Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel water soluble bis(μ‐chloro) bridged Cu(II) binuclear and mononuclear complexes: Synthesis, characterization and biological evaluation

A water soluble chloro bridged binuclear copper(II) complex (3) and mononuclear complex (4) have been synthesized from chloro substituted 2-oxo-1,2-dihydroquinolin-3-yl-methylene-2 hydroxybenzohydrazide 1 and 2 and CuCl2·2H2O. The structures of the complexes have been determined by single crystal X-ray diffraction. The binding interactions of the ligands and complexes with CT-DNA and protein have been evaluated by absorption and emission spectroscopic method. CT-DNA and ethidium bromide (EB) competitive studies revealed that the compounds could interact with CT-DNA through intercalation binding mode. Interactions of the compounds with BSA were also studied by UV−visible, fluorescence and synchronous fluorescence spectroscopic methods which showed that the compounds had a strong binding affinity with BSA through static quenching process. The cytotoxic effect of the compounds examined on cancer cell lines, such as A549 (lung cancer) and MCF7 (breast cancer) cell lines showed that all four compounds exhibited substantial cytotoxic activity.
Assessing the risk of acute kidney injury after primary PCI: The simpler the sooner the better

• In patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), five simple variables unrelated to the procedure may accurately identify those at increased risk of contrast-associated acute kidney injury (CA-AKI). • Assessing the risk of CA-AKI at the time of hospital admission for STEMI may facilitate the timely implementation of adequate preventive measures and inform patient centered decisions. • Further research is needed to identify optimal hydration protocols and adjunctive therapies aimed a mitigating the risk of CA-AKI after primary PCI.
Energetics of a protein disorder–order transition in small molecule recognition

Many proteins recognise other proteins via mechanisms that involve the folding of intrinsically disordered regions upon complex formation. Here we investigate how the selectivity of a drug-like small molecule arises from its modulation of a protein disorder-to-order transition. Binding of the compound AM-7209 has been reported to confer order upon an intrinsically disordered ‘lid’ region of the oncoprotein MDM2. Calorimetric measurements revealed that truncation of the lid region of MDM2 increases the apparent dissociation constant of AM-7209 250-fold. By contrast, lid truncation has little effect on the binding of the ligand Nutlin-3a. Insights into these differential binding energetics were obtained via a complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations. The simulations reveal that in apo MDM2 the ordered lid state is energetically disfavoured. AM-7209, but not Nutlin-3a, shows a significant energetic preference for ordered lid conformations, thus shifting the balance towards ordering of the lid in the AM-7209/MDM2 complex. The methodology reported herein should facilitate broader targeting of intrinsically disordered regions in medicinal chemistry.
A toolbox for studying cortical physiology in primates

Lesioning and neurophysiological studies have facilitated the elucidation of cortical functions and mechanisms of functional recovery following injury. Clinical translation of such studies is contingent on their employment in non-human primates (NHPs), yet tools for monitoring and modulating cortical physiology are incompatible with conventional NHP lesioning techniques. To address these challenges, we developed a toolbox demonstrated in seven macaques. We introduce the photothrombotic method to induce focal cortical lesions alongside a quantitative model for the design of lesion profiles based on experimental needs. Large-scale (∼5 cm2) vascular and neural dynamics can be monitored and lesion induction can be validated in vivo with optical coherence tomography angiography and our electrocorticographic array, the latter of which also enables testing stimulation-based interventions. By combining optical and electrophysiological techniques in NHPs, we can enhance our understanding of cortical functions, investigate functional recovery mechanisms, integrate physiological and behavioral findings, and develop treatments for neurological disorders.
Membrane Remodeling and Matrix Dispersal Intermediates During Mammalian Acrosomal Exocytosis

To become fertilization-competent, mammalian sperm must undergo a complex series of biochemical and morphological changes in the female reproductive tract. These changes, collectively called capacitation, culminate in the exocytosis of the acrosome, a large vesicle overlying the nucleus. Acrosomal exocytosis is not an all-or-nothing event, but rather a regulated process in which vesicle cargo disperses gradually. However, the structural mechanisms underlying this controlled release remain undefined. In addition, unlike other exocytotic events, fusing membranes are shed as vesicles; the cell thus loses the entire anterior two-thirds of its plasma membrane and yet remains intact while the remaining non-vesiculated plasma membrane becomes fusogenic. Precisely how cell integrity is maintained through-out this drastic vesiculation process is unclear, as is how it ultimately leads to the acquisition of fusion competence. Here, we use cryo-electron tomography to visualize these processes in unfixed, unstained, fully-hydrated sperm. We show that crystalline structures within the acrosome disassemble during capacitation and acrosomal exocytosis, representing a plausible mechanism for gradual dispersal of the acrosomal matrix. We find that the architecture of the sperm head supports an atypical membrane fission-fusion pathway that maintains cell integrity. Finally, we detail how the acrosome reaction transforms both the micron-scale topography and the nano-scale protein landscape of the sperm surface, thus priming the sperm for fertilization. Significance Mammalian sperm must undergo a complex series of biochemical and morphological changes in the female reproductive tract in order to become fertilization-competent. These changes culminate in acrosomal exocytosis, during which multiple membrane fusions destabilize the acrosomal vesicle and liberate its contents, which include proteins implicated in penetrating and binding to the egg vestments. Here, we use cryo-electron tomography to visualize acrosomal exocytosis intermediates in unfixed, unstained sperm. Our results suggest structural bases for how gradual dispersal of acrosome contents is regulated, as well as for how the cell remains intact after losing much of its plasma membrane, We also show that acrosomal exocytosis transforms both the micron-scale topography and the nano-scale molecular landscape of the sperm surface, thus priming it for interaction and fusion with the egg. These findings yield important insights into sperm physiology and contribute to our understanding of the fundamental yet enigmatic process of mammalian fertilization.
Inferring inter- and intrachromosomal Dobzhansky-Muller incompatibilities from imbalanced segregation of recombinant haplotypes in hybrid populations

Dobzhansky-Muller incompatibilities (DMIs) are a major component of reproductive isolation between species. DMIs imply negative epistasis, exposed when two diverged populations hybridize. Mapping the locations of DMIs has largely relied on classical genetic mapping, but these approaches are stymied by low power and the challenge of identifying DMI loci on the same chromosome, because strong initial linkage of parental haplotypes weakens statistical tests. Here, we propose new statistics to infer negative epistasis from haplotype frequencies in hybrid populations. When two divergent populations hybridize, the variance of two-locus heterozygosity decreases faster with time at DMI loci than at random pairs of loci. If two populations hybridize at near-even admixture proportions, the deviation of the observed variance from its expectation is negative, which enables us to detect signals of intermediate to strong negative epistasis both within and between chromosomes. When the initial proportion of the two parental populations is uneven, only strong DMIs can be detected with our method, unless migration reintroduces haplotypes from the minor parental population. We use the two new statistics to infer candidate DMIs from three hybrid populations of swordtail fish. We identify numerous new DMI candidates some of which are inferred to interact with several loci within and between chromosomes. Moreover, we discuss our results in the context of an expected enrichment in intrachromosomal over interchromosomal DMIs.
Cancer Cells Viscoelasticity Measurement by Quantitative Phase and Flow Stress Induction

Cell viscoelastic properties are affected by the cell cycle, differentiation, pathological processes such as malignant transformation. Therefore, evaluation of the mechanical properties of the cells proved to be an approach to obtaining information on the functional state of the cells. Most of the currently used methods for cell mechanophenotypisation are limited by low robustness or the need for highly expert operation. In this paper, the system and method for viscoelasticity measurement using shear stress induction by fluid flow is described and tested. Quantitative Phase Imaging (QPI) is used for image acquisition because this technique enables to quantify optical path length delays introduced by the sample, thus providing a label-free objective measure of morphology and dynamics. Viscosity and elasticity determination were refined using a new approach based on the linear system model and parametric deconvolution. The proposed method allows high-throughput measurements during live cell experiments and even through a time-lapse, where we demonstrated the possibility of simultaneous extraction of shear modulus, viscosity, cell morphology, and QPI-derived cell parameters like circularity or cell mass. Additionally, the proposed method provides a simple approach to measure cell refractive index with the same setup, which is required for reliable cell height measurement with QPI, an essential parameter for viscoelasticity calculation. Reliability of the proposed viscoelasticity measurement system was tested in several experiments including cell types of different Young/shear modulus and treatment with cytochalasin D or docetaxel, and an agreement with atomic force microscopy was observed. The applicability of the proposed approach was also confirmed by a time-lapse experiment with cytochalasin D washout, where an increase of stiffness corresponded to actin repolymerisation in time. SIGNIFICANCE We present an approach for viscoelasticity measurement using QPI and shear stress induction by fluid flow. Our system builds and extends a recently published approach by parametric deconvolution, which allows us to eliminate the influence of the fluidic system and reliably measure both the shear modulus and viscosity of the cells in high throughput. Additionally, the proposed method enables to simultaneously determine cell refractive index map, cell dry mass map, and morphology, thereby enabling a multimodal cellular characterisation in a single measurement.
Co-translational biogenesis of lipid droplet integral membrane proteins

Membrane proteins destined for lipid droplets (LDs), a major intracellular storage site for neutral lipids, are inserted into the endoplasmic reticulum (ER) and then trafficked to LDs where they reside in a hairpin loop conformation. Here, we show that LD membrane proteins can be delivered to the ER either co- or post-translationally and that their membrane-embedded region specifies pathway selection. The co-translational route for LD membrane protein biogenesis is insensitive to a small molecule inhibitor of the Sec61 translocon, Ipomoeassin F, and instead relies on the ER membrane protein complex (EMC) for membrane insertion. Strikingly, this route can also result in a transient exposure of the short N-termini of LD membrane proteins to the ER lumen, followed by topological rearrangements that enable their transmembrane segment to form a hairpin loop and N-termini to face the cytosol. Our study reveals an unexpected complexity to LD membrane protein biogenesis and identifies a role for the EMC during their co-translational insertion into the ER. SUMMARY STATEMENT Insertion of many lipid droplet membrane proteins into the endoplasmic reticulum (ER) is co-translational, mediated by the ER membrane protein complex (EMC) and involves topology reorientation.
Conjugates for use in peptide therapeutics: A systematic review and meta-analysis

While peptides can be excellent therapeutics for several conditions, their limited in vivo half-lives have been a major bottleneck in the development of therapeutic peptides. Conjugating the peptide to an inert chemical moiety is a strategy that has repeatedly proven to be successful in extending the half-life of some therapeutics. This systematic review and meta-analysis was conducted to examine the available literature and assess it in an unbiased manner to determine which conjugates, both biological and synthetic, provide the greatest increase in therapeutic peptide half-life. Systematic searches run on PubMed, Scopus and SciFinder databases resulted in 845 studies pertaining to the topic, 16 of these were included in this review after assessment against pre-specified inclusion criteria registered on PROSPERO (#CRD42020222579). The most common reasons for exclusion were non-IV administration and large peptide size. Of the 16 studies that were included, a diverse suite of conjugates that increased half-life from 0.1 h to 33.57 h was identified. Amongst these peptides, the largest increase in half-life was seen when conjugated with glycosaminoglycans. A meta-analysis of studies that contained fatty acid conjugates indicated that acylation contributed to a statistically significant extension of half-life. Additionally, another meta-analysis followed by a sensitivity analysis suggested that conjugation with specifically engineered recombinant peptides might contribute to a more efficient extension of peptide half-life as compared to PEGylation. Moreover, we confirmed that while polyethylene glycol is a good synthetic conjugate, its chain length likely has an impact on its effectiveness in extending half-life. Furthermore, we found that most animal studies do not include as much detail when reporting findings as compared to human studies. Inclusion of additional experimental detail on aspects such as independent assessment and randomization may be an easily accomplished strategy to drive more conjugated peptides towards clinical studies.
Evolutionary origin of sex differentiation system in insects

The evolution of the functionality of genes and genetic systems is a major source of animal diversity. Its best example is insect sex differentiation systems: promoting male and female differentiation (dual-functionality) or only male differentiation (single-functionality). However, the evolutionary origin of such functional diversity is largely unknown. Here, we investigate the ancestral functions of doublesex, a key factor of insect sex differentiation system, using the apterygote insect, Thermobia domestica, and reveal that its doublesex is essential for only males at the phenotypic level, but contributes to promoting female-specific vitellogenin expression in females. This functional discordance between the phenotypic and transcription-regulatory levels in T. domestica shows a new type of functionality of animal sex differentiation systems. Then, we examine how the sex differentiation system transited from the single-functionality to the dual-functionality in phenotypes and uncover that a conserved female-specific motif of doublesex is detected in taxa with the dual-functional doublesex. It is estimated that the role of the sex differentiation system for female phenotypes may have evolved through accumulating mutations in the protein motif structures that led to the enhancement of its transcription-regulatory function.
KIF2C regulates synaptic plasticity and cognition by mediating dynamic microtubule invasion of dendritic spines

Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed polymerization especially the depolymerization mechanism that regulates dynamic microtubules in synapses is still unclear. In this study, we find that KIF2C, a dynamic microtubule depolymerization protein without known function in the nervous system, plays a vital role in the structural and functional plasticity of synapses and regulates cognitive function. Using RNAi knockdown and conditional knockout approaches, we showed that KIF2C regulates spine morphology and synaptic membrane expression of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Moreover, KIF2C deficiency leads to impaired excitatory transmission, long-term potentiation, and altered cognitive behaviors in mice. Mechanistically, KIF2C regulates microtubule dynamics and microtubule invasion of spines in neurons by its microtubule depolymerization capability in a neuronal activity-dependent manner. This study explores a novel function of KIF2C in the nervous system and provides an important regulatory mechanism on how microtubule invasion of spines regulates synaptic plasticity and cognition behaviors.
The heterogeneity of the DNA damage response landscape determines patient outcomes in ovarian cancer

Defective DNA damage response (DDR) pathways allow cancer cells to accrue genomic aberrations and evade normal cellular growth checkpoints. Defective DDR also determines response to chemotherapy. However, the interaction and overlap between the two double strand repair pathways and the three single strand repair pathways is complex, and has remained poorly understood. Here we show that, in ovarian cancer, a disease hallmarked by chromosomal instability, explant cultures show a range of DDR abrogation patterns. Defective homologous recombination (HR) and non-homologous end joining (NHEJ) are near mutually exclusive with HR deficient (HRD) cells showing increased abrogation of the single strand repair pathways compared to NHEJ defective cells. When combined with global markers of DNA damage, including mitochondrial membrane functionality and reactive oxygen species burden, the pattern of DDR abrogation allows the construction of DDR signatures which are predictive of both ex vivo cytotoxicity, and more importantly, patient outcome. Significance Holistic assessment of the DDR is possible, shows improved ability to predict response to chemotherapy over single pathway assessment, and is applicable to a variety of ovarian cancer types. Such an assessment has clinical utility in settings of therapeutic dilemma such as retreatment for relapse.
Dataset on Emotions using Naturalistic Stimuli (DENS)

Emotion is a constructed phenomenon that emerges from the dynamic interaction of multiple components neurologically, physiologically and behaviorally. Such dynamics can not be captured by static and controlled experiments. Hence, the study of emotion with a naturalistic paradigm is needed. In this dataset, multimedia naturalistic stimuli are used to acquire the emotional dynamics using EEG, ECG, EMG and behavioural scales. The stimuli are multimedia videos collected from youtube for 372 affective words, analyzed with multimedia content analysis to filter out non-emotional stimuli and then validated with university students. The validated stimuli had the least variance in subjective ratings on self-assessment scales. The stimuli are then used to acquire neurological dynamics along with peripheral channels and subjective ratings-valence, arousal, dominance, liking, familiarity, relevance and emotion category. Both the raw data and pre-processed data is provided along with the pre-processing pipeline. This data can be utilized to study dynamic activation and connectivity in the whole brain source localization study, understand the mutual interaction between the central and autonomic nervous system, understand temporal hierarchy using multiresolution tools, and perform machine learning-based classification and complex networks analysis. The data is accessible at 10.18112/openneuro.ds003751. v1.0. 0
Integrated transcriptomic meta-analysis provides novel insights into breast cancer molecular subtypes

Breast cancer is the most common cancer in women worldwide. There are four major breast cancer subtypes (luminal A, luminal B, HER2-enriched and triple-negative/TNBC). TNBC is the most aggressive form with the worst prognosis. However, the differences among the subtypes have not been completely established at the molecular level, thereby limiting therapeutic and diagnostic options for TNBC. We performed a meta-analysis of microarray and RNA-sequencing data to identify candidate genes with an expression-based association in each molecular subtype of breast cancer. The protein interaction network of the candidate genes was analyzed to discover functionally significant gene clusters and hub genes. Potential therapeutic candidates for TNBC were explored through gene-miRNA interactions. We identified 316, 347, 382, and 442 candidate genes in luminal A, luminal B, HER2 and TNBC subtypes, respectively. A total of 135 (26 up- and 109 down-regulated) candidate genes were shared by all four subtypes. Functional analysis of the candidate genes indicated up-regulation of ‘cell cycle’ and ‘p53 signaling’ pathways and down-regulation of multiple signaling pathways. COL10A1 was found to be highly up-regulated in all subtypes. It may be a good target for research towards multiple types of applications, including therapeutics. KIF4A, a commonly up-regulated X-chromosome gene was significantly associated with the survival of breast cancer patients. Protein interaction network and centrality analysis revealed that low-moderately differentially regulated genes play an important role in functional cascades across proteins in breast cancer subtypes and may be potential candidates for therapeutics. Targeting FN1 (fibronectin 1), the key up-regulated hub gene by miR-1271 5p may be an important molecular event to be targeted for potential therapeutic application in TNBC.
Virucidal activity of CPC-containing oral rinses against SARS-CoV-2 variants and are active in the presence of human saliva

The role of human saliva in aerosol-based transmission of SARS-CoV-2 has highlighted the need to understand the potential of oral hygiene products to inactivate the virus. Here we examined the efficacy of mouthwashes containing cetylpyridinium chloride (CPC) or chlorhexidine (CHX) in inactivating SARS-CoV-2. After 30 seconds contact under standard aqueous conditions CPC mouthwashes achieved a ≥4.0log10 PFU/mL reduction in SARS-CoV-2 (USA-WA1/2020) titres whereas comparable products containing CHX achieved <2.0log10 PFU/mL reduction. Further testing with CPC mouthwashes demonstrated efficacy against multiple SARS-CoV-2 variants, with inactivation below the limit of detection observed against the Alpha (B.1.1.7), Beta (B.1.351) and Gamma (P.1) variants. Virucidal efficacy of CPC mouthwash was also observed in the presence of human saliva with the product delivering ≥4.0log10 PFU/mL reduction in SARS-CoV-2 titres after 30 seconds providing additional evidence for the virucidal efficacy of CPC mouthwashes under simulated physiological conditions. Together these data suggest CPC-based mouthwashes are effective at inactivating SARS-CoV-2 and further supports the use of mouthwash to mitigate the risk of transmission during dentistry procedures.