Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture.

OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.

Small Group Conversations in a POGIL-Based Class: How English Learners Engage in a Joint Knowledge Construction Process to Reach a Shared Understanding.

Collaboration is an aspect of engagement that focuses on learning through group work and having discussions with other learners. Active learning approaches are a way to foster collaborative engagement because they provide more opportunities for interaction among learners. Process Oriented Guided Inquiry Learning (POGIL), a socially mediated active learning approach, uses verbalizing and discussing ideas with peers in small groups to reach a shared understanding. Due to the growing number of immigrants in the United States, the number of English Learners (ELs) in American classrooms has been increasing rapidly. ELs encounter challenges such as unfamiliarity with American science class norms and expectations, feelings of not being valued and socially accepted, and instructors' lower expectations of them. These challenges can impact this group of students' learning and achievements. Previous studies have discussed that learning chemistry can be more challenging for EL students due to the critical role of language in learning. We argue that ELs use discourse moves differently compared to non-ELs in a POGIL-based class in terms of engaging in conversations that can lead to a shared understanding at the group level through a joint knowledge construction process. Our findings indicated that, in our sample, ELs were less likely to engage in discursive moves than non-ELs. This difference may result in missed opportunities for a shared understanding and joint knowledge construction. In addition to differences between EL and non-EL students in our samples, we also found differences between EL students who attended K-12 schools in the United States compared to international EL students. Implications for future studies of these possibly distinct EL populations are considered.

Non-starch polysaccharides in beer and brewing: A review of their occurrence and significance.

It has become apparent that beer (both alcoholic and nonalcoholic) contains appreciable amounts of non-starch polysaccharides, a broad subgroup of dietary fiber. It is worth noting that the occurrence of non-starch polysaccharides in alcoholic beer does not imply this should be consumed as a source of nutrition. But the popularity of nonalcoholic beer is growing, and the lessons learnt from non-starch polysaccharides in brewing can be largely translated to nonalcoholic beer. For context, we briefly review the origins of dietary fiber, its importance within the human diet and the significance of water-soluble dietary fiber in beverages. We review the relationship between non-starch polysaccharides and brewing, giving focus to the techniques used to quantify non-starch polysaccharides in beer, how they affect the physicochemical properties of beer and their influence on the brewing process. The content of non-starch polysaccharides in both regular and low/nonalcoholic beer ranges between 0.5 - 4.0 g/L and are predominantly composed of arabinoxylans and ß-glucans. The process of malting, wort production and filtration significantly affect the soluble non-starch polysaccharide content in the final beer. Beer viscosity and turbidity are strongly associated with the content of non-starch polysaccharides.

Statistical Thermodynamics Unveils How Ions Influence an Aqueous Diels-Alder Reaction.

The kinetics of Diels-Alder (DA) reactions in water has been known to be altered by salts for a long time. Yet the question how salts influence the reaction rate, either as rate-enhancing or rate-reducing additives, has so far remained unresolved. Conflicting hypotheses involve (i) indirect salt contributions through the modulation of internal pressure and (ii) making (or breaking) of the so-called "water-structure" by salts that strengthen (or weaken) the hydrophobic effect. In contrast to the qualitative nature of these hypotheses, here we answer this question quantitatively through a combination of transition state theory and fluctuation adsorption-solvation theory (FAST) using the DA reaction between anthracene-9-carbinol and N-ethylmaleimide as an example. We show that rate enhancement is driven by the salting out of the hydrophobic reactant, while rate-enhancing salts exhibit stronger affinity to the transition state.

The properties of residual water molecules in ionic liquids: a comparison between direct and inverse Kirkwood-Buff approaches.

We study the properties of residual water molecules at different mole fractions in dialkylimidazolium based ionic liquids (ILs), namely 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIM/BF4) and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM/BF4) by means of atomistic molecular dynamics (MD) simulations. The corresponding Kirkwood-Buff (KB) integrals for the water-ion and ion-ion correlation behavior are calculated by a direct evaluation of the radial distribution functions. The outcomes are compared to the corresponding KB integrals derived by an inverse approach based on experimental data. Our results reveal a quantitative agreement between both approaches, which paves a way towards a more reliable comparison between simulation and experimental results. The simulation outcomes further highlight that water even at intermediate mole fractions has a negligible influence on the ion distribution in the solution. More detailed analysis on the local/bulk partition coefficients and the partial structure factors reveal that water molecules at low mole fractions mainly remain in the monomeric state. A non-linear increase of higher order water clusters can be found at larger water concentrations. For both ILs, a more pronounced water coordination around the cations when compared to the anions can be observed, which points out that the IL cations are mainly responsible for water pairing mechanisms. Our simulations thus provide detailed insights in the properties of dialkylimidazolium based ILs and their effects on water binding.

Structure-property relationships in protic ionic liquids: a study of solvent-solvent and solvent-solute interactions.

The ionic nature of a functionalized protic ionic liquid cannot be rationalized simply through the differences in aqueous proton dissociation constants between the acid precursor and the conjugate acid of the base precursor. The extent of proton transfer, i.e. the equilibrium ionicity, of a tertiary ammonium acetate protic ionic liquid can be significantly increased by introducing an hydroxyl functional group on the cation, compared to the alkyl or amino-functionalized analogues. This increase in apparent ionic nature correlates well with variations in solvent-solute and solvent-solvent interaction parameters, as well as with physicochemical properties such as viscosity.

Structure-property relationships in protic ionic liquids: a thermochemical study.

How does cation functionality influence the strength of intermolecular interactions in protic ionic liquids (PILs)? Quantifying the energetics of PILs can be an invaluable tool to answer this fundamental question. With this in view, we have determined the standard molar enthalpy of vaporization, , and the standard molar enthalpy of formation, , of three tertiary ammonium acetate PILs with varying cation functionality, and of their corresponding precursor amines, through a combination of Calvet-drop microcalorimetry, solution calorimetry, and ab initio calculations. The obtained results suggest that these PILs vaporize as their neutral acid and base precursors. We also found a strong correlation between of the PILs and of their corresponding amines. This suggests that, within this series of PILs, the influence of cation modification on their cohesive energies follows a group additivity rule. Finally, no correlation between the of PILs and the extent of proton transfer, as estimated from the difference in aqueous pKa between the precursor acid and the conjugate acid of the precursor base, was observed.

Repeatability of adaptation in experimental populations of different sizes.

The degree to which evolutionary trajectories and outcomes are repeatable across independent populations depends on the relative contribution of selection, chance and history. Population size has been shown theoretically and empirically to affect the amount of variation that arises among independent populations adapting to the same environment. Here, we measure the contribution of selection, chance and history in different-sized experimental populations of the unicellular alga Chlamydomonas reinhardtii adapting to a high salt environment to determine which component of evolution is affected by population size. We find that adaptation to salt is repeatable at the fitness level in medium (Ne = 5 × 10(4)) and large (Ne = 4 × 10(5)) populations because of the large contribution of selection. Adaptation is not repeatable in small (Ne = 5 × 10(3)) populations because of large constraints from history. The threshold between stochastic and deterministic evolution in this case is therefore between effective population sizes of 10(3) and 10(4). Our results indicate that diversity across populations is more likely to be maintained if they are small. Experimental outcomes in large populations are likely to be robust and can inform our predictions about outcomes in similar situations.

Residual water in ionic liquids: clustered or dissociated?

How do residual water molecules in ionic liquids (ILs) interact with themselves, as well as with the ions? This question is crucial in understanding why the physical properties of ILs--and chemical reactions performed in them--are strongly affected by the residual water content. There have been three conflicting hypotheses regarding the structure and behaviour of the residual water: (i) water molecules are separated from one another, while interacting strongly with the ions, and dispersed throughout the medium; (ii) water molecules self-associate or form clusters in the ILs; (iii) residual water weakens ion-ion interactions. A satisfactory resolution of these conflicting suggestions has been hindered by the complexity and long range of the interactions in the water-IL mixture and by the often profound differences in physical structure between various different ILs. Here we present a route to resolve this question through a combination of a statistical thermodynamic theory (Kirkwood-Buff theory) with density and osmotic data from the literature. The structure of water-IL mixtures is shown to be water content dependent; at the lowest measured water concentration, strong water-IL interaction and water-water separation are observed in accordance to (i), whereas water in a more hydrophobic IL environment seems to self-associate at moderately low water concentrations, in accordance with (ii).

Togaram1 is expressed in the neural tube and its absence causes neural tube closure defects.

Neural tube closure defect pathomechanisms in human embryonic development are poorly understood. Here we identified spina bifida patients expressing novel variants of the TOGARAM gene family. TOGARAM1 has been associated with the ciliopathy Joubert syndrome, but its connection to spina bifida and role in neural development is unknown. We show that Togaram1 is expressed in the neural tube and Togaram1 knockout mice have abnormal cilia, reduced sonic hedgehog (Shh) signaling, abnormal neural tube patterning, and display neural tube closure defects. Neural stem cells from Togaram1 knockout embryos showed reduced cilia and defects in Shh signaling. Overexpression in IMCD3 and HEK293 cells of TOGARAM1 carrying the variant found in the spina bifida patient resulted in cilia defect along with reduced pericentriolar material one (PCM1), a critical constituent of centriolar satellites involved in transporting proteins toward the centrosome and primary cilia. Our results demonstrate the role of TOGARAM1 in regulating Shh signaling during early neural development that is critical for neural tube closure and elucidates potential mechanisms whereby the ciliopathy-associated gene TOGARAM1 gives rise to spina bifida aperta in humans.

A Longitudinal Study Identifying the Characteristics and Content Knowledge of Those Seeking Certification to Teach Secondary Biology in the United States.

Teacher content knowledge has been identified as a key prerequisite to effective instruction, and current educational policies require measurement of teacher content knowledge to assess candidacy for licensure. The primary instruments used in the United States are the Praxis Subject Assessment exams, which are designed to measure the subject-specific content knowledge needed to be a teacher. The Praxis Biology Subject Assessment exam, used by 42 U.S. states in the past decade, is the most common national measure used to determine biology content knowledge for teacher certification. Demographic and performance data from examinees (N = 43,798) who took the Praxis Biology Subject Assessment from 2006 to 2015 were compared to present a much-needed picture of who is seeking certification to teach biology, how different groups of aspiring biology teachers have performed, and how demographic makeup of prospective biology teachers compares with reports in previous studies describing the composition of the biology teacher workforce. Results indicate the majority of students self-reported as White (76%), female (66%), having undergraduate grade point averages (GPAs) at or above a 3.0 (76%) and majoring in biology (45%). Additionally, the demographic data were included in a linear regression model to determine the factors that explained the most variance in performance of the examinee. The model revealed substantial differences in average performance and pass rates between examinees of different genders, races, undergraduate majors, undergraduate GPAs, and census regions. This suggests that if the examinee is a White science, technology, engineering, and mathematics major, man with a 3.5 or higher undergraduate GPA, resides in the western United States, or plans to teach in a suburban school, the examinee will on average outperform their counterparts on the exam. From our analyses, we suggest several measures for the improvement of the biology teaching workforce and establish potential issues in the teacher pipeline that may impact the quality and diversity of U.S. biology teachers.

Navigating Tensions of Research and Teaching: Biology Graduate Students' Perceptions of the Research-Teaching Nexus within Ecological Contexts.

Graduate students represent both a significant component of the instructional team for biology departments as well as being students themselves learning to become academics. However, little is known about how biology graduate students perceive the relationships among their academic roles, particularly research and teaching. The present study used a cross-sectional survey to elicit the perceptions biology graduate students hold about the relationship between research and teaching. This work is an important first step in understanding the socialization processes of graduate students. Findings indicated that the majority of biology graduate students (65.5% of n = 255) hold synergistic perceptions of research and teaching. This is in spite of the mixed messages that biology graduate students hear about this relationship, including both "Teaching detracts from research" and "Teaching supports research." Findings from this study have implications for multiple stakeholders in graduate education, including professional developers who need to be cognizant of the messages that are received and internalized by biology graduate students while engaged in professional development opportunities. Results also suggest that work is needed to address how messages are prioritized and internalized during graduate school.

Fourteen Recommendations to Create a More Inclusive Environment for LGBTQ+ Individuals in Academic Biology.

Individuals who identify as lesbian, gay, bisexual, transgender, queer, and otherwise nonstraight and/or non-cisgender (LGBTQ+) have often not felt welcome or represented in the biology community. Additionally, biology can present unique challenges for LGBTQ+ students because of the relationship between certain biology topics and their LGBTQ+ identities. Currently, there is no centralized set of guidelines to make biology learning environments more inclusive for LGBTQ+ individuals. Rooted in prior literature and the collective expertise of the authors who identify as members and allies of the LGBTQ+ community, we present a set of actionable recommendations to help biologists, biology educators, and biology education researchers be more inclusive of individuals with LGBTQ+ identities. These recommendations are intended to increase awareness of LGBTQ+ identities and spark conversations about transforming biology learning spaces and the broader academic biology community to become more inclusive of LGBTQ+ individuals.

Prevailing Questions and Methodologies in Biology Education Research: A Longitudinal Analysis of Research in CBE-Life Sciences Education and at the Society for the Advancement of Biology Education Research.

Biology education research (BER) is a growing field, as evidenced by the increasing number of publications in CBE-Life Sciences Education ( LSE) and expanding participation at the Society for the Advancement of Biology Education Research (SABER) annual meetings. To facilitate an introspective and reflective discussion on how research within LSE and at SABER has matured, we conducted a content analysis of LSE research articles ( n = 339, from 2002 to 2015) and SABER abstracts ( n = 652, from 2011 to 2015) to examine three related intraresearch parameters: research questions, study contexts, and methodologies. Qualitative data analysis took a combination of deductive and inductive approaches, followed by statistical analyses to determine the correlations among different parameters. We identified existing research questions, study contexts, and methodologies in LSE articles and SABER abstracts and then compared and contrasted these parameters between the two data sources. LSE articles were most commonly guided by descriptive research questions, whereas SABER abstracts were most commonly guided by causal research questions. Research published in LSE and presented at SABER both prioritize undergraduate classrooms as the study context and quantitative methodologies. In this paper, we examine these research trends longitudinally and discuss implications for the future of BER as a scholarly field.

Targeting of G-Quadruplex Harboring Pre-miRNA 92b by LNA Rescues PTEN Expression in NSCL Cancer Cells.

Since the elevated levels of microRNAs (miRNAs) often cause various diseases, selective inhibition of miRNA maturation is an important therapeutic strategy. Commonly used anti-miRNA strategies are limited to targeting of mature miRNAs, as the upstream targeting of miRNA maturation with an oligonucleotide is challenging due to the presence of a stable pre-miRNA stem-loop structure. Previously, we reported that about 16% of known human pre-miRNAs have the potential to adopt G-quadruplex (GQ) structures alternatively to canonical stem-loops. Herein, we showed that a rationally designed locked nucleic acid (LNA) binds specifically the GQ conformation of pre-miRNA 92b and inhibits pre-miRNA maturation. Further, we showed that the LNA treatment rescues PTEN expression in non-small-cell lung cancer (NSCLC) cells, which is suppressed by the elevated level of miRNA 92b. Treatment of LNA significantly decreases the IC50 of doxorubicin for NSCLC cells. This strategy can be developed as a novel anti-miRNA therapeutic approach to target GQ harboring miRNAs. This can potentially be a more powerful approach than targeting of the mature miRNA, as it is an upstream targeting and can reduce both 3' and the 5' mature miRNA levels at once.