A potential surrogate model for efficient inference of stochastic GLUT4 translocation.

Utilizing the Bayesian network algorithm for noninvasive prenatal paternity testing (NIPPT) and efficacy evaluation of NIPPT system.

It all began, so they say, with Theodore Woodward, "Don't look for zebras on Greene Street." This aphorism has since been passed on to generations of residents and medical students at the University of Maryland School of Medicine and beyond. A zebra is a "medical condition whose appearance at a particular time and place, in a particular person, is both unexpected and astonishing. The 'condition' may be an item from the history, a physical finding, a laboratory test, or a diagnosis." This maxim nudges clinicians to consider competing or paradoxical hypotheses when assessing patients for common, unexpected, and rare diseases. Whereas errors are unavoidable, considering zebras (uncommon diagnoses) helps avoid "not-to-miss" diagnoses, patient harm, and the associated regret of failure. Perhaps there's also the tug to "bag the big one." On the one hand, pursuing zebras may result in overestimating probability assessments with the potential for harming patients and wasting resources, while applying the science of formal medical decision-analysis lessens the chances of overzealous workups. Unfortunately, conducting studies to evaluate the utility of clinical findings for rare diseases is difficult. The key is to identify symptoms and signs, preferably in combination, with high specificity and sensitivity. On the other hand, assuming horses (common diagnoses) for too long also has its risks. Both the failure to recognize when the current therapeutic plan is ineffective and to appreciate the diagnostic value of the history, physical, and routine laboratory tests can delay the search for alternative hypotheses and ultimately efficacious treatment. Sir William Osler admonished us over a century ago, "Use the knife and cautery to cure the moral necrosis which you will feel in the posterior parietal region, in Gall and Spurzheim's centre of self-esteem, where you will find a sore spot after you have made a mistake in diagnosis."

Evaluating evidential strength of statistically nonsignificant meta-analyses with likelihood ratios: a meta-epidemiological study.

What is the relation between major depressive disorder and amygdala reactivity?

Continued drug use is thought to affect neural networks involved in attention and reward processing, with increased attentional bias being granted to drug-related versus non-drug-related cues. However, cannabis literature on this topic remains scarce, particularly longitudinal research using ERPs. This Stage II Preregistered Research Report investigated disruptions associated with cannabis (ab)use in ERP components and explored their role as potential biomarkers of future use. One hundred forty-two young adults (55 current users, 35 abstinent users, 52 nonusers, aged 18-38 years) completed a cannabis cue-reactivity task and the monetary incentive delay (MID) task during electroencephalographic data collection. We analyzed the P3, late positive potential (LPP), and reward positivity. Participants completed a 3-month follow-up on cannabis use. Compared with nonusers, current cannabis users (but not abstinent users) showed higher P3 amplitudes (when subtracting neutral cues to cannabis cues) in the cannabis cue-reactivity task. Exploratory analyses revealed that higher P3 amplitudes were associated with greater monthly cannabis use and predicted reductions in use after 3 months. In the MID task, current users showed a trend for blunted early and full-window LPP amplitudes across all monetary cues. Exploratory analysis suggested that increased LPP amplitudes to monetary loss cues and feedback, as well as blunted early LPP to non-gain feedback, may predict greater reductions in cannabis use 3 months later. As for abstinent cannabis users, they showed enhanced LPP amplitudes to cannabis versus neutral cues relative to nonusers; however, no significant group differences emerged in the MID task. These results provide exploratory evidence for a hyperactive attentional system to cannabis-related cues and a hypoactive system to other rewarding stimuli in current cannabis users; still, these effects were not uniform across ERP components or groups. In addition, this hyperactive system, revealed in components such as P3, also appears to predict reductions (vs. increases) in cannabis use over time, highlighting the complex interactions between neural activity and behavior. We discuss the findings in light of the attentional bias toward cannabis cues in current users while acknowledging alternative hypotheses that warrant examination in future research.

improving students’ TOEFL ICT scores at Universitas dr. Soebandi. The research employed a quantitative approach using a quasi-experimental design. The population of this study consisted of university students, while the sample was selected through purposive sampling from two second-semester Pharmacy classes, namely Class 23A and Class 23B, with a total of 60 students. Class 23A was assigned as the experimental group and taught using Discussion-Based Learning, while Class 23B served as the control group and was taught using the conventional lecture method. Data were collected through TOEFL pre-test and post-test instruments adapted from Barron’s TOEFL, 6th Edition by Pamela J. Sharpe. The data were analysed using the Independent Sample T-Test through SPSS. The findings showed that the average pre-test scores of the experimental and control groups were relatively similar, namely 382 and 379, indicating comparable initial ability. After the treatment, the post-test results revealed that the experimental group achieved an average score of 437, while the control group obtained 405. The score improvement of the experimental group (+55) was higher than that of the control group (+26). Statistical analysis showed that the significance value (Sig. 2-tailed) was 0.014, which was lower than 0.05, and the t-count value (3.32) was higher than the t-table value (2.00). Therefore, the null hypothesis was rejected and the alternative hypothesis was accepted. It can be concluded that Discussion-Based Learning had a significant positive effect on improving students’ TOEFL ICT scores.

On tests for outliers in linear regression through standard linear hypothesis test and a test motivated by Cook's distance

Unlike other red algae, the perennial species Palmaria palmata exhibits pronounced sexual dimorphism with a microscopic female gametophytic phase that does not produce cystocarps. To investigate how these unique features of its life cycle influence its reproductive mode, we analyzed the relative proportion of macroscopic individuals (tetrasporophytes vs. male gametophytes) across multiple geographic scales and between intertidal and subtidal habitats along the western coast of France (892 individuals collected from 17 locations). Because female gametophytes are microscopic and cannot be directly sampled in the field, their frequencies were inferred under two alternative hypotheses: (H1) assuming an equal sex ratio (i.e., the proportion of females equal to males) and (H2) assuming the proportion of females equals tetrasporophytes, given that tetrasporophytes develop directly on a female gametophyte. Under H1, our results predict a demographic advantage of tetrasporophytes over gametophytes. Moreover, tetrasporophytes were significantly more abundant in intertidal than in subtidal zones, likely reflecting their greater resilience to environmental fluctuations. Conversely, under H2, the sex ratio was significantly biased toward female gametophytes and the estimated proportion of tetrasporophytes was lower than that of gametophytes. In addition, the relative contribution of self-fertilization and clonal reproduction were assessed using 11 microsatellite markers. These findings confirm that this species reproduces mainly sexually and suggest that sexual dimorphism may limit selfing and enhance the survival of the tetrasporophyte, which develops directly on the female, thereby compensating for the absence of cystocarps. Overall, our results provide valuable insights into the reproductive strategies and adaptive potential of this commercially important alga.

Socially shared emotions shape the activity of the medial prefrontal cortex during inference of others' emotional states.

Total vertical craniopagus represent one of the most complex craniofacial malformations and a demanding surgical challenge. Traditional imaging remains static and insufficient to fully anticipate dynamic venous redistribution during staged separation. We implemented an integrated virtual and physical simulation framework in the multistep separation of total vertical craniopagus twins, within an Avatar Patient Approach as an evolution of the Digital Twin Medicine approach focused on controlled physiological decoupling and operative risk reduction. Multimodal imaging Data sets were coregistered into a unified 3-dimensional anatomic space. These Data sets generated a dual avatar system: (1) immersive, multiuser virtual reality models within a collaborative metaverse; and (2) operable, multimaterial physical simulators enabling layered manual rehearsal. Both virtual and physical avatars were iteratively updated after each surgical stage, transforming simulation from a single preoperative event into a longitudinal adaptive workflow. The integrated simulation reshaped the multistep approach, allowing venous partition strategies and refined cranial reconstruction planning to be discussed, replicated, and enhanced multidisciplinarily. Iterative model updating allowed anticipation of anatomic evolution between steps and facilitated scenario testing under alternative surgical hypotheses. Mental training was intended to support the development of 3-dimensional anatomic imagination, cognitive automatism, and surgical strategy definition. The platform helped reduce procedural uncertainty during planning and supported strategic decision-making. Twin Medicine through dynamic virtual and physical avatars, redefines craniopagus separation surgery as a continuously adapting digital-physical continuum rather than a sequence of isolated operations. This paradigm establishes an iterative framework for managing extreme surgical complexity in pediatric neurosurgery.

Examination of Candidates for Dyson Spheres: An Alternative Hypothesis Based on Stellar Flares

Plastid stromules are frequently observed under stress, yet their function remains enigmatic. In the current study, we tested two alternative hypotheses: stromules might channel metabolic flux from plastids to peroxisomes during jasmonate biosynthesis, or they might serve as conduits for plastid-nucleus retrograde signaling. We used Nicotiana tabacum BY-2 cells to investigate stromulation in non-photosynthetic plastids. Fluorescent markers for stroma, plastid outer membrane, peroxisomes, and the OPDA exporter were combined with confocal visualization and AI-based quantification of stromule frequency and length. Exogenous methyl jasmonate (MeJA) and salicylic acid (SA) each triggered a rapid (∼60 min) ∼3-fold increase in stromule frequency. This increase primarily resulted from more initiation events, rather than elongation. Disrupting microtubules with oryzalin stopped MeJA from causing stromule formation, while actin depolymerization had no effect. Inhibition of jasmonate biosynthesis with phenidone prevented SA-triggered stromule formation. Induction of genes for jasmonate biosynthesis (AOC) and response (JAZ1, JAZ3) by MeJA was amplified when stromulation was suppressed by oryzalin, suggesting that stromules act as modulators of jasmonate-dependent gene expression. The GFP-fusion of the OPDA exporter JASSY showed a significant preference for stromules, and over 80% of them associated with peroxisomes. Stromule frequency was highest during the cell-expansion phase. We discuss our findings in the context of a role for stromules in stress-dependent retrograde signaling from plastids to the nucleus.

Deciphering the miR-29c-3p / TET3 regulatory axis within the SARS-CoV-2-infected midbrain.

To navigate social environments, people make inferences and predictions about others' minds (e.g., their beliefs, preferences, intentions), an ability known as mentalizing. Although the neural basis of mentalizing has been studied extensively, the cognitive processes that support it have been challenging to characterize. One hypothesis is that particular mentalizing processes, subserved by particular brain regions, support inferences about particular categories of mental content (e.g., beliefs or preferences) with defined boundaries. An alternative hypothesis is that apparent categorical distinctions arise from variability along continuous, underlying dimensions. Here, we report evidence that regions of the brain's mentalizing network, including medial prefrontal cortex (MPFC) and right TPJ, show diverging sensitivity to the underlying dimension of transience, that is, how temporary or enduring the state is that one attributes to another person. During fMRI scanning, participants received information about others and inferred their stable or transient beliefs or preferences in a 2 × 2 design. Overall, the right TPJ, left TPJ, and posterior cingulate were more engaged during inferences about transient than stable mental content, whereas dorsal, middle, and ventral MPFCs were more engaged during inferences about stable than transient mental content. Findings support suggestions that MPFC and right TPJ make dissociable contributions to mentalizing and show that differences in the transience of the mental content under consideration, not only the categorical type of mental content itself, contributes importantly to this dissociation. Results contribute to scientific understanding of the structure of human social cognition, with implications for conceptualizations of atypical social thinking.

In their vertebrate hosts, malaria parasites typically inhabit erythrocytes where they harvest the cell's abundant supply of hemoglobin as a nutrient source. A byproduct of hemoglobin digestion is free heme, which the parasites detoxify by converting it to a brown crystal known as hemozoin. Hemozoin is a hallmark of Plasmodium infection, and this enzymatic pathway is well studied in mammalian Plasmodium species. Despite their evolutionary relatedness to mammalian Plasmodium, wildlife malaria parasites, particularly those that infect birds and lizards, are understudied, leaving their vast genetic diversity to be explored. Plasmodium floridense, Plasmodium azurophilum, and Plasmodium leucocytica infect Anolis lizards throughout the Caribbean islands, including the endemic anole on the island of Saba. Like other Plasmodium species, P. floridense infects red blood cells and produces hemozoin. P. azurophilum also infects red blood cells, however, its sister species, P. leucocytica, infects white blood cells. This is atypical for Plasmodium parasites and represents an expansion into a new cellular niche. Two of these three parasites (P. azurophilum and P. leucocytica) also do not produce hemozoin and have seemingly evolved alternative mechanisms of hemoglobin digestion for nutrient acquisition. To investigate this, we assembled parasite transcriptomes from infected Saban anole blood samples and analyzed them for hemoglobin digestion transcripts. The transcriptome results indicate that all three lizard parasites transcribe the genes canonically involved in the hemoglobin digestion pathway. This is the first evidence that these parasites possess genes for the same digestive enzymes as the better characterized mammalian Plasmodium, indicating conservation of this pathway across the Plasmodium tree. However, there is evidence for shifts in selective pressure on some of these proteins in all three lizard-infective species. These genes may not be as functionally important relative to other Plasmodium species. Since the genes are not yet pseudogenes, however, there remains the alternative hypothesis that these genes also play additional roles in malaria parasite biology.

Clade size distributions under the coalescent diversification model.

Affective biases shape cognitive and emotional behaviour and are important in major depressive disorder (MDD). Modulation of affective biases by the NMDA antagonist, ketamine, may underlie its antidepressant effects but not all NMDA antagonists are efficacious. Some studies suggest ketamine's efficacy involves non-NMDA mechanisms e.g. via its active metabolite HNK (2R, 6R)-hydroxynorketamine), but an alternative hypothesis is that pharmacodynamic differences relating to ion trapping and/or affinity may be relevant. This study used a rat model of affective biases to investigate how different NMDA antagonists influence retrieval of a negatively biased memory, both acutely (<60 min) and ~24 h post-treatment. We compared compounds tested clinically (lanicemine, memantine, CP101,606), reference antagonists with different pharmacodynamic profiles (phencyclidine, PCP; ephenidine), and HNK. PCP, lanicemine, and ephenidine but not CP101,606 acutely attenuated negative biases. At 24 h, these effects were sustained for CP101,606 and ephenidine with a trend towards inducing a positive bias. Lanicemine's effects were sustained only at high doses and PCP and memantine had no effects. HNK looked like ketamine but only at doses higher than those achieved through metabolism of the effective ketamine dose. These findings suggest that sustained modulation of affective biases, particularly when the treatment facilitates re-learning with a more positive affective valence, correlates with therapeutic efficacy. Based on preliminary findings using reference NMDA antagonists, differences in antidepressant efficacy may relate to ion trapping properties. Very high or very low ion trapping appear less effective than intermediate compounds like ketamine and ephenidine or subunit-selective antagonists like CP101,606.

Synthetic opioids pose a chemically evolvable threat, in which extreme potency and rapid diversification allow fentanyl analogues to outpace structure-specific countermeasures. Immune strategies largely responded by copying the parent chemotype, implicitly treating small-molecule recognition as scaffold-dependent. Here, we examined an alternative hypothesis: adaptive immunity can recover fentanyl-class identity from transferable spatial and physicochemical information. Replacing the canonical piperidine of fentanyl with a 2-azaspiro[3.3]heptane, we created a chemically orthogonal immunogen with a radically altered three-dimensional arrangement. Despite this, vaccination elicited high-titer cross-reactive antibodies, broad fentanyl-analogue binding, and protection matching a fentanyl-derived benchmark. Fentanyl antinociception shifted into the ∼1.1-2.1 mg kg-1 range, preserved ventilation during respiratory challenge, and reduced brain fentanyl from 61.9 ± 10.0 to 17.2 ± 0.7 nM. These results reveal programmable antibody recognition, demonstrating that molecular class identity arises not from direct structural mimicry but through higher-order spatial and physicochemical relationships.

Genome assemblies for thousands of species make a resolved tree of life achievable, though this goal is hindered by computational burden and poor modelling of large datasets. We have developed an approach to systematically identify robust and challenging nodes in ancient phylogenies using multi-protein, clade-specific matrices containing different taxa and different genes. In each matrix, we include one randomly selected species for each of the major clades, infer single-copy orthologues, and analyse the resulting concatenated supermatrices using mixture models. We assess node support for competing topologies under different strategies, such as removing distant relatives and recoding, using amino acid and nucleotide data. We applied this approach to chelicerates, a group with an unresolved phylogeny in which the position of marine horseshoe crabs as the sister of arachnids is contentious. Furthermore, we also analysed two other ancient animal clades: molluscs and vertebrates, as examples of better resolved groups. While their phylogenies show stable support, chelicerate phylogenies are method and dataset-dependent. Our results suggest that, despite varying levels of support for alternative hypotheses, the evolutionary history of chelicerates remains unresolved even with the genomic data currently available.