Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolutionary Trajectory of the Replication Mode of Bacterial Replicons

Chromosome replication is an essential process for cell division. The mode of chromosome replication has important impacts on the structure of the chromosome and replication speed. ABSTRACT As typical bacterial replicons, circular chromosomes replicate bidirectionally and circular plasmids replicate either bidirectionally or unidirectionally. Whereas the finding of chromids (plasmid-derived chromosomes) in multiple bacterial lineages provides circumstantial evidence that chromosomes likely evolved from plasmids, all experimentally assayed chromids were shown to use bidirectional replication. Here, we employed a model system, the marine bacterial genus Pseudoalteromonas, members of which consistently carry a chromosome and a chromid. We provide experimental and bioinformatic evidence that while chromids in a few strains replicate bidirectionally, most replicate unidirectionally. This is the first experimental demonstration of the unidirectional replication mode in bacterial chromids. Phylogenomic and comparative genomic analyses showed that the bidirectional replication evolved only once from a unidirectional ancestor and that this transition was associated with insertions of exogenous DNA and relocation of the replication terminus region (ter2) from near the origin site (ori2) to a position roughly opposite it. This process enables a plasmid-derived chromosome to increase its size and expand the bacterium’s metabolic versatility while keeping its replication synchronized with that of the main chromosome. A major implication of our study is that the uni- and bidirectionally replicating chromids may represent two stages on the evolutionary trajectory from unidirectionally replicating plasmids to bidirectionally replicating chromosomes in bacteria. Further bioinformatic analyses predicted unidirectionally replicating chromids in several unrelated bacterial phyla, suggesting that evolution from unidirectionally to bidirectionally replicating replicons occurred multiple times in bacteria. IMPORTANCE Chromosome replication is an essential process for cell division. The mode of chromosome replication has important impacts on the structure of the chromosome and replication speed. Bidirectional replication is the rule for bacterial chromosomes, and unidirectional replication has been found only in plasmids. To date, no bacterial chromosomes have been experimentally demonstrated to replicate unidirectionally. Here, we showed that the chromids (plasmid-derived chromosomes) in Pseudoalteromonas replicate either uni- or bidirectionally and that a single evolutionary transition from uni- to bidirectionality explains this diversity. These uni- and bidirectionally replicating chromids likely represent two stages during the evolution from a small and unidirectionally replicating plasmid to a large and bidirectionally replicating chromosome. This study provides insights into both the physiology of chromosome replication and the early evolutionary history of bacterial chromosomes.
Pembrolizumab in the adjuvant treatment of melanoma: efficacy and safety

ABSTRACT Introduction: Regional or distant metastases from melanoma may be surgically resected but remain at high-risk of recurrence. Over the last few years, several treatments have been approved to mitigate this risk. These include anti-PD-1 agents, specifically pembrolizumab and nivolumab. Areas covered: Herein, we will discuss the landscape of pembrolizumab safety and efficacy used in the adjuvant setting for high-risk, resected melanoma. We place this in context with other available adjuvant therapies, and discuss subgroup analyses. Expert opinion: Anti-PD-1 therapy with either pembrolizumab or nivolumab has become a standard of care for patients with resected stage III or IV melanoma. In our practice, we generally offer these agents (which have comparable safety and efficacy profiles) to patients with resected stage IIIb–IV melanoma regardless of BRAF mutation status.
Retrospective evaluation of the performance of the electrical impedance spectroscopy system Nevisense in detecting keratinocyte cancers

Keratinocyte cancers, also referred to as non‐melanoma skin cancers (NMSCs), are one of the most common malignant skin tumors. We performed a retrospective analysis of lesions from patients of a private dermatology practice to evaluate the use of electrical impedance spectroscopy (EIS) in detecting keratinocyte malignancies. The aim of the study is to assess the accuracy of the technique and to rate its use as supportive tool in NMSC diagnosis.
Temperature sensitive microgel suspensions: Colloidal phase behavior and rheology of soft spheres

Rheological properties and the equilibrium colloidal phase behavior of concentrated dispersions of a temperature sensitive microgel were investigated. The temperature sensitive hydrogel particles consist of poly (N-isopropylacrylamid) (PNiPAM) chemically crosslinked with N,N′ methylenbisacrylamid (BIS). With increasing temperature the microgel particles decrease in size (hydrodynamic radius 142 nm at 10 °C and 58 nm at 35 °C) and with it the effective volume fraction, which leads to dramatic changes in rheology—vanishing yield stress and decreasing viscosity and elastic properties. The relative zero-shear viscosity and the plateau modulus at different temperatures superpose to mastercurves when plotted vs the effective volume fraction. The monodisperse hydrogel particles form colloidal crystals and glasses in concentrated solution but at higher effective volume fractions as compared to model hard sphere suspensions. Comparison of the experimental freezing point with soft sphere computer simulations indica.
Complete genome sequences of Chesapeake Bay Synechococcus strains CBW1002 and CBW1006 isolated in winter.

Synechococcus are picocyanobacteria with a cosmopolitan distribution. They are capable of surviving in a wide variety of environmental conditions such as temperature, salinity, turbidity, and many other environmental factors. Synechococcus have been isolated from the Chesapeake Bay during winter months and they show an impressive tolerance to cold temperatures. Cold adapted Synechococcus are unique and diverse, as they have complex phylogenetic lineages closely related to subalpine cluster II, Bornholm Sea cluster, CB7 cluster and some novel lineages which are independent from summer estuarine strains in subcluster 5.2. CBW1002 and CBW1006 are the first complete genomes to represent Bornholm Sea cluster Synechococcus strains. They have some of the largest genomes among the Synechococcus (3.8 Mb) and share many unique and cryptic homologs which could give insight into their ability to tolerate such cold and dynamic conditions in the Chesapeake Bay estuary.
[Establishment of a mouse model bearing orthotopic temozolomide-resistant glioma].

OBJECTIVE To establish a mouse model bearing orthotopic temozolomide (TMZ)-resistant glioma that mimics the development of drug resistance in gliomas in vivo. METHODS Seventy-eight adult C57BL/6 mice were randomly divided into 6 groups (n=13), including 3 TMZ induced groups with low, medium and high doses (5, 25, and 50 mg/kg, respectively) and 3 control groups. In each group, 5 mice were used for evaluating tumor size, 5 for observing survival, and 3 for collecting tumor tissues for primary cell culture. In low-dose TMZ induced group, 3 mice bearing orthotopic murine glioma GL261 cell xenografts received intraperitoneal injections of 5 mg/kg TMZ for 5 days followed by a 10-day washout period before collecting glioma tissues. Tumor cell suspensions were prepared and injected in the mice in the medium-dose group, which were treated with the same protocol but with an increased TMZ dose, and the tumor cells harvested from 3 mice were injected in the high-dose group. The mice bearing GL261 cell xenografts in the 3 control groups received no treatment or were injected with medium- or high-dose TMZ. Cell colony forming assay was used to assess TMZ resistance of each generation of the tumor cells; CCK8 assay was used to determine drug resistance index of the cells. RESULTS The mouse models bearing TMZresistant glioma was successfully established. The cells from the high-dose induced group showed a significantly higher colony-forming rate than those from the high-dose control group (P < 0.05), and had a drug resistance 4.25 times higher than that of the cells from untreated control group. High-dose TMZ significantly reduced the tumor volume in the control group (P < 0.05) but not in the high-dose induced group (P < 0.01). The survival time of the tumor-bearing mice was significantly shortened in the high-dose induced group (P=0.0018). CONCLUSIONS Progressive increase of TMZ doses in mice bearing orthotopic gliomas can effectively induce TMZ resistance of the gliomas.
Adiabatic Compressibility, Intermolecular Free Length and Specific Acoustic Impedance of Antibiotic Ceftriaxone Sodium

The nature and the relative strength of the intermolecular interaction between the components of the liquid mixtures have been successfully investigated by the ultrasonic method. The field of ultrasound is fairly vast and apart from day to day applications it is widely used in medical ultrasonic next to X-ray, non-destructive testing, acoustic in building etc. The molecular interactions in liquid provide valuable information about behavior of liquids and solutions. The thermodynamic and acoustical study elucidated the nature of interactions between molecules of liquids and solutions ceftriaxone sodium used as an antibiotic in pharmaceutical. The ultrasonic velocity and density have been measured for aqueous solution of ceftriaxone sodium at different concentrations, temperatures and different frequencies such as 2MHz, 4MHz and 6 MHz. From the experimental data, ultrasonic parameters such as adiabatic compressibility, specific acoustic impedance and intermolecular free length have been computed. The results are interpreted in terms of molecular interaction between components of aqueous solution of ceftriaxone sodium.
Trauma, mental health and the COVID-19 crisis: are we really all in it together?

As the world adapts to varying levels of social lockdown – and the lifting of restrictions – due to the COVID-19 pandemic, evidence is mounting that quarantine and other social restrictions negatively affect the mental health of the general population (Kumar & Nayar, 2020). This universal public health threat has impacted all communities, but there is a growing evidence base that different groups are more at risk from the virus. One group that we argue are at increased risk are survivors of childhood trauma; a population also disproportionately represented in mental health services (Sugaya et al., 2012). This editorial describes the triad of injuries impacting trauma survivors; and consider how these social, physical and psychological effects interact with the current COVID-19 pandemic. A careful balance is needed between recognising the life-changing impacts of traumatic injury whilst understanding the individual variation among survivors. Trauma aftermaths can be mitigated with access to meaningful support. We discuss evidence of increased risks to trauma survivors during the current pandemic, what specific support survivors might need, and how communities impacted by COVID-19 can learn from survivor activism. We are trauma survivor academics, students, activists and clinicians writing from different life experiences and identities. As this article was being written the global movement of Black Lives Matter has been reignited following the death of George Floyd. This has resonated for us in recognising the collective trauma caused by systemic racism, and the ways in which structural prejudice can interact with individual trauma leaving some people at increased risk of poor mental health and negative treatment in mental health services (e.g. McKenzie & Bhui, 2007). We want to be transparent that we cannot represent the voices of all survivors.
Coupling of a Novel TIMP3 Peptide to Carboxypeptidase G2 for Pro-Drug Activation at the Tumour Site

Broad-spectrum cytotoxic drugs have been used in cancer therapy for decades. However, their lack of specificity to cancer cells often results in serious side-effects, limiting efficacy. For this reason, antibodies have been used to attempt to specifically target cytotoxic drugs to tumours. One such approach is antibody-directed enzyme prodrug therapy (ADEPT) which uses a tumour-directed monoclonal antibody, coupled to an enzyme, to convert a systemically administered non-toxic prodrug into a toxic one only at the tumour site. Among the main drawbacks of ADEPT is the immunogenicity of the antibody-enzyme complex, which is exacerbated by slow clearance due to size, hence limiting repeated administration. Additionally, the mono-specificity of the antibody could potentially result in drug resistance with repeated administration. We have identified a novel short peptide sequence, p700, derived from a human tissue inhibitor of metalloproteinases-3 (TIMP-3), which binds to and inhibits a number of tyrosine kinase growth factor receptors (VEGFRs1-3, FGFRs 1-4 and PDGFRα) which are known to be upregulated in many tumours and tumour vasculature. In this report, we fused p700 to His-tagged, codon-optimised, carboxypeptidase G2 (CPG2). CPG2 is a bacterial enzyme used in ADEPT, which activates potent nitrogen-mustard pro-drugs by removal of an inhibitory glutamic acid residue. Recombinant CPG2-p700 was highly expressed in Escherichia coli and successfully purified by nickel affinity chromatography. Biolayer interferometry showed that CPG2-p700 had a 100-fold increase in binding affinity for VEGFR2 compared with CPG2 alone and retained its catalytic activity, as determined by methotrexate cleavage. In the presence of CPG2-p700, the ZD2676P pro-drug showed significant cytotoxicity for 4T1 cells compared with prodrug alone or CPG2 alone. p700 is, therefore, a potentially useful alternative to monoclonal antibodies for enzyme pro-drug therapy and could equally be used for effective delivery of other cytotoxic drugs to tumour tissue.
Facile depositing strategy to fabricate a hetero-affinity hybrid film for improving gas-sensing performance

A novel co-spray method was proposed to fabricate a reduced graphene oxide (rGO)-poly (3-hexylthiophene) (P3HT) hybrid sensing device utilizing immiscible solution for ammonia detection at room temperature. The spectrum and Scanning Electron Microscopy (SEM) results revealed uniformly crimped morphology and favorable π-π interaction for the hybrid film. The hybrid film-based sensor showed obviously enhanced ammonia sensing performance, such as increased response, reduced response time, and reinforced sensitivity, in comparison to bare rGO, P3HT, and traditional rGO/P3HT layered film-based sensors, which could be attributed to an adsorption energy barrier and the p-n heterojunction effect. The synergetic strengthened sensing mechanism is discussed. Meanwhile, recovery ratio was introduced to evaluate the abnormal baseline drift induced high-response behavior. The excellent sensing properties of the hybrid sensor indicate that the co-spray method could be an alternative process for the preparation of hetero-affinity hybrid films or functional devices.
Algorithm-Driven Substance Use Disorder Treatment for Inner-City Clients With Serious Mental Illness and Multiple Impairments

Abstract Mental health clients with serious mental illness in urban settings experience multiple chronic stresses related to poverty, unemployment, discrimination, homelessness, incarceration, hospitalization, posttraumatic stress disorder, pain syndromes, traumatic brain injury, and other problems. Substance use disorder exacerbates these difficulties. This study examined the efficacy of algorithm-driven substance use disorder treatments for 305 inner-city mental health clients with multiple challenges. Researchers assessed substance use quarterly using a combination of standardized self-reports and case manager ratings. Of the 305 multiply impaired clients who began treatment, 200 (66%) completed 2 years of treatment. One fourth (n = 53) of the completers were responders who developed abstinence and improved community function; one half (n = 97) were partial responders, who reduced substance use but did not become abstinent; and one fourth (n = 50) were nonresponders. Evidence-based interventions for substance use disorder can be effective for multiply impaired, inner-city clients, but numerous complications may hinder recovery.
High pressure phase diagram of helium-hydrogen calculated through fluid integral equations and density functional theory of freezing

The HMSA integral equation has been solved for the binary mixture He-H2 over a range of densities and compositions at 100 K and 300 K. Comparison of the radial distribution functions and the pressures shows that these results are in good agreement with those of two-component MC simulations close to the binodal curve or melting line. The HMSA equation of state rather than the usual van de Waals one fluid approximation was used to calculate the Gibbs free enthalpy; the latter was used to determine the fluid-fluid phase separation in the mixture. The spinodal curve calculated from the composition fluctuation structure factor SCC(k), is not consistent with the binodal curve, probably due to inconsistencies in this structure factor. The direct correlation functions that result from the integral equations were used to calculate the freezing of the mixture with the Haymet and Oxtoby version of density functional theory of freezing, where the grand potential of the solid is expanded up to second order. To force quantitative agreement with experimental results, the fourth star was omitted from the HCP reciprocal lattice. An important result is the solubility of helium in the hydrogen-rich solid of a few mole percent. The authors also find the interesting phenomenon of density inversion between the hydrogen-rich solid and the hydrogen-rich fluid.
Body Temperature-Triggered Mechanical Instabilities for High-Speed Soft Robots

Nature offers bionic inspirations for elegant applications of mechanical principles such as the concept of snap buckling, which occurs in several plants. Exploiting mechanical instabilities is the key to fast movement here. We use the snap-through and snap-back instability observed in natural rubber balloons to design an ultrafast purely mechanical elastomer actuator. Our design eliminates the need in potentially harmful stimulants, high voltages, and is safe in operation. We trigger the instability and thus the actuation by temperature changes, which bring about a liquid/gas phase transition in a suitable volatile fluid. This allows for large deformations up to 300% area expansion within response times of a few milliseconds. A few degree temperature change, readily provided by the warmth of a human hand, is sufficient to reliably trigger the actuation. Experiments are compared with the appropriate theory for a model actuator system; this provides design rules, sensitivity, and operational limitations, paving the way for applications ranging from object sorting to intimate human-machine interaction.
Parenteral lipid emulsions in the preterm infant: current issues and controversies

Parenteral lipid emulsions are a necessary component of nutrition for extremely low gestational age newborns until adequate levels of enteral intake are established. Historically, Intralipid, a 100% soybean oil emulsion, has filled this role. Newer multicomponent lipid emulsions containing a mixture of other oils, including olive oil and fish oil, are now available as options, although the regulatory approval for use in neonates varies worldwide. When dosed at currently published recommendations, each of these lipid emulsions meets total fat and energy requirements without a risk of essential fatty acid deficiency. Thus, when choosing which lipid emulsion to provide, the answer must be based on the metabolic differences induced as a result of these fatty acid-rich emulsions and whether the emulsions provide a health advantage or pose a health risk. The questions of induced fatty acid profiles, health benefit and health risk are discussed sequentially for multicomponent lipid emulsions. Despite the growing acceptance of multicomponent lipid emulsions, there is concern regarding changes in blood fatty acid levels and potential health risk without strong evidence of benefit. There remains no ideal parenteral lipid emulsion option for the preterm infant. Standardising future animal and human studies in lipid delivery with the inclusion of lipid metabolism data will iteratively provide answers to inform the optimal lipid emulsion for the preterm infant.
The Protect Effects of Chitosan Oligosaccharides on Intestinal Integrity by Regulating Oxidative Status and Inflammation under Oxidative Stress

The aim of this study was to evaluate the effects of the dietary supplementation of chitosan oligosaccharides (COS) on intestinal integrity, oxidative status, and the inflammation response with hydrogen peroxide (H2O2) challenge. In total, 30 rats were randomly assigned to three groups with 10 replications: CON group, basal diet; AS group, basal diet + 0.1% H2O2 in drinking water; ASC group, basal diet + 200 mg/kg COS + 0.1% H2O2 in drinking water. The results indicated that COS upregulated (p < 0.05) villus height (VH) of the small intestine, duodenum, and ileum; mucosal glutathione peroxidase activity; jejunum and ileum mucosal total antioxidant capacity; duodenum and ileum mucosal interleukin (IL)-6 level; jejunum mucosal tumor necrosis factor (TNF)-α level; duodenum and ileum mucosal IL-10 level; the mRNA expression level of zonula occludens (ZO)-1 in the jejunum and ileum, claudin in the duodenum, nuclear factor-erythroid 2-like 2 in the jejunum, and heme oxygenase-1 in the duodenum and ileum; and the protein expression of ZO-1 and claudin in jejunum; however, it downregulated (p < 0.05) serum diamine oxidase activity and D-lactate level; small intestine mucosal malondialdehyde content; duodenum and ileum mucosal IL-6 level; jejunum mucosal TNF-α level; and the mRNA expression of IL-6 in the duodenum and jejunum, and TNF-α in the jejunum and ileum. These results suggested COS could maintain intestinal integrity under oxidative stress by modulating the intestinal oxidative status and release of inflammatory cytokines.
What is the elephant in the room when considering new therapies for fungal diseases?

Abstract The global scenario of antimicrobial resistance is alarming, and the development of new drugs has not appeared to make substantial progress. The constraints on drug discovery are due to difficulties in finding new targets for therapy, the high cost of development, and the mismatch between the time of drug introduction in a clinic and microorganism adaptation to a drug. Policies to address neglected diseases miss the broad spectrum of mycosis. Society is not aware of the actual threat represented by fungi to human health, food security, and biodiversity. The evidence discussed here is critical for warning governments to establish effective surveillance policies for fungi. HIGHLIGHTS Fungal diseases are ignored even among neglected disease classifications. There are few options to treat mycoses, which is an increasing concern regarding fungal resistance to drugs, as evidenced by the spread of Candida auris. Fungal diseases represent a real threat to human health and food security. Investment in research to investigate the potential of repurposing drugs already in use could obtain results in the short term.