Miracle-dz/UniFAR-FTUs huggingface dataset:
Styrylpyridinium Derivatives as New Potent Antifungal Drugs and Fluorescence Probes

The incidence of Candida glabrata infections increases every year due to its higher resistance to commonly used antifungal drugs. We characterized the antifungal mechanism of action of eight new styrylpyridinium derivatives, with various N-alkyl chains (-C6H13, -C8H17, -C10H21, -C12H25) and different substituents, on C. glabrata strains differing in their drug resistance due to the presence or absence of two major drug-efflux pumps. We found that the tested styrylpyridinium compounds affected the growth of C. glabrata cells in a compound- and strain-dependent manner, and apparently they were substrates of CgCdr1 and CgCdr2 pumps. Further, we determined the impact of the tested compounds on plasma membrane integrity. The ability to cause damage to a plasma membrane depended on the compound, its concentration and the presence of efflux pumps, and corresponded well with the results of growth and survival tests. We also tested possible synergism with three types of known antifungal drugs. Though we did not observe any synergism with azole drugs, styrylpyridinium compounds 5 and 6 together with FK506 demonstrated excellent antifungal properties, whereas compounds 2, 3, 5, and 6 exhibited a significant synergistic effect in combination with terbinafine. Based on our results, derivatives 2 and 6 turned out to be the most promising antifungal drugs. Moreover, compound 6 was not only able to effectively permeabilize the yeast plasma membrane, but also exhibited significant synergism with FK506 and terbinafine. Finally, we also characterized the spectroscopic properties of the tested styrylpyridinium compounds. We measured their absorption and fluorescence spectra, determined their localization in yeast cells and found that their fluorescence characteristics differ from the properties of current commercial vacuolar styrylpyridinium markers and allow multi-color staining. Compounds 1, 3, 7, and 8 were able to accumulate in plasma and vacuolar membranes, and compounds 2, 5, and 6 stained the whole interior of dead cells. In summary, of the eight tested compounds, compound 6 is the most promising antifungal drug, compound 8, due to its minimal toxicity, is the best candidate for a new vacuolar-membrane probe or new benchmark substrate of C. glabrata Cdr pumps, and derivative 5 for a new vital dye.
Automated Detection of Acute Lymphoblastic Leukemia From Microscopic Images Based on Human Visual Perception

Microscopic image analysis plays a significant role in initial leukemia screening and its efficient diagnostics. Since the present conventional methodologies partly rely on manual examination, which is time consuming and depends greatly on the experience of domain experts, automated leukemia detection opens up new possibilities to minimize human intervention and provide more accurate clinical information. This paper proposes a novel approach based on conventional digital image processing techniques and machine learning algorithms to automatically identify acute lymphoblastic leukemia from peripheral blood smear images. To overcome the greatest challenges in the segmentation phase, we implemented extensive pre-processing and introduced a three-phase filtration algorithm to achieve the best segmentation results. Moreover, sixteen robust features were extracted from the images in the way that hematological experts do, which significantly increased the capability of the classifiers to recognize leukemic cells in microscopic images. To perform the classification, we applied two traditional machine learning classifiers, the artificial neural network and the support vector machine. Both methods reached a specificity of 95.31%, and the sensitivity of the support vector machine and artificial neural network reached 98.25 and 100%, respectively.
Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin–melanocortin pathway (LEP, LEPR, POMC, BDNF, MC4R, PCSK1, SIM1, BDNF, TrkB, etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity (FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2, among others) and with neurodegenerative or neurodevelopmental diseases (APOE, CD38, SIRT1, TNFα, PAI-1, TREM2, SYT4, FMR1, TET3, among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene–environment would lead to a better understanding of the etiology of these diseases.
Right Temporoparietal Junction Modulates In-Group Bias in Facial Emotional Mimicry: A tDCS Study

The present study employs transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, to explore the possible role of the right temporoparietal junction (rTPJ) in regulating in-group bias in facial emotional mimicry. Participants received either anodal or cathodal stimulation, or they were assigned to a sham condition. After that, they passively viewed a series of video clips depicting different emotions (happiness and anger) that were performed either by ethnic in-group or out-group models. The emotion-specific muscle activities, zygomatic major (ZM) and corrugator supercilii (CS) were recorded simultaneously as the index of facial emotional mimicry. The results first confirm the in-group bias in facial emotional mimicry in the sham condition, as shown in prior studies, though it only occurs in happy mimicry. Moreover, the in-group bias in facial emotional mimicry is modulated by the cortical excitability over the rTPJ, which may be attributed to the accompanied change of overlap of the mental representations of in-group and out-group. This study provides a close look at the neural underpinning of the modulation of facial emotional mimicry by group membership and highlights the role of rTPJ in on-line control of co-activated self and other representations in social cognition.
Increased Neutrophil Count and Decreased Neutrophil CD15 Expression Correlate With TB Disease Severity and Treatment Response Irrespective of HIV Co-infection

Tuberculosis remains a leading cause of death globally despite curative treatment, partly due to the difficulty of identifying patients who will not respond to therapy. Simple host biomarkers that correlate with response to drug treatment would facilitate improvement in outcomes and the evaluation of novel therapies. In a prospective longitudinal cohort study, we evaluated neutrophil count and phenotype at baseline, as well as during TB treatment in 79 patients [50 (63%) HIV-positive] with microbiologically confirmed drug susceptible TB undergoing standard treatment. At time of diagnosis, blood neutrophils were highly expanded and surface expression of the neutrophil marker CD15 greatly reduced compared to controls. Both measures changed rapidly with the commencement of drug treatment and returned to levels seen in healthy control by treatment completion. Additionally, at the time of diagnosis, high neutrophil count, and low CD15 expression was associated with higher sputum bacterial load and more severe lung damage on chest x-ray, two clinically relevant markers of disease severity. Furthermore, CD15 expression level at diagnosis was associated with TB culture conversion after 2 months of therapy (OR: 0.14, 95% CI: 0.02, 0.89), a standard measure of early TB treatment success. Importantly, our data was not significantly impacted by HIV co-infection. These data suggest that blood neutrophil metrics could potentially be exploited to develop a simple and rapid test to help determine TB disease severity, monitor drug treatment response, and identify subjects at diagnosis who may respond poorly to treatment.
Does an Optimal Relationship Between Injury Risk and Workload Represented by the “Sweet Spot” Really Exist? An Example From Elite French Soccer Players and Pentathletes

Objective To examine the relationships between the occurrence and severity of injuries using three workload ratios (ACWR, EWMA, REDI) in elite female soccer players and international male and female pentathletes. Materials and Methods Female soccer players in the U16 to U18 national French teams (n = 24) and international athletes (n = 12, 4 women and 8 men) in the French modern pentathlon team were monitored throughout an entire season. The Acute Chronic Workload Ratio (ACWR), the Exponentially Weighted Moving Averages (EWMA), and the Robust Exponential Decreasing Index (REDI) were calculated for internal load by the ROE method in soccer and external load in pentathlon. The occurrence and severity of injuries (determined according to time-loss) were quantified in the sweet spot zone [0.8; 1.3] and compared to the other zones of load variation: [0; 0.8], [1.3; 1.5], [1.5; +8], using the three ratios. Results Over the study period, a total of sixty-six injuries (2.75 per athlete) were reported in the soccer players and twelve in pentathletes (1 per athlete). The cumulative severity of all injuries was 788 days lost in soccer and 36 in pentathlon: respectively, 11.9 days lost per injury in soccer player and 3.0 per pentathlete. The mean values across the three methods in soccer showed a higher number of injuries detected in the [0; 0.8] workload ratio zone: 22.3 ± 6.4. They were 17.3 ± 3.5 in the sweet spot ([0.8–1.3] zone) and 17.6 ± 5.5 in the [1.5; +8] zone. In comparison to the [1.5; +8] zone, soccer players reported a higher number of days lost to injuries in the presumed sweet spot and in the [0–0.8] zone: 204.7 ± 28.7 and 275.0 ± 120.7 days, respectively. In pentathletes, ten of the twelve injuries (83.3%) occurred in the presumed sweet spot. REDI was the only method capable of tracking workloads over all-time series. Conclusion In the present cohort of elite soccer players and pentathletes, acute chronic workload calculations showed an association with injury occurrence and severity but did not provide evidence supporting existence of a sweet spot diminishing injury risk.
Immune Factor, TNFα, Disrupts Human Brain Organoid Development Similar to Schizophrenia—Schizophrenia Increases Developmental Vulnerability to TNFα

Schizophrenia (SZ) is a neurodevelopmental genetic disorder in which maternal immune activation (MIA) and increased tumor necrosis factor-α (TNF-α) may contribute. Previous studies using iPSC-derived cerebral organoids and neuronal cells demonstrated developmental malformation and transcriptional dysregulations, including TNF receptors and their signaling genes, common to SZ patients with diverse genetic backgrounds. In the present study, we examined the significance of the common TNF receptor dysregulations by transiently exposing cerebral organoids from embryonic stem cells (ESC) and from representative control and SZ patient iPSCs to TNF. In control iPSC organoids, TNF produced malformations qualitatively similar in, but generally less pronounced than, the malformations of the SZ iPSC-derived organoids. TNF and SZ alone disrupted subcortical rosettes and dispersed proliferating Ki67+ neural progenitor cells (NPC) from the organoid ventricular zone (VZ) into the cortical zone (CZ). In the CZ, the absence of large ramified pan-Neu+ neurons coincided with loss of myelinated neurites despite increased cortical accumulation of O4+ oligodendrocytes. The number of calretinin+ interneurons increased; however, they lacked the preferential parallel orientation to the organoid surface. SZ and SZ+TNF affected fine cortical and subcortical organoid structure by replacing cells with extracellular matrix (ECM)-like fibers The SZ condition increased developmental vulnerability to TNF, leading to more pronounced changes in NPC, pan-Neu+ neurons, and interneurons. Both SZ- and TNF-induced malformations were associated with the loss of nuclear (n)FGFR1 form in the CZ and its upregulation in deep IZ regions, while in earlier studies blocking nFGFR1 reproduced cortical malformations observed in SZ. Computational analysis of ChiPseq and RNAseq datasets shows that nFGFR1 directly targets neurogenic, oligodendrogenic, cell migration, and ECM genes, and that the FGFR1-targeted TNF receptor and signaling genes are overexpressed in SZ NPC. Through these changes, the developing brain with the inherited SZ genome dysregulation may suffer increased vulnerability to TNF and thus, MIA.
Physiological and PIP Transcriptional Responses to Progressive Soil Water Deficit in Three Mulberry Cultivars

Although mulberry cultivars Wubu, Yu711, and 7307 display distinct anatomical, morphological, and agronomic characteristics under natural conditions, it remains unclear if they differ in drought tolerance. To address this question and elucidate the underlying regulatory mechanisms at the whole-plant level, 2-month old saplings of the three mulberry cultivars were exposed to progressive soil water deficit for 5 days. The physiological responses and transcriptional changes of PIPs in different plant tissues were analyzed. Drought stress led to reduced leaf relative water content (RWC) and tissue water contents, differentially expressed PIPs, decreased chlorophyll and starch, increased soluble sugars and free proline, and enhanced activities of antioxidant enzymes in all plant parts of the three cultivars. Concentrations of hydrogen peroxide (H2O2), superoxide anion (O2 •−), and malonaldehyde (MDA) were significantly declined in roots, stimulated in leaves but unaltered in wood and bark. In contrast, except the roots of 7307, soluble proteins were repressed in roots and leaves but induced in wood and bark of the three cultivars in response to progressive water deficit. These results revealed tissue-specific drought stress responses in mulberry. Comparing to cultivar Yu711 and 7307, Wubu showed generally slighter changes in leaf RWC and tissue water contents at day 2, corresponding well to the steady PIP transcript levels, foliar concentrations of chlorophyll, O2 •−, MDA, and free proline. At day 5, Wubu sustained higher tissue water contents in green tissues, displayed stronger responsiveness of PIP transcription, lower concentrations of soluble sugars and starch, lower foliar MDA, higher proline and soluble proteins, higher ROS accumulation and enhanced activities of several antioxidant enzymes. Our results indicate that whole-plant level responses of PIP transcription, osmoregulation through proline and soluble proteins and antioxidative protection are important mechanisms for mulberry to cope with drought stress. These traits play significant roles in conferring the relatively higher drought tolerance of cultivar Wubu and could be potentially useful for future mulberry improvement programmes.
Novel Variation and Evolution of AvrPiz-t of Magnaporthe oryzae in Field Isolates

The product of the avirulence (Avr) gene of Magnaporthe oryzae can be detected by the product of the corresponding resistance (R) gene of rice and activates immunity to rice mediated by the R gene. The high degree of variability of M. oryzae isolates in pathogenicity makes the control of rice blast difficult. That resistance of the R gene in rice has been lost has been ascribed to the instability of the Avr gene in M. oryzae. Further study on the variation of the Avr genes in M. oryze field isolates may yield valuable information on the durable and effective deployment of R genes in rice production areas. AvrPiz-t and Piz-t are a pair of valuable genes in the Rice-Magnaporthe pathosystem. AvrPiz-t is detectable by Piz-t and determines the effectiveness of Piz-t. To effectively deploy the R gene Piz-t, the distribution, variation, and evolution of the corresponding Avr gene AvrPiz-t were found among 312 M. oryzae isolates collected from Yunnan rice production areas of China. PCR amplification and pathogenicity assays of AvrPiz-t showed that 202 isolates (64.7%) held AvrPiz-t alleles and were avirulent to IRBLzt-T (holding Piz-t). There were 42.3–83.3% avirulent isolates containing AvrPiz-t among seven regions in Yunnan Province. Meanwhile, 11 haplotypes of AvrPiz-t encoding three novel AvrPiz-t variants were identified among 100 isolates. A 198 bps insertion homologous to solo-LTR of the retrotransposon inago2 in the promoter region of AvrPiz-t in one isolate and a frameshift mutation of CDS in another isolate were identified among 100 isolates, and those two isolates had evolved to virulent from avirulent. Synonymous mutation and non-AUG-initiated N-terminal extensions keeps the AvrPiz-t gene avirulence function in M. oryzae field isolates in Yunnan. A haplotype network showed that H3 was an ancestral haplotype. Structure variance for absence (28.2%) or partial fragment loss (71.8%) of AvrPiz-t was found among 39 virulent isolates and may cause the AvrPiz-t avirulence function to be lost. Overall, AvrPiz-t evolved to virulent from avirulent forms via point mutation, retrotransposon, shift mutation, and structure variance under field conditions.
Sugar Signaling During Fruit Ripening

Sugars play a key role in fruit quality, as they directly influence taste, and thus consumer acceptance. Carbohydrates are the main resources needed by the plant for carbon and energy supply and have been suggested to be involved in all the important developmental processes, including embryogenesis, seed germination, stress responses, and vegetative and reproductive growth. Recently, considerable progresses have been made in understanding regulation of fruit ripening mechanisms, based on the role of ethylene, auxins, abscisic acid, gibberellins, or jasmonic acid, in both climacteric and non-climacteric fruits. However, the role of sugar and its associated molecular network with hormones in the control of fruit development and ripening is still poorly understood. In this review, we focus on sugar signaling mechanisms described up to date in fruits, describing their involvement in ripening-associated processes, such as pigments accumulation, and their association with hormone transduction pathways, as well as their role in stress-related responses.
The Challenges of Leveraging Threat Intelligence to Stop Data Breaches

Despite the significant increase in cybersecurity solutions investment, organizations are still plagued by security breaches, especially data breaches. As more organizations experience crippling security breaches, the wave of compromised data is growing significantly. The financial consequences of a data breach are set on the rise, but the cost goes beyond potential fines. Data breaches could have a catastrophic impact not only in loss of company's reputation and stock price, but also in economic terms. Threat Intelligence has been recently introduced to enable greater visibility of cyber threats, in order to better protect organizations' digital assets and prevent data breaches. Threat intelligence is the practice of integrating and analyzing disjointed cyber data to extract evidence-based insights regarding an organization's unique threat landscape. This helps explain who the adversary is, how and why they are comprising the organization's digital assets, what consequences could happen following the attack, what assets actually could be compromised, and how to detect or respond to the threat. Every organization is different and threat intelligence frameworks are custom-tailored to the business process itself and the organization's risks, as there is no “one-size-fits-all” in cyber. In this paper, we review the problem of data breaches and discuss the challenges of implementing threat intelligence that scales in today's complex threat landscape and digital infrastructure. This is followed by an illustration of how the future of effective threat intelligence is closely linked to efficiently applying Artificial Intelligence and Machine Learning approaches, and we conclude by outlining future research directions in this area.
Preparation of a Sensor Based on Biomass Porous Carbon/Covalent-Organic Frame Composites for Pesticide Residues Detection

In this work, a covalent-organic framework with high carbon and nitrogen content microstructures (named COF-LZU1), assisted by 3D nitrogen-containing kenaf stem composites (represented as COF-LZU1/3D-KSCs), was constructed. Moreover, it was utilized for immobilizing acetylcholinesterase (AChE) for identifying trichlorfon, a commonly applied organophosphorus (OP) pesticide. The development of COF-LZU1/3D-KSC was affirmed by SEM, PXRD, and EDXS. The findings confirmed that COF-LZU1 microstructures were uniformly developed on 3D-KSC holes using a one-step synthesis approach, which can substantially enhance the effective surface area. Also, the COF-LZU1/3D-KSC composite contains not only the nitrogen element in COF-LZU1 but also the nitrogen element in 3D-KSC, which will greatly improve the biocompatibility of the material. The AChE/COF-LZU1/3D-KSC integrated electrode was fabricated by directly fixing a large amount of AChE on the composite. At the same time, the integrated electrode had good detection efficiency for trichlorfon. Improved stabilization, a wide-linear-range (0.2–19 ng/mL), and a lower detection limit (0.067 ng/mL) have been displayed by the sensor. Therefore, this sensor can be used as an important platform for the on-site detection of OP residue.