Miracle-dz/UniFAR-FTUs huggingface dataset:
High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons

Dendritic computations signaled into neuronal output by the initiation and propagation of regenerative dendritic spikes are a feature of the electrical operation of rodent neocortical pyramidal neurons, that have a central role in neocortical circuit function. However, it remains poorly explored whether these mechanisms are operational in the human neocortex. To directly compare the dendritic computational properties of the most numerous class of pyramidal neuron in the human and rat neocortex we made simultaneous electrical recordings from the soma and apical dendrites of layer 2/3 pyramidal neurons maintained in acute brain slices of analogous cortical areas under identical experimental conditions. In both species correlated dendritic excitatory input led to the initiation of sodium channel-mediated dendritic spikes, which had stereotyped biophysical properties. Dendritic sodium spikes in human and rat layer 2/3 pyramidal neurons could be generated across a similar wide input range, exhibited a similar frequency range of activation, and forward propagated with high fidelity to drive neuronal output. Our findings therefore reveal that the dendritic computational properties of human layer 2/3 pyramidal neurons are phylogenetically conserved.
Increased male investment in sperm competition results in reduced maintenance of gametes

Male animals often show higher mutation rates than their female conspecifics. A hypothesis for this male-bias is that competition over fertilization of female gametes leads to increased male investment into reproduction at the expense of maintenance and repair, resulting in a trade-off between male success in sperm competition and offspring quality. Here, we provide evidence for this hypothesis by harnessing the power of experimental evolution to study effects of sexual selection on the male germline in the seed beetle Callosobruchus maculatus. We first show that 50 generations of evolution under strong sexual selection, coupled with experimental removal of natural selection resulted in males that are more successful in sperm competition. We then show that these males produce progeny of lower quality if engaging in socio-sexual interactions prior to being challenged to surveil and repair experimentally induced damage in their germline, and that the presence of male competitors alone can be enough to elicit this response. We identify 18 candidate genes that showed differential expression in response to the induced germline damage, with several of these previously implicated in processes associated with DNA repair and cellular maintenance. These genes also showed significant expression changes across socio-sexual treatments of fathers and predicted the reduction in quality of their offspring, with expression of one gene also being strongly correlated to male sperm competition success. Sex differences in expression of the same 18 genes indicate a substantially higher female investment in germline maintenance. While more work is needed to detail the exact molecular underpinnings of our results, our findings provide rare experimental evidence for a trade-off between male success in sperm competition and germline maintenance. This suggests that sex-differences in the relative strengths of sexual and natural selection are causally linked to male mutation bias. The tenet advocated here, that the choices of an individual can affect plasticity of its germline and the resulting genetic quality of subsequent generations, has several interesting implications for mate choice processes.
Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

Absence of Isc1, the yeast homologue of mammalian neutral sphingomyelinase type 2, leads to severe mitochondrial dysfunction. We show that deletion of another type-C phospholipase, the phosphatidylglycerol (PG)-specific Pgc1, rescues this defect. Phosphatidylethanolamine (PE) levels and cytochrome c oxidase activity, reduced in isc1Δ cells, were restored to wild-type levels in the pgc1Δisc1Δ mutant. Pgc1 substrate, PG, inhibited in vitro activity of Isc1 and phosphatidylserine decarboxylase Psd1, an enzyme crucial for PE biosynthesis. We also identify a mechanism by which the balance between the current demand for PG and its consumption is controlled. We document that the product of PG hydrolysis, diacylglycerol, competes with the substrate of PG-phosphate synthase, Pgs1, and thereby inhibits the biosynthesis of excess PG. This feedback loop does not work in the absence of Pgc1, which catalyzes PG degradation. Finally, Pgc1 activity is partially inhibited by products of Isc1-mediated hydrolysis. The described functional interconnection of the two phospholipases contributes significantly to lipid homeostasis throughout the cellular architecture. Summary The coordinated action of two different type-C phospholipases is documented, which provides a balance between mitochondrial phospholipid biosynthesis and sphingolipid metabolism. The regulatory role of specific lipids, phosphatidylglycerol, diacylglycerol and ceramide in this process is demonstrated.
Mitochondrial Matrix Protease ClpP Agonists Inhibit Cancer Stem Cell Function in Breast Cancer Cells by Disrupting Mitochondrial Homeostasis

Mitochondria are multifaceted organelles which are important for bioenergetics, biosynthesis and signaling in metazoans. Mitochondrial functions are frequently altered in cancer to promote both the energy and the necessary metabolic intermediates for biosynthesis required for tumor growth. Cancer stem cells (CSCs) contribute to chemotherapy resistance, relapse, and metastasis. Recent studies have shown that while non-stem, bulk cancer cells utilize glycolysis, breast CSCs are more dependent on oxidative phosphorylation (OxPhos) and therefore targeting mitochondria may inhibit CSC function. We previously reported that small molecule ONC201, which is an agonist for the mitochondrial caseinolytic protease (ClpP), induces mitochondrial dysfunction in breast cancer cells. In this study, we report that ClpP agonists inhibit breast cancer CSC function in vitro and in vivo. Mechanistically, we found that OxPhos inhibition downregulates multiple pathways required for CSC function, such as the mevalonate pathway, YAP, Myc, and the HIF pathway. ClpP agonists showed significantly greater inhibitory effect on CSC functions compared with other mitochondria-targeting drugs. Further studies showed that ClpP agonists deplete NAD(P)+ and NAD(P)H and induce redox imbalance, and dysregulate one-carbon metabolism and proline biosynthesis. Downregulation of these pathways by ClpP agonists further contribute to the inhibition of CSC function. In conclusion, ClpP agonists inhibit breast CSC functions by disrupting mitochondrial homeostasis in breast cancer cells and inhibiting multiple pathways critical to CSC function.
AlphaFold encodes the principles to identify high affinity peptide binders

Machine learning has revolutionized structural biology by solving the problem of predicting structures from sequence information. The community is pushing the limits of interpretability and application of these algorithms beyond their original objective. Already, AlphaFold’s ability to predict bound conformations for complexes has surpassed the performance of docking methods, especially for protein-peptide binding. A key question is the ability of these methods to differentiate binding affinities between several peptides that bind the same receptor. We show a novel application of AlphaFold for competitive binding of different peptides to the same receptor. For systems in which the individual structures of the peptides are well predicted, predictions in which both peptides are introduced capture the stronger binder in the bound state, and the other peptide in the unbound form. The speed and robustness of the method will be a game changer to screen large libraries of peptide sequences to prioritize for detailed experimental characterization.
Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

The treatment of primary prostate cancer delicately balances an active surveillance approach for low-risk disease with multimodal treatment including surgery, radiation therapy, and hormonal therapy for high-risk disease. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we sought to comprehensively describe the tumor microenvironment of localized prostate cancer contrasting this with adjacent normal samples and healthy controls. We performed single-cell RNA sequencing and high-resolution spatial transcriptomic analysis. This revealed tumor context dependent changes in gene expression. Our data point towards an immune suppressive tumor microenvironment associated with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We inferred cell-to-cell relationships at an unprecedented scale for ligand-receptor interactions within undissociated tissue sections. Our work provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions. Highlights Characterization of prostate cancer by combined scRNA-seq and spatial transcriptomic analysis Primary prostate cancer establishes a suppressive immune microenvironment The prostate tumor microenvironment exhibits a high angiogenic gene expression pattern A new computational analysis pipeline to deconvolute context-specific differential gene expression
Faster NTRU on ARM Cortex-M4 With TMVP-Based Multiplication

This paper focuses on speeding up NTRU - one of the lattice-based finalists of the NIST PQC competition - by improving the ring multiplication. The Number Theoretic Transform (NTT), Toom-Cook, and Karatsuba are the most commonly used algorithms for implementing NTRU. In this paper, we propose Toeplitz matrix-vector product (TMVP) based algorithms for multiplication for all parameter sets of NTRU. We implement the proposed algorithms on ARM Cortex-M4. The results show that the TMVP-based multiplication algorithms we propose are more efficient than the others in the literature in most cases. Our algorithm for ntruhps2048509 outperform the Toom-Cook and NTT methods in the literature by 25.4% and 21.5%. We also observe the impact of these improvements on the overall performance of NTRU. We speed up the key generation, encryption, decryption, encapsulation, and decapsulation algorithms of ntruhps2048509 by 12.5%, 14.3%, 17.7%, 3.9%, and 14.7%, respectively, compared to state-of-the-art implementation. Moreover, our algorithms require less stack space than the others.
Conditional Variational AutoEncoder based on Stochastic Attack

Over the recent years, the cryptanalysis community leveraged the potential of research on Deep Learning to enhance attacks. In particular, several studies have recently highlighted the benefits of Deep Learning based Side-Channel Attacks (DLSCA) to target real-world cryptographic implementations. While this new research area on applied cryptography provides impressive result to recover a secret key even when countermeasures are implemented (e.g. desynchronization, masking schemes), the lack of theoretical results make the construction of appropriate and powerful models a notoriously hard problem. This can be problematic during an evaluation process where a security bound is required. In this work, we propose the first solution that bridges DL and SCA in order to get this security bound. Based on theoretical results, we develop the first Machine Learning generative model, called Conditional Variational AutoEncoder based on Stochastic Attacks (cVAE-SA), designed from the well-known Stochastic Attacks, that have been introduced by Schindler et al. in 2005. This model reduces the black-box property of DL and eases the architecture design for every real-world crypto-system as we define theoretical complexity bounds which only depend on the dimension of the (reduced) trace and the targeting variable over F2n . We validate our theoretical proposition through simulations and public datasets on a wide range of use cases, including multi-task learning, curse of dimensionality and masking scheme.
Mechanisms Involved in the Stimulatory and Inhibitory Effects of 5-Hydroxytryptamine on Vagal Mechanosensitive Afferents in Rat Lung

Mechanosensitive vagal afferents in the lung, rapidly and slowly adapting receptors (RARs and SARs, respectively), play an important role in eliciting the reflexes that regulate the normal airway function. A profound bronchoconstrictive effect of 5-hydroxytryptamine (5-HT) has been extensively reported in various animal species, but its influence on the SAR and RAR activity is not known. This study investigated the effect of 5-HT on these receptors, and the possible mechanisms involved. Single-fiber activities of these afferents were measured in anesthetized, open-chest, and mechanically ventilated rats. Our results showed that intravenous injection of 5-HT evoked a consistent and pronounced stimulation of phasic RARs. In contrast, 5-HT generated an inconsistent and paradoxical action on SARs: no effect in 29% (5 of 17) of the SARs; stimulation in 35% (6 of 17); and inhibition in the remainder. These responses of both RARs and SARs to 5-HT were reproducible and dose-dependent. After the injection of a high dose of 5-HT (16 μg/kg), the receptor responses slowly reached a peak (after ∼8 s) and returned toward the baseline in ∼20 s, accompanied by a consistent increase in total pulmonary resistance and a decrease in dynamic lung compliance in a temporal pattern very similar to the increased receptor activity. When these changes in lung mechanics induced by 5-HT were prevented by pretreatment with salbutamol, a β2 adrenergic receptor agonist, the delayed responses of both RARs and SARs to 5-HT were also abolished, except that the immediate stimulatory effect on a subset of RARs, the silent RARs, was not affected. In conclusion, 5-HT generated a delayed stimulatory effect on RARs and a paradoxical effect on SARs, which resulted primarily from the 5-HT-induced changes in mechanical properties of the lung.
Novel Secreted Peptides From Rhizopus arrhizus var. delemar With Immunomodulatory Effects That Enhance Fungal Pathogenesis

Secreted fungal peptides are known to influence the interactions between the pathogen and host innate immunity. The aim of this study is to screen and evaluate secreted peptides from the fungus Rhizopus arrhizus var. delemar for their immunomodulatory activity. By using mass spectrometry and immuno-informatics analysis, we identified three secreted peptides CesT (S16), Colicin (S17), and Ca2+/calmodulin-dependent protein kinase/ligand (CAMK/CAMKL; S27). Culturing peripheral blood-derived monocytic macrophages (PBMMs) in the presence of S16 or S17 caused cell clumping, while culturing them with S27 resulted in the formation of spindle-shaped cells. S27-treated PBMMs showed cell cycle arrest at G0 phase and exhibited alternatively activated macrophage phenotype with pronounced reduction in scavenger receptors CD163 and CD206. Homology prediction indicated that IL-4/IL-13 is the immunomodulatory target of S27. Confirming this prediction, S27 initiated macrophage activation through phosphorylation of STAT-6; STAT-6 inhibition reversed the activity of S27 and reduced the formation of spindle-shaped PBMMs. Lastly, S27 treatment of PBMMs was associated with altered expression of key iron regulatory genes including hepcidin, ferroportin, transferrin receptor 1, and ferritin in a pattern consistent with increased cellular iron release; a condition known to enhance Rhizopus infection. Collectively, R. arrhizus var. delemar secretes peptides with immunomodulatory activities that support fungal pathogenesis. Targeting the IL-4/IL-13R/STAT-6 axis is a potential therapeutic approach to enhance the PBMM-mediated fungal phagocytosis. This represents a potential new approach to overcome lethal mucormycosis.
Combined Effect of CYP2C19 Genetic Polymorphisms and C-Reactive Protein on Voriconazole Exposure and Dosing in Immunocompromised Children

Background Pediatric patients have significant interindividual variability in voriconazole exposure. The aim of the study was to identify factors associated with voriconazole concentrations and dose requirements to achieve therapeutic concentrations in pediatric patients. Methods Medical records of pediatric patients were retrospectively reviewed. Covariates associated with voriconazole plasma concentrations and dose requirements were adjusted by using generalized linear mixed-effect models. Results A total of 682 voriconazole steady-state trough concentrations from 91 Chinese pediatric patients were included. Voriconazole exposure was lower in the CYP2C19 normal metabolizer (NM) group compared with the intermediate metabolizer (IM) group and the poor metabolizer (PM) group (p = 0.0016, p < 0.0001). The median daily dose of voriconazole required to achieve therapeutic range demonstrated a significant phenotypic dose effect: 20.8 mg/kg (range, 16.2–26.8 mg/kg) for the CYP2C19 NM group, 18.2 mg/kg (range, 13.3–21.8 mg/kg) for the CYP2C19 IM group, and 15.2 mg/kg (range, 10.7–19.1 mg/kg) for the CYP2C19 PM group, respectively. The extent of impact of C-reactive protein (CRP) levels on voriconazole trough concentrations and dose requirements varied between CYP2C19 phenotypes. Increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole trough concentration by 22.22, 50, 64.81, and 75% respectively, in the NM group; by 39.26, 94.48, 123.93, and 146.63%, respectively, in the IM group; and by 17.17, 37.34, 46.78, and 53.65%, respectively, in the PM group. Meanwhile, increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole dose requirements by 7.15, 14.23, 17.35, and 19.43%, respectively, in the PM group; with decreases in voriconazole dose requirements by 3.71, 7.38, 8.97, and 10.03%, respectively, in the NM group; and with decreases by 4, 9.10, 11.05, and 12.35%, respectively, in the IM group. In addition, age and presence of immunosuppressants had significant effects on voriconazole exposure. Conclusions Our study suggests that CYP2C19 phenotypes, CRP concentrations, age, and the presence of immunosuppressants were factors associated with the pharmacokinetic changes in voriconazole. There was heterogeneity in the effect of CRP on voriconazole plasma concentrations across different CYP2C19 genotypes. Combining relevant factors with dose adaptation strategies in therapeutic drug monitoring may help to reduce the incidence of subtherapeutic and supratherapeutic concentrations in clinical practice.
Sex and Age Differences in Patient-Reported Acute Stroke Symptoms

Background Identification of sex- and age-related differences in the presentation of atypical symptoms at stroke onset may reduce prehospital delay and improve stroke treatment if acknowledged at first contact. Aim To explore sex- and age-related differences in patient-reported typical and atypical symptoms of a stroke. Methods We used data from a cross-sectional survey at two non-comprehensive stroke units in the Capital Region of Denmark. Patient-reported symptoms, stroke knowledge, and behavioral response were analyzed by the Chi-square test or a Fisher's exact test separated by sex. Multivariable logistic regression adjusted for covariates were used to explore sex- and age-related differences according to each patient-reported typical or atypical symptoms. Results In total, 479 patients with acute stroke were included (median age 74 years [25th to 75th percentile: 64–80], and 40.1% were women). Female sex was associated with higher odds of presenting with atypical symptoms, such as loss of consciousness (OR 2.12 [95% CI 1.08–4.18]) and nausea/vomiting (OR 2.33 [95% CI 1.24–4.37]), and lower odds of presenting with lower extremity paresis (OR 0.59 [95% CI 0.39–0.89). With each year of age, the odds decreased of presenting with sensory changes (OR 0.95 [95% CI 0.94–0.97]) and upper extremity paresis (OR 0.98 [95% CI 0.96–0.99]), whereas odds of presenting with dysphagia (OR 1.06 [95% CI 1.02–1.11]) increased. Conclusions Patients of female sex and younger age reported on admission more frequently atypical stroke symptoms. Attention should be drawn to this possible atypical first presentation to facilitate correct identification and early stroke revascularization treatment to improve the outcome for both sexes.
Boredom and Media Multitasking

Media multitasking entails simultaneously engaging in multiple tasks when at least one of the tasks involves media (e.g., online activities and streaming videos). Across two studies, we investigated one potential trigger of media multitasking, state boredom, and its relation to media multitasking. To this end, we manipulated participants’ levels of state boredom using video mood inductions prior to administering an attention-demanding 2-back task during which participants could media multitask by playing a task-irrelevant video. We also examined whether trait boredom proneness was associated media multitasking. We found no direct evidence that state boredom leads to media multitasking. However, trait boredom proneness correlated with greater amounts of media multitasking in Experiment 1, but not in Experiment 2. Surprisingly, in both experiments, post-task ratings of state boredom were equivalent across conditions, alerting us to the short-lived effects of video mood inductions and the boring nature of cognitive tasks.
Epidemiological Study on Mycoplasma pneumoniae and Chlamydia pneumoniae Infection of Hospitalized Children in a Single Center During the COVID-19 Pandemic

Background Since the outbreak of COVID-19, a series of preventive and control measures in China have been used to effectively curb the spread of COVID-19. This study aimed to analyze the epidemiological characteristics of Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) in hospitalized children with acute respiratory tract infection during the COVID-19 pandemic. Methods MP IgM antibody and CP IgM antibody were detected in all hospitalized children due to acute respiratory tract infection in the Children’s Hospital Affiliated to Zhejiang University from January 2019 to December 2020. These data were compared between 2019 and 2020 based on age and month. Results The overall detection rate of MP and CP in 2020 was significantly lower than that in 2019 (MP: 21.5% vs 32.9%, P<0.001; CP: 0.3% vs 0.9%, P<0.001). This study found a 4-fold reduction in the number of children positive for MP and a 7.5-fold reduction in the number of children positive for CP from 2019 to 2020. The positive cases were concentrated in children aged >1 year old. In 2019, the positive rate of MP was detected more commonly in children 3 years of age or older than in younger children. In 2020, the higher positive rate of MP reached a peak in the 3- to 6-year age group (35.3%). CP was detected predominantly in children aged 6 years older in 2019 and 2020, with positive rates of 4.8% and 2.6%, respectively. Meanwhile, the positive rates of MP in 2019 were detected more commonly in July, August and September, with 47.2%, 46.7% and 46.3%, respectively. Nevertheless, the positive rates of MP from February to December 2020 apparently decreased compared to those in 2019. The positive rates of CP were evenly distributed throughout the year, with 0.5%-1.6% in 2019 and 0.0%-2.1% in 2020. Conclusions A series of preventive and control measures for SARS-CoV-2 during the COVID-19 pandemic can not only contain the spread of SARS-CoV-2 but also sharply improve the infection of other atypical pathogens, including MP and CP.