Miracle-dz/UniFAR-FTUs huggingface dataset:
Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

Model‐informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti‐infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug‐drug interactions. Examples are presented for state‐of‐the‐art, empiric, mechanistic, interdisciplinary, and real‐world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration‐based models, mechanism‐based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; “depth” and “breadth” of MIDD methods. “MIDD depth” refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired‐resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. “MIDD breadth” refers to greater adoption of model‐centered approaches to anti‐infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.
On the multiple orientation relationship of the Mg/γ-Mg17Al12 precipitation system

The six orientation relationships (ORs) found in the Mg/γ-Mg17Al12 precipitation system were summarized and systematically interpreted based on the atomic structure of the precipitate γ-Mg12Al17 and the invariant deformation element (IDE) model for diffusional phase transformations. It was found that the pseudo-twinning relationship between the six ORs is a reflection of the pseudo-twinning relationship between the close- or near-close-packing planes ({\overline 8}\hskip.75{\overline 7}\hskip.75{\overline 7}), ({\overline 4}11), (033), (411) and (8{\overline 7}\hskip.75{\overline 7}) in the precipitate γ-Mg12Al17. As a result, the Pitsch–Schrader OR is the starting point for the other five ORs. Multiple morphologies, growth directions and habit planes could be rationally interpreted by the IDE model. This implies that a multiple orientation relationship between the variants of precipitates is favourable in order to minimize the gross energy of precipitation systems in which the matrix has a simple structure while the precipitate has a complicated structure, such as Mg/γ-Mg12Al17, Mg/δ-Zn2Zr3 and Mg/η-MgZn2 couples.
Mechanical Properties of Homopolymer Interfaces: Transition from Simple Pullout to Crazing with Increasing Interfacial Width

The fracture toughness Gc of interfaces between several styrene-based homopolymers was investigated by the asymmetric double cantilever beam method while the width of the same interfaces ai was investigated in parallel by neutron reflectivity. Gc was found to be a direct function of ai provided that the molecular weights of the homopolymers were sufficiently high. The dependence of Gc on ai could be divided in three regimes: a low toughness regime for ai 11 nm where Gc was independent of ai. A molecular analysis of the transition from regime I to II showed that the average interpenetration distance of the homopolymers needed to activate the plastic deformation mechanisms was much less than the average distance between entanglement points in the bulk polymers. This result can be explained by the fact that a significant portion of the load-bearing strands may be loops rather than chain ends.
The difference of disrupted rhythms of life, work and entertainment between patients with FGIDs and healthy people and their associations with psychological disorders under COVID-19 pandemic

Aims: To investigate the differences in disrupted rhythms between healthy people and patients with functional gastrointestinal disorders (FGIDs) and their associations with mood disorders during the coronavirus disease 2019 (COVID-19) pandemic. Methods: The rhythm scales were composed of subscales 1 and 2 for the assessment of life-work and entertainment rhythms, respectively; Zung’s Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to assess mood disorders. Results: A total of 671 patients with FGIDs and 4373 healthy people successfully participated. The scores of subscales 1 and 2 for patients with FGIDs were significantly higher than those for healthy people (p < .005). The SAS and SDS scores, their prevalence rates were significantly higher than those for the healthy group (all p < .001). Health status, current occupation, life-work rhythm, SDS, and SAS were independent related factors of FGIDs. The score of life-work-entertainment rhythm was significantly positively correlated with SDS and SAS (both p < .001). Conclusion: Disrupted rhythms in patients with FGIDs under the COVID-19 pandemic were more frequently and significantly positively associated with mood disorders.
Role of MRI in idiopathic inflammatory myopathies: a review article

Idiopathic inflammatory myopathies are a rare heterogeneous group of chronic, autoimmune conditions characterized by the slow, progressive weakness of the skeletal muscles and inflammatory infiltrates in the muscle tissue. The predominant role of magnetic resonance imaging (MRI) in myositis imaging is to assess disease activity and to identify the target site for biopsy. Its role in phenotyping the disease is less explored. The aim of the present review was to examine the role of MRI in differentiating between the common inflammatory myopathies, i.e. dermatomyositis, polymyositis, and sporadic inclusion body myositis, and to describe the specific spectrum of MRI findings in various inflammatory myopathies.
Activation of bovine oocytes by protein synthesis inhibitors: new findings on the role of MPF/MAPKs†

Abstract The present study evaluated the mechanism by which protein synthesis inhibitors activate bovine oocytes. The aim was to analyze the dynamics of MPF and MAPKs. MII oocytes were activated with ionomycin (Io), ionomycin+anisomycin (ANY) and ionomycin+cycloheximide (CHX) and by in vitro fertilization (IVF). The expression of cyclin B1, p-CDK1, p-ERK1/2, p-JNK, and p-P38 were evaluated by immunodetection and the kinase activity of ERK1/2 was measured by enzyme assay. Evaluations at 1, 4, and 15 hours postactivation (hpa) showed that the expression of cyclin B1 was not modified by the treatments. ANY inactivated MPF by p-CDK1Thr14-Tyr15 at 4 hpa (P < 0.05), CHX increased pre-MPF (p-CDK1Thr161 and p-CDK1Thr14-Tyr15) at 1 hpa and IVF increased p-CDK1Thr14-Tyr15 at 17 hours postfertilization (hpf) (P < 0.05). ANY and CHX reduced the levels of p-ERK1/2 at 4 hpa (P < 0.05) and its activity at 4 and 1 hpa, respectively (P < 0.05). Meanwhile, IVF increased p-ERK1/2 at 6 hpf (P < 0.05); however, its kinase activity decreased at 6 hpf (P < 0.05). p-JNK in ANY, CHX, and IVF oocytes decreased at 4 hpa (P < 0.05). p-P38 was only observed at 1 hpa, with no differences between treatments. In conclusion, activation of bovine oocytes by ANY, CHX, and IVF inactivates MPF by CDK1-dependent specific phosphorylation without cyclin B1 degradation. ANY or CHX promoted this inactivation, which seemed to be more delayed in the physiological activation (IVF). Both inhibitors modulated MPF activity via an ERK1/2-independent pathway, whereas IVF activated the bovine oocytes via an ERK1/2-dependent pathway. Finally, ANY does not activate the JNK and P38 kinase pathways. Summary sentence Activation of bovine oocytes by protein synthesis inhibitors modulate MPF by CDK1-dependent specific phosphorylation and via an MAPKs-independent pathway.
Cortical Activity Linked to Clocking in Deaf Adults: fNIRS Insights with Static and Animated Stimuli Presentation

The question of the possible impact of deafness on temporal processing remains unanswered. Different findings, based on behavioral measures, show contradictory results. The goal of the present study is to analyze the brain activity underlying time estimation by using functional near infrared spectroscopy (fNIRS) techniques, which allow examination of the frontal, central and occipital cortical areas. A total of 37 participants (19 deaf) were recruited. The experimental task involved processing a road scene to determine whether the driver had time to safely execute a driving task, such as overtaking. The road scenes were presented in animated format, or in sequences of 3 static images showing the beginning, mid-point, and end of a situation. The latter presentation required a clocking mechanism to estimate the time between the samples to evaluate vehicle speed. The results show greater frontal region activity in deaf people, which suggests that more cognitive effort is needed to process these scenes. The central region, which is involved in clocking according to several studies, is particularly activated by the static presentation in deaf people during the estimation of time lapses. Exploration of the occipital region yielded no conclusive results. Our results on the frontal and central regions encourage further study of the neural basis of time processing and its links with auditory capacity.
Green synthesis of cerium oxide nanoparticles using Acorus calamus extract and their antibiofilm activity against bacterial pathogens

The emergence of multidrug resistance in bacterial pathogens has increased drastically and it has become prevalent in clinical infections. In last few decades, there is a large gap in the discovery of new antibiotics with novel mode of action. The situation of antimicrobial resistance has become so alarming that if not action is taken, infectious diseases will become major cause of global mortality and morbidity by 2050. The growing interest of researchers in nanotechnology and their possible application in healthcare is being seen as a new hope in discovery of novel antimicrobial agents. Among various approaches employed for the nanoparticle synthesis, biological methods are considered more advantageous and environment friendly. Biofilms are considered as novel target for the development of new antimicrobial entities. In this study, cerium oxide nanoparticles (CeO2‐NPs) were synthesized using Acorus calamus aqueous extract and tested for the antibiofilm activity both against Gram +ve and Gram −ve bacteria. The average size of synthesized CeO2‐NPs was found to be 22.03 nm. The biofilms of the test bacteria were inhibited by more than 75% by the treatment with CeO2‐NPs. The quantitative biofilm data were further verified by light microscopy, electron microscopy, and confocal microscopy. The confocal and electron microscopic analysis confirmed that treatment with CeO2‐NPs reduced the development and colonization of the bacteria on solid support. Moreover, it was found that the colonization and biofilm development by test bacteria were fairly reduced on the glass surface. Moreover, a dose‐dependent inhibition of preformed biofilms was also found. The exopolysaccharides (EPS) production by the test bacteria were substantially reduced by the supplementation of CeO2‐NPs in culture media. The findings of this study highlight the efficacy of cerium oxide nanoparticles against bacterial pathogens that may be exploited for the development of new alternative antimicrobial agent.
Dental, Occlusal, and Craniofacial Features of Children With Microcephaly Due to Congenital Zika Infection: 3 Cases Report From Valle del Cauca, Cali—Colombia—2020

Objective: Describes dental, occlusal, and craniofacial characteristics of 3 children aged 3 to 4 years with microcephaly due to congenital Zika infection in Cali Valle del Cauca, 2020. Design: Three children case report with congenital Zika virus microcephaly. Setting: Institutional Patients: Three children with maternal viral infection confirmed by polymerase chain reaction during first trimester of pregnancy were included and were born from 2016 to 2017. Interventions: Oral and mouth functional examination was performed including soft tissue examination; lingual and labial frenulum; evaluation of swallowing and chewing; craniofacial analysis; dimension of dental arch; intercanine and intermolar distance, palate form; relationship and growth of maxilla, mandible, and facial dental midline using plaster models; and complementary image analysis. Main Outcome Measures: Child and mother sociodemographic features, craniofacial measurements; dental and oral features; maxillary and mandibular measures; and speech, swallowing, and chewing disorders. Results: Small head circumference at birth and at the time of clinical evaluation was compared to normal children of approximately their age. Upper third of the face was short, and presence of hypertonic masticatory muscles with hypotonic swallowing muscles, dysphagia, dyslalia, bruxism, lip incompetence, tongue interposition, and hypersalivation and epilepsy were the main medical problem. They have complete primary dentition with normal dental morphology, tooth eruption altered, dental caries, and dental malocclusion was identified. Conclusion: There are no changes in the dental formula and dental morphology in the deciduous dentition. They present severe chewing and speaking limitation, facial disproportion, and occlusal problems that warrant dental and medical attention.
Principal Discriminant Variate Method for Classification of Multicollinear Data: Applications to Near-Infrared Spectra of Cow Blood Samples

A new regularized discriminant analysis technique, the principal discriminant variate (PDV) method, has been developed for effectively handling multicollinear data commonly encountered in multivariate spectroscopy-based classification. The motivation behind this method is to seek a sequence of discriminant directions that not only optimize the separability between different classes, but also account for a maximized variation present in the data. This motivation furnishes the PDV method with improved stability in prediction without significant loss of separability. Different formulations for the PDV methods are suggested, and an effective computing procedure is proposed for a PDV method. Two sets of near-infrared (NIR) spectra data, one corresponding to the blood plasma samples from two cows and the other associated with the whole blood samples from mastitic and healthy cows, have been used to evaluate the behavior of the PDV method in comparison with principal component analysis (PCA), discriminant partial least-squares (DPLS), soft independent modeling of class analogies (SIMCA), and Fisher linear discriminant analysis (FLDA). Results obtained demonstrate that the NIR spectra of blood plasma samples from different classes are clearly discriminated by the PDV method, and the proposed method provides superior performance to PCA, DPLS, SIMCA, and FLDA, indicating that PDV is a promising tool in discriminant analysis of spectra-characterized samples with only small compositional differences.
Estimation of the energetic parameters associated with the continuous aerobic biodegradation of phenol by monoculture of Pseudomonas aeruginosa and Pseudomonas fluorescence

The objective of this study was to estimate and analyse the growth parameters of indigenous monoculture of Pseudomonas aeruginosa and Pseudomonas fluorescence on phenol in an aerobic chemostat culture. The biodegradation data were checked for consistency using carbon and available electron balances and growth parameters were estimated using two forms of growth models: reparameterised Pirt’s model based on Monod approach and a modified model based on substrate consumption rate. The results showed that the biodegradation data were consistent; growth parameter estimates using the two forms of models were similar and that phenol could be oxidatively metabolised with a maximum of about 35.4%–36% and 31%–33% of the energy contained in it incorporated into the P. aeruginosa and P. fluorescence biomass, respectively. The balance (63%–64.6%) for P. aeruginosa, and (67%–69%) for P. fluorescence, is evolved as heat with little energy needed for the maintenance of the respective organisms.
Multicellular 3D Models to Study Tumour-Stroma Interactions

Two-dimensional (2D) cell cultures have been the standard for many different applications, ranging from basic research to stem cell and cancer research to regenerative medicine, for most of the past century. Hence, almost all of our knowledge about fundamental biological processes has been provided by primary and established cell lines cultured in 2D monolayer. However, cells in tissues and organs do not exist as single entities, and life in multicellular organisms relies on the coordination of several cellular activities, which depend on cell–cell communication across different cell types and tissues. In addition, cells are embedded within a complex non-cellular structure known as the extracellular matrix (ECM), which anchors them in a three-dimensional (3D) formation. Likewise, tumour cells interact with their surrounding matrix and tissue, and the physical and biochemical properties of this microenvironment regulate cancer differentiation, proliferation, invasion, and metastasis. 2D models are unable to mimic the complex and dynamic interactions of the tumour microenvironment (TME) and ignore spatial cell–ECM and cell–cell interactions. Thus, multicellular 3D models are excellent tools to recapitulate in vitro the spatial dimension, cellular heterogeneity, and molecular networks of the TME. This review summarizes the biological significance of the cell–ECM and cell–cell interactions in the onset and progression of tumours and focuses on the requirement for these interactions to build up representative in vitro models for the study of the pathophysiology of cancer and for the design of more clinically relevant treatments.
Septins coordinate cell wall integrity and lipid metabolism in a sphingolipid-dependent process

During normal development and response to environmental stress, fungi must coordinate synthesis of the cell wall and plasma membrane. Septins, small cytoskeletal GTPases, colocalize with membrane sterol-rich regions and facilitate recruitment of cell wall synthases during dynamic wall remodeling. In this study we show that null mutants missing an Aspergillus nidulans core septin present in hexamers and octamers (ΔaspAcdc11, ΔaspBcdc3, or ΔaspCcdc12) are sensitive to multiple cell wall-disturbing agents known to activate the cell wall integrity MAPK pathway and that this sensitivity can be remediated by osmotic support. The null mutant missing the octamer-exclusive core septin (ΔaspDcdc10) showed similar osmotic-remedial sensitivity, but only to a single cell wall-disturbing agent and the null mutant missing the noncore septin (ΔaspE) showed very mild osmotic-remedial sensitivity to a different single agent. Representative core septin null mutants showed changes in cell wall polysaccharide composition, organization, and chitin synthase localization. Double mutant analysis with ΔmpkA suggested core septins interact with the cell wall integrity pathway. Null mutants missing any of the five septins were resistant to ergosterol-disrupting agents. The ΔaspAcdc11, ΔaspBcdc3, and ΔaspCcdc12 mutants showed increased sensitivity to sphingolipid-disrupting agents that was remediated by addition of exogenous phytosphingosine. Representative core septins were mislocalized after treatment with sphingolipid-disrupting agents, but not after treatment with ergosterol-disrupting agents. When challenged with both sphingolipid-disturbing and cell wall-disturbing agents in combination, remediation of the lipid defect restored proper growth to ΔaspAcdc11, ΔaspBcdc3, and ΔaspCcdc12, but remediation of the cell wall defect did not. Our data suggest that the core hexamer and octamer septins are involved in cell wall integrity signaling with the noncore septin playing a minor role; that all five septins are involved in monitoring ergosterol metabolism; that the hexamer septins are required for sphingolipid metabolism; and that septins require sphingolipids to coordinate the cell wall integrity response.
Bionic Integrated Positioning Mechanism Based on Bioinspired Polarization Compass and Inertial Navigation System

In this paper, to address the problem of positioning accumulative errors of the inertial navigation system (INS), a bionic autonomous positioning mechanism integrating INS with a bioinspired polarization compass is proposed. In addition, the bioinspired positioning system hardware and the integration model are also presented. Concerned with the technical issue of the accuracy and environmental adaptability of the integrated positioning system, the sun elevation calculating method based on the degree of polarization (DoP) and direction of polarization (E-vector) is presented. Moreover, to compensate for the latitude and longitude errors of INS, the bioinspired positioning system model combining the polarization compass and INS is established. Finally, the positioning performance of the proposed bioinspired positioning system model was validated via outdoor experiments. The results indicate that the proposed system can compensate for the position errors of INS with satisfactory performance.
Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by Campylobacter jejuni, is a tripartite genotoxin composed of CdtA, CdtB, and CdtC subunits. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against radioresistant PCa.