injection of reconstituted LPS every other day with a beginning dose of 10 μg LPS/kg body weight and subsequent doses increasing by 12%, while CON gilts received intravenous injections of comparable volumes of saline. Gilts farrowed naturally, and at day 66 of age, a total of 59 pigs, both barrows and gilts began a 3-phase feeding regimen designed to meet or exceed nutrient requirements for growing-finishing pigs. Pigs were weighed on days 0, 35, 70, and 105 of the finishing trial to determine average daily gain, average daily feed intake, and gain-to-feed ratio (G:F). On day 106, pigs were slaughtered under the supervision of the U.S. Department of Agriculture Food Safety Inspection Service. Ending live weight, hot carcass weight, and dressing percentage were determined. The left side of carcasses was weighed and fabricated to determine carcass cutting yields. The semitendinosus was collected for histological samples. Fresh belly characteristics and loin quality were measured. Two chops were collected for Warner–Bratzler shear force and proximate analysis. No differences (P ≥ 0.13) between LPS and CON pigs were observed for growth performance in phases 1, 2, 3, or overall (days 0 to 105) performance with the exception of overall G:F reduced in CON pigs compared with LPS pigs (P = 0.03). There was a tendency for carcass yield to be reduced (P = 0.06; 0.82% units) in LPS pigs compared with CON pigs. Additionally, longissimus muscle area tended to be reduced (P = 0.10) 2.27 cm2 in LPS compared with CON pigs. Loin chop quality traits including instrumental color, subjective color, marbling, firmness, pH, and drip loss were not different (P ≥ 0.09) between LPS and CON pigs. Fresh belly characteristics were not different (P ≥ 0.22) between LPS and CON pigs. There were no differences in primal and subprimal weights, except that LPS pigs tended to have a reduction (P ≥ 0.07) in tenderloin and Canadian back weights compared with CON pigs. Furthermore, LPS pigs had no differences (P ≥ 0.25) in muscle fiber composition or size; however, LPS pigs tended (P = 0.10) to have a 13% reduction in estimated muscle fibers number compared with CON pigs. In summary, mid-gestational inflammation did not result in reduced meat quality, growth performance, or carcass yields of offspring.
Habitat integrity and interspecific relationships affect the diversity of freshwater crabs (Decapoda: Brachyura: Pseudothelphusidae, Trichodactylidae) in eastern Amazon streams
Authors: Rivera-Pérez Juan Mateo , Cruz Gabriel Martins , Penha Izabella Cristina da Silva , Juen Leandro
Published: July 2024

Freshwater crabs play a crucial role in aquatic ecosystems by contributing to decomposition of organic matter and facilitating energy flow in food webs. They also serve as sensitive indicators of habitat modification, pollution, and other anthropogenic activities. We assessed the relationship between the integrity of Amazonian stream habitats and the abundance and interspecific competition among species of freshwater crab species in Pará, Brazil. Our findings, based on surveys across 35 streams of varying habitat integrity and employing generalized linear models for data analysis, revealed that the loss of riparian vegetation and increased streambank erosion negatively impacted the abundance of freshwater crabs of the family Trichodactylidae. Interactions between species also influenced the abundance of species of Pseudothelphusidae and Trichodactylidae, where their co-occurrence in the streams was analyzed. Our findings underscore the importance of understanding how environmental changes affect the diversity of freshwater crabs and that such changes can be valuable in identifying and mitigating long-term environmental impacts on streams.
Exploring the efficacy of pyrethroid incorporated nets for the control of stored product moth species: immediate and delayed effects onEphestia kuehniellaandPlodia interpunctella(Lepidoptera: Pyralidae)
Authors: Altunç Yunus Emre , Sakka Maria K , Gourgouta Marina , Morrison William R , Güncan Ali , Athanassiou Christos G
Published: July 2024

Insect pests pose a significant threat to stored commodities, necessitating the exploration of alternative pest management strategies. Long-lasting insecticide-incorporated nets (LLINs) have emerged as a promising tool, offering selectivity and reduced ecological impact compared to conventional chemical approaches. However, their efficacy against Ephestia kuehniella Zeller and Plodia interpunctella (Hübner) (Lepidoptera: Pyralidae), cosmopolitan stored product moth species, has remained underexplored. This study investigated the immediate and delayed effects of 2 commercial pyrethroid-incorporated nets, Carifend (0.34% α-cypermethrin) and D-Terrence (0.4% deltamethrin), on the adult and larval stages. Both LLINs demonstrated high efficacy in controlling E. kuehniella and P. interpunctella, with mortality rates reaching up to 100% depending on exposure and post-exposure durations. Particularly, rapid knockdown was observed with D-Terrence net inducing 100% of adults in P. interpunctella after 30 min exposure. LLINs achieved almost 100% immediate mortality rate against adults after just 1 day of exposure. In addition, immediate rates of affected individuals reached as high as 81% and 91% in E. kuehniella and P. interpunctella larvae, respectively, following just 5 h of exposure to the D-Terrence. Different responses were observed between the adult and larval stages, with larvae exhibiting higher tolerance and potential for recovery from the affected phase after short exposures. There were increasing mortality rates after greater exposure to LLIN. Findings highlight the potential of LLINs as a pest management tool in storage facilities against these important stored product moths. Understanding the responses between life stages and the significance of delayed effects is crucial for optimizing LLIN deployment strategies.
Towards a polarized semantics for assertion and denial
Authors: Carrara Massimiliano , Chiffi Daniele , De Florio Ciro
Published: July 2024

Recent logic and linguistic literature suggest that certain forms of denial cannot be reduced to a simple assertion of negation. In particular, the existence of mathematical and empirical conjectures offers a basis for refuting Frege’s thesis of equivalence between denial and assertion of negation. Following this line of thought we develop a formal framework with two primitive illocutionary operators for assertion and denial, where denial is not a simple negation of assertion. We introduce a semantics for the operators mentioned above. Finally, we discuss the relations between asserted and denied contents.
Cerebral Cortical Dysplasia or Dysgenesis
Authors: Sarnat Harvey B. , Flores-Sarnat Laura
Published: July 2024

Embryonic and fetal ontogenesis of the central nervous system is realized by genetically programmed developmental processes with precise timing of onset. Both anatomical development and timing are altered in brain malformations. Keratan sulfate (KS) proteoglycan is a key axonal pathfinding guide and insulator of tracts and fascicles within the central nervous system and an essential determinant of the equilibrium of excitation and inhibition at the level of the individual neuron during development. KS is selective by repelling glutamatergic axons and facilitating GABAergic axons at sites of synapse formation. Its demonstration by immunocytochemistry provides another perspective for understanding epileptogenesis at the cellular level in brain resections for epilepsy and at autopsy, including fetal tissues. Examples of malformations in which epileptogenesis is influenced by KS are polymicrogyria, schizencephaly, focal cortical dysplasias, holoprosencephaly, and Down syndrome.
Excitation-Inhibition Balance in Absence Seizure Ictogenesis
Authors: Lőrincz Magor L. , Crunelli Vincenzo , David Francois
Published: July 2024

Thirty percent of children with absence seizures are pharmaco-resistant, and 60% suffer from neuropsychiatric comorbidities that often persist even after full pharmacological control of the seizures. This highlights the need for a detailed comprehension of the cellular and network mechanisms of these nonconvulsive seizures. Generally, network hyperexcitability and hypersynchrony underlying seizure ictogenesis are thought to originate from impaired inhibition or enhanced excitation. In absence seizures, there is a markedly enhanced synchrony in cortico-thalamic and cortico-basal ganglia-thalamic networks, but solid evidence from genetic animal models indicates that at the single-cell and neuronal population levels GABAergic inhibition is generally increased while excitation is mostly either unchanged or decreased. Here, recent results on intrinsic conductances and network mechanisms within cortico-thalamic and cortico-basal ganglia-thalamic circuits are highlighted that support this view.
Adult Neurogenesis in Epileptogenesis and Comorbidities
Authors: Cho Kyung-Ok , Hsieh Jenny
Published: July 2024

Epilepsy is a lifelong, devastating disease that affects all ages. Epileptic seizures generate abnormal adult-born granule cells (abGCs) in the dentate gyrus, which can contribute to the development of epilepsy and comorbidities. In this chapter, we present the characteristic features and potential significance of abGC abnormalities: increased proliferation and subsequent reduction of neural progenitors, persistent hilar basal dendrites, sprouting of mossy fibers, production of hilar ectopic granule cells, and dispersion of granule cells. We also describe several key molecules that regulate seizure-induced aberrant neurogenesis. We then discuss the role of reactive astrocytes and microglia in each step of hippocampal neurogenesis during the epileptogenesis. Finally, we review the crucial findings regarding the functional implications of abnormal abGCs in epileptogenesis and summarize comorbid illnesses such as cognitive impairment and mood disturbances. Seizure-generated abGCs represent an attractive target for treating epilepsy and associated psychiatric dysfunction. Therefore, developing novel and selective antiepileptic drugs will require more basic research on the molecular mechanisms governing aberrant hippocampal neurogenesis, as well as exploiting human and non-human primate models.
Adenosine Kinase
Authors: Murugan Madhuvika , Boison Detlev
Published: July 2024

Adenosine is an endogenous anticonvulsant, which is inversely linked to the expression levels of adenosine kinase (ADK), a ribokinase that metabolizes adenosine into AMP. ADK exists as two distinct isoforms, with unique cellular compartmentalization and functions. The short isoform (ADK-S) is localized primarily in the cytoplasm of astrocytes, where it controls, in conjunction with equilibrative adenosine transporters, the extracellular levels of adenosine and hence adenosine receptor-mediated mechanisms. On the other hand, the long isoform of ADK (ADK-L) is localized in the nucleus of astrocytes and a subset of neurons, where it regulates adenosine receptor independent epigenetic mechanisms. Overexpression of ADK-S was sufficient to generate spontaneous electrographic seizures, whereas increased ADK-L has been associated with epileptogenesis. Hence, targeting specific ADK isoforms is a rational approach for the suppression of seizures and the development of epilepsy. Systemic adenosine augmentation therapies are effective in seizure suppression, although accompanied by widespread cardiovascular side effects. The refinement of therapeutic administration strategies, the development of isoform-specific ADK inhibitors, or a combination of the two, will enable the formulation of more selective therapies for epilepsy and its prevention. Therapeutic tools to achieve focal adenosine augmentation, such as engineered stem cells and silk-based polymers, demonstrate robust protection from induced and spontaneous seizures. Metabolic therapies such as the ketogenic diet therapy have also been indicated to prevent disease progression via epigenetic mechanisms mediated by ADK. Small-molecule, ADK isoform-specific inhibitors are now in development with the goal to translate ADK-based therapies into clinical applications.
Inflammatory Astrocytic TGFβ Signaling Induced by Blood–Brain Barrier Dysfunction Drives Epileptogenesis
Authors: Yang Lynn T. , Anthony Giovanni , Kaufer Daniela
Published: July 2024

Under healthy conditions, the brain is protected by the blood–brain barrier (BBB), a selective barrier function of the central nervous system vasculature restricting the passage of most macromolecules and cells from the blood into the brain. BBB dysfunction (BBBD) occurs in various epileptogenic conditions including stroke, traumatic injury, status epilepticus, and aging. This chapter summarizes recent findings which demonstrate that BBBD is sufficient to induce epileptogenesis, and identifies the epileptogenic cascade triggered by BBBD. This cascade includes (1) cross-BBB influx of albumin from the serum into the brain neuropil, (2) albumin binding to and activating astrocytic transforming growth factor beta (TGFβ) receptor ALK5, (3) mounting of inflammatory signaling and TGFβ1 positive feedback, (4) transcriptional changes in astrocytes that induce astrocytic decoupling and downregulation of K+ and glutamate buffering capacity, (5) degradation of extracellular matrix, and (6) growth of new excitatory synapses and reorganization of neural networks to favor excitatory activity. These changes epitomize the major hallmarks of epileptogenesis across animal models of acquired epilepsy and in tissue samples from patients, providing a “missing link” for how epileptogenic injuries trigger these pathological changes. Inhibition of TGFβR signaling blocks this cascade of events and prevents epileptogenesis. These findings highlight the potential of BBB-stabilizing treatments as an epilepsy-preventive therapeutic approach, and BBBD quantification as a biomarker for predicting postinjury epilepsy outcomes.
BDNF/TrkB Signaling and Epileptogenesis
Authors: Harward Stephen C. , Huang Yang Zhong , McNamara James O.
Published: July 2024

The epilepsies are one of the most common neurologic disorders with a diversity of etiologies. Despite tremendous advances in both medical and surgical therapies, availability of preventive and disease-modifying therapies is an important unmet medical need. Insight into the molecular and cellular mechanisms underlying epileptogenesis will hopefully provide novel targets for such therapies. To this end, multiple investigations using a variety of acquired epilepsy models deploying diverse etiologies (traumatic, ischemic, or seizure-induced) have identified the neurotrophin BDNF and its cognate receptor TrkB as key molecules in the pathogenesis. However, as detailed in this chapter, BDNF/TrkB signaling plays unique roles in each model. In addition to its contributions to epileptogenesis, BDNF/TrkB signaling contributes to neuronal survival following some epilepsy-inducing insults. Selective inhibition of distinct signaling pathways downstream of TrkB enables limiting TrkB-mediated epileptogenesis while preserving the protective functions. This chapter provides a critical review of the data supporting this diversity of roles for both BDNF and TrkB in the epilepsies and proposes strategies to disentangle these varying roles to develop therapies appropriate for clinical application.
EEG Biomarkers of Epileptogenesis
Authors: Kamintsky Lyna , Milikovsky Dan Z. , Friedman Alon
Published: July 2024

Insults to the brain (e.g., stroke, head trauma, infection, status epilepticus) can precipitate the development of epilepsy—months or even years after the initial insult. While not all patients with such injuries will go on to develop epilepsy, in a subgroup of individuals the injury will trigger epileptogenesis—a complex chain of events that transforms a nonepileptic brain into one that is prone to generating spontaneous seizures. To date, there are no clinically available tools capable of predicting which individuals are at high risk of post-insult epilepsy. A growing number of studies attempt to bridge this gap, by evaluating the utility of different diagnostic modalities (e.g., neuroimaging, molecular testing, electroencephalogram [EEG] analysis) in capturing changes reflective of the epileptogenic process. EEG holds particular promise as a modality for reflecting epileptogenic changes, due to its high temporal resolution and subsequent ability to capture a wide variety of brain-activity signatures. With the added advantages of portability, relative ease of use, safety, and low cost, a successful EEG-based biomarker is likely to become widely accessible in clinical settings. This chapter will discuss the most promising EEG signatures of epileptogenesis (interictal spikes, high-frequency oscillations, theta dynamics, and nonlinear dynamics), and the challenges of translating these biomarkers into clinically applicable tools. We conclude by highlighting the potential value of biomarker paradigms that (1) combine several signatures and (2) examine dynamic changes in these signatures over time.
Behavioral Biomarkers of Epileptogenesis and Epilepsy Severity
Authors: Ali Idrish , Casillas-Espinosa Pablo M. , Jones Nigel C. , O’Brien Terence J.
Published: July 2024

Currently, there are no established biomarkers which predict the risk of epilepsy following an epileptogenic brain insult, or which predict outcomes of pharmacological or surgical interventions following epilepsy diagnosis. Epilepsy appears to share bidirectional mechanistic relationships with its associated behavioral comorbidities such as neuropsychiatric and cognitive impairments, with several pieces of evidence suggesting that behavioral abnormalities exist before the initial diagnosis of epilepsy. Here, we discuss the preclinical and clinical evidence of these relationships, and the potential for behavioral and cognitive disorders to be harnessed as predictive biomarkers for risk of epilepsy or treatment outcomes.
Potassium Channels in Genetic Epilepsy
Authors: Weston Matthew C. , Tzingounis Anastasios V.
Published: July 2024

The past 70 years have provided a foundation for understanding potassium channel function at the single-channel, cellular, and circuit levels. Basic science of epilepsy has implicated potassium channel dysfunction in the pathogenesis of acquired epilepsy, and, more recently, genetic studies have revealed a large number of variants in potassium channel–encoding genes that cause epilepsy in humans. Identification and functional assessment of these variants have demonstrated they alter protein function, generating several hypotheses for how potassium channel dysfunction leads to the hypersynchronous neural activity characteristic of seizures. However, appreciation of the developmental, cellular, and synaptic complexity of the brain has increased in parallel to our knowledge of potassium channels, complicating the most straightforward idea that potassium channel dysfunction merely leads to depolarization of principal neurons, which causes seizures. The fact that many potassium channel–related epilepsies remain treatment refractory underscores the lack of a mechanistic understanding of this process. This chapter reviews our current understanding of the genetic and functional changes in potassium channels that may lead to epilepsy, within the framework of features of the excitable neuronal membrane known to be controlled by potassium currents. From there, the chapter expands into cell-type-specific roles of potassium channels, their effects on circuit development, and novel molecular interactions, and the evidence that these factors may play a role in epileptogenesis. Finally, the chapter highlights newer experimental approaches that have the potential to clarify the mechanisms through which potassium channel dysfunction leads to epilepsy and pave the way for more effective treatments.
High-Voltage-Activated Calcium Channels in Epilepsy
Authors: Rossignol Elsa
Published: July 2024

Voltage-gated calcium channels support an array of fundamental biological processes in various systems. In the brain, they determine neuronal responses to stimulation, dendritic properties, neuronal firing mode, and synaptic release. They also regulate multiple critical developmental processes, including neuronal proliferation, migration, connectivity, and structural activity-dependent plasticity. For these reasons, mutations in voltage-gated calcium channels result in a variety of neurological disorders displaying epilepsy as a core feature. This chapter summarizes the molecular, cellular, and network mechanisms by which mutations in high-voltage-activated calcium channels result in epilepsy, with a particular focus on CaV1.2 (CACNA1C), CaV1.3 (CACNA1D), CaV2.1 (CACNA1A), and CaV2.3 (CACNA1E)-associated disorders.
Therapeutic Window for the Treatment of Lafora Disease
Authors: Varea Olga , Guinovart Joan J. , Duran Jordi
Published: July 2024

Lafora disease, a devastating form of myoclonus epilepsy, progresses swiftly with neurodegeneration and rapidly leads to dementia. It is caused by mutations in two genes, either laforin (EPM2A) or malin (NHLRC1 or EPM2B). The hallmark of the disease is the accumulation of intracellular insoluble aggregates of abnormal glycogen, called Lafora bodies. The identification of Lafora bodies as the underlying cause of the disease prompted the design of therapeutic strategies for this condition based on the prevention of glycogen accumulation. In this chapter, two therapeutic strategies are analyzed, namely the suppression of glycogen synthase expression and the restoration of malin in malin-deficient mice. Both strategies were tested in mice at different stages of the disease to determine the therapeutic window for treatment. Glycogen synthase suppression arrests the accumulation of Lafora bodies in the brain only when induced at an early stage of Lafora disease. In contrast, the restoration of malin not only arrests the accumulation of Lafora bodies even at an advanced stage of the disease but also induces changes in the composition of the preexisting Lafora bodies and, importantly, ameliorates the inflammatory response. Therefore, malin restoration is presented as a gene replacement therapy to be developed for future application in patients with malin-deficient Lafora disease. Both approaches are significantly more effective when implemented at early stages, thus highlighting the importance of early diagnosis for the successful treatment of the condition.
Dissecting Epileptic and Cognitive Network Dysfunction in Epilepsy
Authors: Lenck-Santini Pierre-Pascal , Holmes Gregory
Published: July 2024

Cognitive and behavioral impairment can drastically affect the quality of life of patients with epilepsy, particularly when seizures appear in early childhood. Treating such deficits is therefore critical, and understanding the mechanisms involved is an important step toward this goal. Although seizures are believed to play a critical role in these deficits, the underlying etiology of the epilepsy may also directly affect brain function. Unfortunately, dissociating the impact of seizure activity from the impact of etiology is complex. Experimental strategies developed to make this dissociation consist of three levels of investigation: behavioral performance analysis, neural coding properties of epileptic networks, and organization of neuronal dynamics through brain rhythms and oscillations. From this strategy, evidence suggests that both seizures and cognitive deficits take their origin in a discoordination of epileptic networks, caused by GABAergic dysfunction and/or the abnormal presence of excitatory loops. Such network discoordination manifests itself in the form of abnormal rhythmical activity or of epileptiform activity. Restoring such rhythmopathies might be the focus of future therapeutic perspectives.
Management of Febrile Status Epilepticus
Authors: Garcia-Curran Megan M. , Baram Tallie Z.
Published: July 2024

The majority of seizures that arise with fever in infants and children are brief and cause few long-term consequences. A subset of the seizures is prolonged and, when lasting >30 minutes, are termed febrile status epilepticus (FSE). Human and experimental animal data indicate that FSE may be associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) and cognitive problems. Current clinical approaches in the treatment of febrile seizures recommend administration of benzodiazepines to abort the seizure and prevent the evolution of FSE. However, the minimal duration of FSE that leads to epilepsy and memory deficits is unclear, and the first FSE in a child—which is sufficient to provoke long-term consequences—is often difficult to anticipate and abort. Ongoing human and experimental animal studies are beginning to uncover the mechanisms by which FSE can lead to injury, epilepsy, and cognitive deficits in both normal and predisposed individuals. These mechanisms include neuroinflammation and large-scale changes in neuronal gene expression and synaptic connectivity within hippocampal circuits. Future therapy will focus on aborting adverse FSE-induced consequences using mechanism-based interventions.
Ionic Mechanisms of Ictogenic Disinhibition
Authors: Staley Kevin J.
Published: July 2024

Seizures are a consequence of an imbalance between excitation and inhibition. Of course, most of the time the brain does not generate seizure activity, even in severely epileptic patients. So there must be a way for the balance of excitation and inhibition to shift to engender seizure activity. Here two types of shifts are considered. The first is a temporal shift in the efficacy of inhibition. The neurotransmitter GABA, released from interneurons and acting on postsynaptic GABAA receptors, is the principal mechanism of synaptic inhibition in the brain. The GABAA receptor is unique in that it gates an anionic membrane current that can change direction under both physiological and pathological circumstances. Some of the pathological shifts can lead to seizure activity. The second shift in the efficacy of inhibition is anatomical. Some GABAA synapses that were meant to gate anion flow in the inhibitory direction instead gate anion flux in the opposite direction. This can occur as a consequence of either dysgenesis or the effects of injury and recovery from injury. This chapter reviews the basis for the direction of GABAA currents, and then discusses how they can be altered in time and space to increase the probability of seizure activity. Finally, therapeutic interventions are discussed.
First deep X-ray observations of the Fermi-detected steep-spectrum source and radio-loud NLS1 galaxy 3C 286
Authors: Yao Su , Komossa S , Kraus A , Grupe D
Published: July 2024

A well-known calibrator source in radio astronomy, 3C 286 ($z=0.85$), is a compact steep-spectrum (CSS) radio source and spectroscopically classified as a narrow-line Seyfert 1 (NLS1) galaxy. It is also known for its damped Ly $\alpha$ system from an intervening galaxy at $z=0.692$ detected in both ultraviolet (UV) and radio spectra. In addition, despite being a misaligned active galactic nuclei (AGN), 3C 286 is also detected in $\gamma$-rays by Fermi. Thus, this unique object combines the characteristics of CSS sources, NLS1 galaxies, and $\gamma$-ray emitters with misaligned jets, providing an excellent laboratory for extending our knowledge of AGN disc–jet coupling. Despite its significance, 3C 286 has been rarely observed in X-rays. In this study, we present our deep XMM–Newton and Chandra observations of 3C 286. The results reveal that the X-ray spectrum can be well-described by models including an intervening absorber with redshift and column density consistent with previous UV and radio observations. The most important finding is that the spectrum cannot be described by a single power law, but a soft excess is required which is parametrized by a blackbody. Furthermore, we find evidence suggesting the presence of off-nuclear X-ray emission at a radius that corresponds to the location of the radio lobes. While further theoretical work is still needed, our findings offer new clues to understand the specific mechanism for $\gamma$-ray emission from this unique object.
A Cross-Sectional Evaluation of the Virtual Outpatient Management of People With Mpox
Authors: Warrell Clare E , Chaudhry Zain , Shawe-Taylor Marianne , Mastoraki Evanthia , Delmonte Sen Ashwin , Rafferty Hannah , De Wilton Angus , Mescall Naomi , Houlihan Catherine , Gothard Philip , Jungmann Eva , Logan Sarah , Rampling Tommy , Waters Laura , Browne Rita , Marks Michael , Shaw Emily
Published: July 2024

Background

To report on the implementation and outcomes of a virtual ward established for the management of mpox during the 2022 outbreak, we conducted a 2-center, observational, cross-sectional study over a 3-month period.

Methods

All patients aged ≥17 years with laboratory polymerase chain reaction–confirmed monkeypox virus managed between 14 May and 15 August 2022, at the Hospital for Tropical Diseases at University College London Hospitals National Health Service (NHS) Foundation Trust and sexual health services at Central North and West London NHS Foundation Trust, were included. Main outcomes included the proportion of patients managed exclusively on the virtual ward, proportion of patients requiring inpatient admission, proportion of patients with human immunodeficiency virus, and duration of lesion reepithelialization.

Results

Among confirmed cases (N = 221), 86% (191/221) were managed exclusively on the virtual ward, while 14% (30/221) required admission. Treatment for concomitant sexually transmitted infections was provided to 25% (55/221) of patients, antibiotics for other infective complications to 16% (35/221), and symptomatic relief to 27% (60/221). The median time from onset to complete lesion reepithelialization and de-isolation was 18 days (range, 8–56 days). Eleven percent (24/221) of individuals disengaged from services within 4 days of testing.

Conclusions

The virtual ward model facilitated safe and holistic outpatient management of mpox, while minimizing admissions. This approach could serve as a model for future outbreak responses.
Timeframe for Conversion to Psychosis From Individuals at Clinical High-Risk: A Quantile Regression
Authors: Zhang TianHong , Wei YanYan , Tang XiaoChen , Xu LiHua , Hu YeGang , Liu HaiChun , Wang ZiXuan , Chen Tao , Li ChunBo , Wang JiJun
Published: July 2024

Background and Hypothesis

The time taken for an individual who is at the clinical high-risk (CHR) stage to transition to full-blown psychosis may vary from months to years. This temporal aspect, known as the timeframe for conversion to psychosis (TCP), is a crucial but relatively underexplored dimension of psychosis development.

Study Design

The sample consisted of 145 individuals with CHR who completed a 5-year follow-up with a confirmed transition to psychosis within this period. Clinical variables along with functional variables such as the Global Assessment of Function (GAF) score at baseline (GAF baseline) and GAF-drop from the highest score in the past year. The TCP was defined as the duration from CHR identification to psychosis conversion. Participants were categorized into 3 groups based on TCP: “short” (≤6 months, ≤33.3%), “median” (7–17 months, 33.3%–66.6%), and “long” (≥18 months, ≥66.6%). The quantile regression analysis was applied.

Study Results

The overall sample had a median TCP of 11 months. Significant differences among the three TCP groups were observed, particularly in GAF-drop (χ2 = 8.806, P = .012), disorganized symptoms (χ2 = 7.071, P = .029), and general symptoms (χ2 = 6.586, P = .037). Greater disorganized symptoms (odds ratio [OR] = 0.824, P = .009) and GAF-drop (OR = 0.867, P = .011) were significantly associated with a shorter TCP, whereas greater general symptoms (OR = 1.198, P = .012) predicted a longer TCP. Quantile regression analysis demonstrated a positive association between TCP and GAF baseline above the 0.7 quantile and a negative association between TCP rank and GAF drop below the 0.5 quantile.

Conclusions

This study underscores the pivotal role of functional characteristics in shaping TCP among individuals with CHR, emphasizing the necessity for a comprehensive consideration of temporal aspects in early prevention efforts.
The Great Flood: Race-Moderated Associations between Social Work Students’ Protective Mechanisms and Adaptive Coping
Authors: Lemieux Catherine M , Kim Youn Kyoung
Published: July 2024

The postdisaster experiences of 167 social work students in the aftermath of the Great Flood of 2016 were examined. Using a cross-sectional survey design and validated self-report measures, the current study examined the association between students’ protective factors (hope, altruism, spiritual support; at 8, 20, and 12 items, respectively) and six adaptive coping mechanisms, and further sought to determine whether such associations varied according to students’ race (white vs. African American). Six hierarchical multiple linear regression analyses were conducted using each of the adaptive coping strategies (acceptance, active coping, positive reframing, self-distraction, planning, and venting). Results showed that students’ race moderated the associations between altruism and active coping, spiritual support and active coping, spiritual support and self-distraction, altruism and planning, spiritual support and planning, and altruism and venting. The decomposition of the significant interactions indicated that the effect of altruism on active coping, planning, and venting was greater among white than among African American participants; the effect of spiritual support on active coping, self-distraction, and planning was greater among African American than among white participants. Recommendations include educating all students about risks incurred when working with traumatized populations. Research examining postdisaster coping responses of social workers can inform culturally responsive supervision approaches.