Miracle-dz/UniFAR-FTUs huggingface dataset:
Human Neocortical Neurosolver (HNN), a new software tool for interpreting the cellular and network origin of human MEG/EEG data

Magneto- and electro-encephalography (MEG/EEG) non-invasively record human brain activity with millisecond resolution providing reliable markers of healthy and disease states. Relating these macroscopic signals to underlying cellular- and circuit-level generators is a limitation that constrains using MEG/EEG to reveal novel principles of information processing or to translate findings into new therapies for neuropathology. To address this problem, we built Human Neocortical Neurosolver (HNN, https://hnn.brown.edu) software. HNN has a graphical user interface designed to help researchers and clinicians interpret the neural origins of MEG/EEG. HNN’s core is a neocortical circuit model that accounts for biophysical origins of electrical currents generating MEG/EEG. Data can be directly compared to simulated signals and parameters easily manipulated to develop/test hypotheses on a signal’s origin. Tutorials teach users to simulate commonly measured signals, including event related potentials and brain rhythms. HNN’s ability to associate signals across scales makes it a unique tool for translational neuroscience research.
A tripartite cooperative mechanism confers resistance of the protein kinase A catalytic subunit to dephosphorylation

Phosphorylation of specific residues in the activation loops of AGC kinase group (protein kinase A, G, and C families) is required for activity of most of these kinases, including the catalytic subunit of PKA (PKAc). Although many phosphorylated AGC kinases are sensitive to phosphatase-mediated dephosphorylation, the PKAc activation loop uniquely resists dephosphorylation, rendering it “constitutively” phosphorylated in cells. Previous biophysical experiments and structural modeling have suggested that the N-terminal myristoylation signal and the C-terminal FXXF motif in PKAc regulate its thermal stability and catalysis. Here, using site-directed mutagenesis, molecular modeling, and in cell-free and cell-based systems, we demonstrate that substitutions of either the PKAc myristoylation signal or the FXXF motif only modestly reduce phosphorylation and fail to affect PKAc function in cells. However, we observed that these two sites cooperate with an N-terminal FXXW motif to cooperatively establish phosphatase resistance of PKAc while not affecting kinase-dependent phosphorylation of the activation loop. We noted that this tripartite cooperative mechanism of phosphatase resistance is functionally relevant, as demonstrated by changes in morphology, adhesion, and migration of human airway smooth muscle cells transfected with PKAc variants containing amino acid substitutions in these three sites. These findings establish that three allosteric sites located at the PKAc N and C termini coordinately regulate the phosphatase sensitivity of this enzyme. This cooperative mechanism of phosphatase resistance of AGC kinase opens new perspectives toward therapeutic manipulation of kinase signaling in disease.
Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies

The intricate interplay between the immune system and microbes is an essential part of the physiological homeostasis in health and disease. Immunological recognition of commensal microbes, such as bacterial species resident in the gut or lung as well as dormant viral species, i.e., cytomegalovirus (CMV) or Epstein-Barr virus (EBV), in combination with a balanced immune regulation, is central to achieve immune-protection. Emerging evidence suggests that immune responses primed to guard against commensal microbes may cause unexpected pathological outcomes, e.g., chronic inflammation and/or malignant transformation. Furthermore, translocation of immune cells from one anatomical compartment to another, i.e., the gut-lung axis via the lymphatics or blood has been identified as an important factor in perpetrating systemic inflammation, tissue destruction, as well as modulating host-protective immune responses. We present in this review immune response patterns to pathogenic as well as non-pathogenic microbes and how these immune-recognition profiles affect local immune responses or malignant transformation. We discuss personalized immunological therapies which, directly or indirectly, target host biological pathways modulated by antimicrobial immune responses.
Unraveling Cryptic Morphological Diversity in a Marine Snail Species Complex Using Nuclear Genomic Data

Abstract: Conus lividus (Hwass in Bruguière, 1792) and Conus sanguinolentus (Quoy and Gaimard, 1834) are closely related Indo-West Pacific cone snails that have largely overlapping distributions. Previous population genetic analyses of these species found that some individuals that were identified as C. lividus possessed mitochondrial gene sequences that were similar or in some cases identical to those of C. sanguinolentus. While these species tend to be easily distinguished based on shell color patterns, it is possible that some individuals of C. sanguinolentus were misidentified as C. lividus. The result though could also be due to introgression of the mitochondrial genome of C. sanguinolentus into C. lividus. We used a ddRAD approach to obtain sequences of short fragments of more than 7,000 nuclear genomic loci to examine patterns of variation and evaluate these explanations. Results showed that the two parental species are genetically differentiated at nuclear loci and all putative hybrids were unambiguously assigned to C. sanguinolentus based on shared patterns of variation. These results demonstrate that variation in shell color patterns of C. sanguinolentus overlaps with that of C. lividus, and extend the distribution of C. sanguinolentus into the Hawaiian Archipelago. Additional analyses of patterns of genetic variation among populations of the two species revealed that while C. lividus shows no genetic population structure, the population of C. sanguinolentus from Hawaii is genetically differentiated from populations elsewhere as found in prior analyses based on mitochondrial sequence data.
Patients' experiences of the caring encounter with the psychiatric emergency response team in the emergency medical service—A qualitative interview study

Mental illnesses are increasing in the population; consequently, the number of psychiatric emergencies handled by the emergency medical services (EMS) has also increased. Alternative response systems have been developed and evaluated, but there is still a lack of knowledge concerning the patients' experiences of being cared for in the EMS by a psychiatric emergency response unit (In Swedish: Psykiatrisk Akut Mobilitet [PAM]).
HD-ZIP I Transcription Factor (PtHB13) Negatively Regulates Citrus Flowering through Binding to FLOWERING LOCUS C Promoter

For floral induction in adult citrus, low temperature is one of the most important environmental factors. FLOWERING LOCUS C (FLC) plays a very important role in low-temperature-induced Arabidopsis flowering by repressed FLC expression under exposure to prolonged low-temperature conditions. However, little is known about the FLC regulation mechanism in perennial woody plants such as citrus. In this study, the functions of citrus FLC homolog (PtFLC) were investigated by ectopic expression in Arabidopsis. Transcription factor of homeodomain leucine zipper I (HD-ZIP I) as an upstream regulator of PtFLC was identified by yeast one-hybrid screen to regulate its transcription. The HD-ZIP I transcription factor was highly homologous to Arabidopsis ATHB13 and thus was named PtHB13. Ectopically expressed PtHB13 inhibited flowering in transgenic Arabidopsis. Furthermore, the expression of PtFLC and PtHB13 showed a seasonal change during the floral induction period and was also affected by low temperature. Thus, we propose that PtHB13 binds to PtFLC promoter to regulate its activity during the citrus floral induction process.
Morning Headache as an Obstructive Sleep Apnea-Related Symptom among Sleep Clinic Patients—A Cross-Section Analysis

Morning headache is considered to be a symptom of obstructive sleep apnea syndrome (OSAS). Despite not being as common as excessive daytime sleepiness or unrefreshing sleep, it can similarly impair everyday activities. The aim of the present study was to evaluate the prevalence of and factors associated with morning headaches (MH) among patients referred for polysomnography due to suspected OSAS. This is a retrospective study on 1131 patients who underwent polysomnography between 2013 and 2015. Morning headaches (MH) were reported in 29% of them. In a logistic regression model, a rise in the n probability of MH was associated with female sex (odds ratio, OR, 1.38, 95% confidence interval, CI, 1.08–1.75), history of hypertension (OR 1.25, 95% CI 1.06–1.46), complaint on unrefreshing sleep (OR 1.42, 95% CI 1.19–1.70), choking at night (OR 1.25, 95% CI 1.05–1.49), and fall in total sleep time (OR 0.872 per each hour, 95% CI 0.76–0.99). The risk between MH and apnea–hypopnea index, blood oxygen saturation parameters or arousal index was found to be statistically insignificant. There is a lack of evidence that MH is associated with the severity of OSAS or nocturnal hypoxemia.
Glycosylated Biotherapeutics: Immunological Effects of N-Glycolylneuraminic Acid

The emerging field of biotherapeutics provides successful treatments for various diseases, yet immunogenicity and limited efficacy remain major concerns for many products. Glycosylation is a key factor determining the pharmacological properties of biotherapeutics, including their stability, solubility, bioavailability, pharmacokinetics, and immunogenicity. Hence, an increased attention is directed at optimizing the glycosylation properties of biotherapeutics. Currently, most biotherapeutics are produced in non-human mammalian cells in light of their ability to produce human-like glycosylation. However, most mammals produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), while humans cannot due to a specific genetic defect. Humans consume Neu5Gc in their diet from mammalian derived foods (red meat and dairy) and produce polyclonal antibodies against diverse Neu5Gc-glycans. Moreover, Neu5Gc can metabolically incorporate into human cells and become presented on surface or secreted glycans, glycoproteins, and glycolipids. Several studies in mice suggested that the combination of Neu5Gc-containing epitopes and anti-Neu5Gc antibodies could contribute to exacerbation of chronic inflammation-mediated diseases (e.g., cancer, cardiovascular diseases, and autoimmunity). This could potentially become complicated with exposure to Neu5Gc-containing biotherapeutics, bio-devices or xenografts. Indeed, Neu5Gc can be found on various approved and marketed biotherapeutics. Here, we provide a perspective review on the possible consequences of Neu5Gc glycosylation of therapeutic protein drugs due to the limited published evidence of Neu5Gc glycosylation on marketed biotherapeutics and studies on their putative effects on immunogenicity, drug efficacy, and safety.
Can we predict who lives long with ovarian cancer?

Women with ovarian cancer benefit from individualized management that incorporates advanced imaging technologies, sophisticated cytoreductive surgery integrated with combination chemotherapy, genetic risk assessment, and tumor molecular profiling. However, advanced ovarian cancer remains a highly lethal disease because of early peritoneal dissemination, rapid development of resistance to key therapeutic agents, and evasion of the host immune response. Over the last 15 years, several models and nomograms have been developed to predict surgical outcomes, progression‐free survival, or overall survival on the basis of clinical and pathologic data available at the primary diagnosis and recurrence. Each of these models has its strengths and limitations, and they provide a basis for future models that will incorporate functional imaging and molecular characteristics.
Use of Medications by Breastfeeding Women in the 2015 Pelotas (Brazil) Birth Cohort Study

Background: This study describes medication use by women up to 3 months postpartum and evaluates the association between medication use by women who were still breastfeeding at 3 months postpartum and weaning at 6 and 12 months. Methods: Population-based cohort, including women who breastfed (n = 3988). Medications were classified according to Hale’s lactation risk categories and Brazilian Ministry of Health criteria. Duration of breastfeeding was analysed using Cox regression models and Kaplan-Meier curves, including only women who were still breastfeeding at three months postpartum. Results: Medication use with some risk for lactation was frequent (79.6% regarding Hale’s risk categories and 12.3% regarding Brazilian Ministry of Health criteria). We did not find statistically significant differences for weaning at 6 or 12 months between the group who did not use medication or used only compatible medications and the group who used medications with some risk for lactation, according to both criteria. Conclusions: Our study found no association between weaning rates across the different breastfeeding safety categories of medications in women who were still breastfeeding at three months postpartum. Therefore, women who took medications and stopped breastfeeding in the first three months postpartum because of adverse side-effects associated with medications could not be addressed in this analysis.
The Dorsomedial Hypothalamus Is Involved in the Mediation of Autonomic and Neuroendocrine Responses to Restraint Stress

We hypothesized that dorsomedial hypothalamus (DMH) modulates autonomic and neuroendocrine responses in rats at rest and when subjected to restraint stress (RS). Male Wistar rats were used, and guide cannulas were bilaterally implanted in the DMH for microinjection of vehicle or the nonspecific synaptic blocker CoCl2 (1 mM/100 nl). A polyethylene catheter was inserted into the femoral artery for the recording of arterial pressure and heart rate (HR). Tail temperature was measured using a thermal camera. The session of RS started 10 min after DMH treatment with vehicle or CoCl2. Under home-cage condition, the pretreatment of DMH with CoCl2 increased baseline blood pressure (BP), and heart rate (HR) without affecting the tail temperature. In addition, it decreased plasma vasopressin levels without affecting plasma corticosterone and oxytocin contents. When rats pretreated with CoCl2 were exposed to RS, the RS-evoked cardiovascular were similar to those observed in vehicle-treated animals; however, because cobalt pretreatment of the DMH increased baseline BP and HR values, and the RS-evoked cardiovascular responses did not exceed those observed in vehicle-treated animals, suggesting a possible celling limit, the possibility that DMH is involved in the modulation of RS-evoked cardiovascular responses cannot be certainly excluded. Nonetheless, the pretreatment of DMH with CoCl2 blocked the reduction in tail temperature caused by RS. The DMH pretreatment with CoCl2 did not modify the RS-evoked increase in plasma corticosterone and oxytocin contents. In conclusion, the present data suggest the involvement of DMH in the maintenance of BP, HR, and vasopressin release under the rest conditions at the home-cage. Furthermore, indicate that DMH is an important thermoregulatory center during exposure to RS, regulating tail artery vasoconstriction.
microRNA and exosome profiling in multiple sclerosis

New DNA sequencing technologies have uncovered non-coding RNA (ncRNA) as a major player in regulating cellular processes and can no longer be dismissed as “junk” or “dark” RNA. Among the ncRNA, microRNA (miRNA) is arguably the most extensively characterized category and a number of studies have implicated them in regulating critical functions that can influence autoimmune demyelination. Of specific interest to multiple sclerosis (MS), miRNA have been implicated in both regulating immune responses and myelination, thus making them an attractive candidate for both pharmacological intervention and as disease biomarkers. In addition, exosomes, small vesicles secreted by most cell types and present in all body fluids, have been also shown to play roles in immune signaling, inflammation and angiogenesis. Therefore, exosomes are also being explored as tools for therapeutic delivery and as biomarkers. This article reviews the recent advances in miRNA and exosome profiling in MS and experimental models.
Fabrication, Structure and Mechanical and Ultrasonic Properties of Medical Ti6Al4V Alloys Part I: Microstructure and Mechanical Properties of Ti6Al4V Alloys Suitable for Ultrasonic Scalpel

Ti6Al4V alloy has been considered as a key component used in ultrasonic scalpels. In this series of papers, the fabrication, structure, and mechanical and ultrasonic properties of medical Ti6Al4V alloys suitable for ultrasonic scalpel are studied systemically. These alloys with low elastic modulus and present a typical bimodal microstructure with relatively high β phase content (~40%) and lamellar α thickness of ≤ 0.9 µm. In the first paper, the relationship between the microstructure and mechanical properties of hot-rolled Ti6Al4V alloys treated by heating treatment is discussed. In the second paper, the dependence of the ultrasonic properties on the microstructure of the heat-treated Ti6Al4V alloys is reported. With increasing solid solution temperature, the content and size of the primary α phase decrease. In contrast, the content and size of the lamellar α phase increase. Additionally, the β phase content first increases and then decreases. The microstructure of Ti6Al4V alloys could be slightly changed by aging treatment. When the solid solution treatment temperature increases to 980 °C from 960 °C, the average size of the lamellar α phase in the alloys increases by 1.1 µm. This results in a decrease in the average yield strength (93 MPa). The elastic modulus of alloys is mainly controlled by the β phase content. The microstructure of alloys by solution-treatment at 960 °C shows the highest β phase content and lowest average elastic modulus of 99.69 GPa, resulting in the minimum resonant frequency (55.06 kHz) and the highest average amplitude (21.48 µm) of the alloys at the length of 41.25 mm.
Evaluation of Antioxidant Systems and Ascorbate-Glutathione Cycle in Feijoa Edible Flowers at Different Flowering Stages

Background: Feijoa (Acca sellowiana (O. Berg)) was initially introduced as an ornamental plant, but nowadays, it is widely cultivated for the numerous beneficial properties of its edible fruits. Feijoa flowers have been included in the list of edible flowers, but despite this, they are still considered niche products due to consumer skepticism and lack of publicity. Methods: This study evaluated the physicochemical traits, antioxidant system, and ascorbate-glutathione cycle in feijoa flowers at five flowering stages based on the Biologische Bundesanstalt, Bundessortenamt und CHemische Industrie (BBCH) scale. Results: The results showed that the optimal stage to harvest feijoa flower is the F2 stage characterized by high bioactive compounds content. Furthermore, the enzymes involved in oxidative stress and the ascorbate-glutathione cycle showed different trends during the flowering stages. Conclusions: This study provides new evidence to understand the possible role of bioactive compounds and ascorbate-glutathione cycle in the regulation of flower development, defining the optimal stage to harvest flowers.
The Vasoactive Mas Receptor in Essential Hypertension

The renin–angiotensin–aldosterone system (RAAS) has been studied extensively, and with the inclusion of novel components, it has become evident that the system is much more complex than originally anticipated. According to current knowledge, there are two main axes of the RAAS, which counteract each other in terms of vascular control: The classical vasoconstrictive axis, renin/angiotensin-converting enzyme/angiotensin II/angiotensin II receptor type 1 (AT1R), and the opposing vasorelaxant axis, angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor (MasR). An abnormal activity within the system constitutes a hallmark in hypertension, which is a global health problem that predisposes cardiovascular and renal morbidities. In particular, essential hypertension predominates in the hypertensive population of more than 1.3 billion humans worldwide, and yet, the pathophysiology behind this multifactorial condition needs clarification. While commonly applied pharmacological strategies target the classical axis of the RAAS, discovery of the vasoprotective effects of the opposing, vasorelaxant axis has presented encouraging experimental evidence for a new potential direction in RAAS-targeted therapy based on the G protein-coupled MasR. In addition, the endogenous MasR agonist angiotensin-(1-7), peptide analogues, and related molecules have become the subject of recent studies within this field. Nevertheless, the clinical potential of MasR remains unclear due to indications of physiological-biased activities of the RAAS and interacting signaling pathways.
Fucoidan inhibits tooth movement by promoting restorative macrophage polarization through the STAT3 pathway

Retention after treatment and effective anchorage control are two essential factors in orthodontics. Our study aimed to explore the effects of fucoidan on orthodontic tooth movement (OTM) and the involvement of macrophages. We established a murine OTM model to test the effect of fucoidan administration. We found that mice injected with fucoidan had a deceleration in OTM and a higher bone mineral density. Moreover, fucoidan increased the proportion of F4/80+CD206+ macrophages and promoted the messenger RNA expression of Arg‐1, CD206, and IL‐10 at both in vivo and in vitro levels. In addition, macrophages showed lower expression of TNF‐α, IL‐1β, and IL‐6 and a decrease in F4/80+CD11c+ cells. Mechanistically, the level of phosphorylated STAT3 was elevated in unpolarized and restorative macrophages after treatment with fucoidan. Taken together, our findings suggest that fucoidan treatment inhibits OTM and enhances the stability of teeth after movement by promoting restorative macrophages through the STAT3 pathway.
3D revelation of phenotypic variation, evolutionary allometry, and ancestral states of corolla shape: a case study of clade Corytholoma (subtribe Ligeriinae, family Gesneriaceae)

Abstract Background Quantification of corolla shape variations helps biologists to investigate plant diversity and evolution. 3D images capture the genuine structure and provide comprehensive spatial information. Results This study applied X-ray micro-computed tomography (µCT) to acquire 3D structures of the corollas of clade Corytholoma and extracted a set of 415 3D landmarks from each specimen. By applying the geometric morphometrics (GM) to the landmarks, the first 4 principal components (PCs) in the 3D shape and 3D form analyses, respectively, accounted for 87.86% and 96.34% of the total variance. The centroid sizes of the corollas only accounted for 5.46% of the corolla shape variation, suggesting that the evolutionary allometry was weak. The 4 morphological traits corresponding to the 4 shape PCs were defined as tube curvature, lobe area, tube dilation, and lobe recurvation. Tube curvature and tube dilation were strongly associated with the pollination type and contained phylogenetic signals in clade Corytholoma. The landmarks were further used to reconstruct corolla shapes at the ancestral states. Conclusions With the integration of µCT imaging into GM, the proposed approach boosted the precision in quantifying corolla traits and improved the understanding of the morphological traits corresponding to the pollination type, impact of size on shape variation, and evolution of corolla shape in clade Corytholoma.