Double-edged Role of KNa Channels in Brain Tuning: Identifying Epileptogenic Network Micro-Macro Disconnection

: Epilepsy is commonly recognized as a disease driven by generalized hyperexcited and hypersynchronous neural activity. Sodium-activated potassium channels (KNa channels), which are encoded by the Slo 2.2 and Slo 2.1 genes, are widely expressed in the central nervous system and considered as “brakes” to adjust neuronal adaptation through regulating action potential threshold or after-hyperpolarization under physiological condition. However, the variants in KNa channels, especially gain-of-function variants, have been found in several childhood epileptic conditions. Most previous studies focused on mapping the epileptic network on the macroscopic scale while ignoring the value of microscopic changes. Notably, paradoxical role of KNa channels working on individual neuron/microcircuit and the macroscopic epileptic expression highlights the importance of understanding epileptogenic network through combining microscopic and macroscopic methods. Here, we first illustrated the molecular and physiological function of KNa channels on preclinical seizure models and patients with epilepsy. Next, we summarized current hypothesis on the potential role of KNa channels during seizures to provide essential insight into what emerged as a micro-macro disconnection at different levels. Additionally, we highlighted the potential utility of KNa channels as therapeutic targets for developing innovative anti-seizure medications.

A Song of Neither Ice nor Fire: Temperature Extremes had No Impact on Violent Conflict Among European Societies During the 2nd Millennium CE

The second millennium CE in Europe is known for both climatic extremes and bloody conflict. Europeans experienced the Medieval Warm Period and the Little Ice Age, and they suffered history-defining violence like the Wars of the Roses, Hundred Years War, and both World Wars. In this paper, we describe a quantitative study in which we sought to determine whether the climatic extremes affected conflict levels in Europe between 1,005 and 1980 CE. The study involved comparing a well-known annual historical conflict record to four published temperature reconstructions for Central and Western Europe. We developed a Bayesian regression model that allows for potential threshold effects in the climate–conflict relationship and then tested it with simulated data to confirm its efficacy. Next, we ran four analyses, each one involving the historical conflict record as the dependent variable and one of the four temperature reconstructions as the sole covariate. Our results indicated that none of the temperature reconstructions could be used to explain variation in conflict levels. It seems that shifts to extreme climate conditions may have been largely irrelevant to the conflict generating process in Europe during the second millennium CE.

Alcohol consumption and telomere length: observational and Mendelian randomization approaches

Alcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD -0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.

Xylem embolism spread is largely prevented by interconduit pit membranes until the majority of conduits are gas-filled

Xylem embolism resistance varies across species influencing drought tolerance, yet little is known about the determinants of the embolism resistance of an individual conduit. Here we conducted an experiment using the optical vulnerability method to test whether individual conduits have a specific water potential threshold for embolism formation and whether pre-existing embolism in neighbouring conduits alters this threshold. Observations were made on a diverse sample of angiosperm and conifer species through a cycle of dehydration, rehydration and subsequent dehydration to death. Upon rehydration after the formation of embolism, no refilling was observed. When little pre-existing embolism was present, xylem conduits had a conserved, individual, embolism resistance threshold that varied across the population of conduits. The consequence of a variable conduit-specific embolism threshold is that a small degree of pre-existing embolism in the xylem results in an apparently more resistant xylem in a subsequent dehydration, particularly in angiosperms with vessels. While our results suggest that pit membranes separating xylem conduits are critical for maintaining a conserved individual embolism threshold for given conduit when little pre-exisiting embolism is present, as the percentage of embolized conduits increases, gas movement, local pressure differences, and connectivity between conduits increasingly contribute to embolism spread.

Semi Analytical Modelling for Drain-Induced Barrier Lowering Reduction in Dual-Metal Gate all Around FET

In the research paper, the semi-analytical modelling is done for low drain-induced barrier lowering (DIBL) dual-metal gate all around FET (DM GAAFET). Vacuum and silicon nitride are considered in the act of the gate oxide material near drain region for dual-metal vacuum oxide gate all around FET (DM-VO GAAFET) and dual-metal nitride oxide gate all around FET (DM-NO GAAFET) respectively, in which surface potential, threshold voltage, and DIBL are modelled for both the devices. The proposed models are validated by comparing DM-NO GAAFET with DM-VO GAAFET. DM-NO GAAFET shows the better device performance than DM-VO GAAFET as the threshold voltage increased by 10% and DIBL decreased by 50% in simulated as well as analytical results. The obtained results are having very close agreement with simulated results for both the GAAFETs.

An Approach For Drain Current Modeling Including Quantum Mechanical Effects For A DMDG Junctionless Field Effect Nanowire Transistor

This paper presents the effects of quantum confinements on the surface potential, threshold voltage, drain current, transconductance, and drain conductance of a Dual Material Double Gate Junctionless Field Effect Nanowire Transistor (DMDG-JLFENT). The carrier energy quantization on the threshold voltage of a DMDG-JLFENT is modeled, and subsequently, other parameters like drain current were analytically presented. The QME considered here is obtained under the quantum confinement condition for an ultra-thin channel, i.e., below 10 nm of Si thickness. The threshold voltage shift due to QME can be used as a quantum correction term for compact modeling of junctionless transistors. The analytical model proposed for surface potential, threshold voltage, drain current, transconductance, and drain conductance were verified by TCAD 3-D quantum simulation results which makes it suitable for SPICE compact modeling.

Investigation of an Alternative Marker for Hypermutability Evaluation in Different Tumors

A growing number of studies have shown immunotherapy to be a promising treatment strategy for several types of cancer. Short tandem repeats (STRs) have been proven to be alternative markers for the evaluation of hypermutability in gastrointestinal (GI) cancers. However, the status of STRs and microsatellite instability (MSI) in other tumors have not yet been investigated. To further compare STR and MSI alterations in different tumors, a total of 407 paired DNAs were analyzed from the following eight tumor types: breast cancer (BC), hepatocellular cancer (HCC), pancreatic cancer (PC), colorectal cancer (CRC), gastric cancer (GC), lung cancer (LC), esophageal cancer (EC), and renal cell cancer (RCC). The STR alteration frequencies varied in different tumors as expected. Interestingly, none of the patients possessed MSI-low (MSI-L) or MSI-high (MSI-H), except for the GI patients. The highest STR alteration was detected in EC (77.78%), followed by CRC (69.77%), HCC (63.33%), GC (54.55%), LC (48.00%), RCC (40.91%), BC (36.11%), and PC (25.71%). The potential cutoff for hypermutability was predicted using the published objective response rate (ORR), and the cutoff of LC and HCC was the same as that of GI cancers (26.32%). The cutoffs of 31.58% and 10.53% should be selected for BC and RCC, respectively. In summary, we compared MSI and STR status in eight tumor types, and predicted the potential threshold for hypermutability of BC, HCC, CRC, GC, LC, EC, and RCC.

In vivo patch-clamp recordings reveal distinct subthreshold signatures and threshold dynamics of midbrain dopamine neurons

The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.