Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.

Building the brain mosaic: an expanded view.

The complexity of the brain is closely tied to its nature as a genetic mosaic, wherein each cell is distinguished by a unique constellation of somatic variants that contribute to functional and phenotypic diversity. Postzygotic variation arising during neurogenesis is recognized as a key contributor to brain mosaicism; however, recent advances have broadened our understanding to include sources of neural genomic diversity that develop throughout the entire lifespan, from embryogenesis through aging. Moving beyond the traditional confines of neurodevelopment, in this review, we delve into the complex mechanisms that enable various origins of brain mosaicism.

TCTP regulates genotoxic stress and tumorigenicity via intercellular vesicular signaling.

Oncogenic intercellular signaling is regulated by extracellular vesicles (EVs), but the underlying mechanisms remain mostly unclear. Since TCTP (translationally controlled tumor protein) is an EV component, we investigated whether it has a role in genotoxic stress signaling and malignant transformation. By generating a Tctp-inducible knockout mouse model (Tctp-/f-), we report that Tctp is required for genotoxic stress-induced apoptosis signaling via small EVs (sEVs). Human breast cancer cells knocked-down for TCTP show impaired spontaneous EV secretion, thereby reducing sEV-dependent malignant growth. Since Trp53-/- mice are prone to tumor formation, we derived tumor cells from Trp53-/-;Tctp-/f- double mutant mice and describe a drastic decrease in tumori-genicity with concomitant decrease in sEV secretion and content. Remarkably, Trp53-/-;Tctp-/f- mice show highly prolonged survival. Treatment of Trp53-/- mice with sertraline, which inhibits TCTP function, increases their survival. Mechanistically, TCTP binds DDX3, recruiting RNAs, including miRNAs, to sEVs. Our findings establish TCTP as an essential protagonist in the regulation of sEV-signaling in the context of apoptosis and tumorigenicity.

Tctp, a unique Ing5-binding partner, inhibits the chromatin binding of Enok in Drosophila.

The MOZ/MORF histone acetyltransferase complex is highly conserved in eukaryotes and controls transcription, development, and tumorigenesis. However, little is known about how its chromatin localization is regulated. Inhibitor of growth 5 (ING5) tumor suppressor is a subunit of the MOZ/MORF complex. Nevertheless, the in vivo function of ING5 remains unclear. Here, we report an antagonistic interaction between Drosophila Translationally controlled tumor protein (TCTP) (Tctp) and ING5 (Ing5) required for chromatin localization of the MOZ/MORF (Enok) complex and H3K23 acetylation. Yeast two-hybrid screening using Tctp identified Ing5 as a unique binding partner. In vivo, Ing5 controlled differentiation and down-regulated epidermal growth factor receptor signaling, whereas it is required in the Yorkie (Yki) pathway to determine organ size. Ing5 and Enok mutants promoted tumor-like tissue overgrowth when combined with uncontrolled Yki activity. Tctp depletion rescued the abnormal phenotypes of the Ing5 mutation and increased the nuclear translocation of Ing5 and chromatin binding of Enok. Nonfunctional Enok promoted the nuclear translocation of Ing5 by reducing Tctp, indicating a feedback mechanism between Tctp, Ing5, and Enok to regulate histone acetylation. Therefore, Tctp is essential for H3K23 acetylation by controlling the nuclear translocation of Ing5 and chromatin localization of Enok, providing insights into the roles of human TCTP and ING5-MOZ/MORF in tumorigenesis.

Restoration of virulence in the attenuated Candid#1 vaccine virus requires reversion at both positions 168 and 427 in the envelope glycoprotein GPC.

Live-attenuated virus vaccines provide long-lived protection against viral disease but carry inherent risks of residual pathogenicity and genetic reversion. The live-attenuated Candid#1 vaccine was developed to protect Argentines against lethal infection by the Argentine hemorrhagic fever arenavirus, Junín virus. Despite its safety and efficacy in Phase III clinical study, the vaccine is not licensed in the US, in part due to concerns regarding the genetic stability of attenuation. Previous studies had identified a single F427I mutation in the transmembrane domain of the Candid#1 envelope glycoprotein GPC as the key determinant of attenuation, as well as the propensity of this mutation to revert upon passage in cell culture and neonatal mice. To ascertain the consequences of this reversion event, we introduced the I427F mutation into recombinant Candid#1 (I427F rCan) and investigated the effects in two validated small-animal models: in mice expressing the essential virus receptor (human transferrin receptor 1; huTfR1) and in the conventional guinea pig model. We report that I427F rCan displays only modest virulence in huTfR1 mice and appears attenuated in guinea pigs. Reversion at another attenuating locus in Candid#1 GPC (T168A) was also examined, and a similar pattern was observed. By contrast, virus bearing both revertant mutations (A168T+I427F rCan) approached the lethal virulence of the pathogenic Romero strain in huTfR1 mice. Virulence was less extreme in guinea pigs. Our findings suggest that genetic stabilization at both positions is required to minimize the likelihood of reversion to virulence in a second-generation Candid#1 vaccine.IMPORTANCELive-attenuated virus vaccines, such as measles/mumps/rubella and oral poliovirus, provide robust protection against disease but carry with them the risk of genetic reversion to the virulent form. Here, we analyze the genetics of reversion in the live-attenuated Candid#1 vaccine that is used to protect against Argentine hemorrhagic fever, an often-lethal disease caused by the Junín arenavirus. In two validated small-animal models, we find that restoration of virulence in recombinant Candid#1 viruses requires back-mutation at two positions specific to the Candid#1 envelope glycoprotein GPC, at positions 168 and 427. Viruses bearing only a single change showed only modest virulence. We discuss strategies to genetically harden Candid#1 GPC against these two reversion events in order to develop a safer second-generation Candid#1 vaccine virus.

Conversion or reversion of interferon gamma release assays for Mycobacterium tuberculosis infection: a systematic review and meta-analysis.

BACKGROUND: Interferon-gamma release assays (IGRA) are widely used for diagnosis of latent tuberculosis infection. However, with repeat testing, IGRA transformation (conversion or reversion) may be detected and is challenging to interpret. We reviewed the frequency of and risk factors for IGRA transformation. METHODS: We screened public databases for studies of human participants that reported the frequency of IGRA transformation. We extracted study and subject characteristics, details of IGRA testing and results. We calculated the pooled frequency of IGRA transformation (and transient transformation) and examined associated risk factors. RESULTS: The pooled frequency of IGRA conversion or reversion from 244 studies was estimated at 7.3% (95% CI 6.1-8.5%) or 22.8% (20.1-25.7%), respectively. Transient conversion or reversion were estimated at 46.0% (35.7-56.4%) or 19.6% (9.2-31.7%) of conversion or reversion events respectively. Indeterminate results seldom reverted to positive (1.2% [0.1-3.5%]). IGRA results in the borderline positive or negative range were associated with increased risk of conversion or reversion (pooled OR: conversion, 4.15 [3.00-5.30]; reversion, 4.06 [3.07-5.06]). BCG vaccination was associated with decreased risk of conversion (0.70, 0.56-0.84), cigarette smoking with decreased risk of reversion (0.44, 0.06-0.82), and female sex with decreased risk of either conversion or reversion (conversion, 0.66 [0.58-0.75]; reversion, 0.46 [0.31-0.61]). CONCLUSIONS: IGRA conversion is less common than reversion, and frequently transient. Research is needed to determine whether individuals with reversion would benefit from tuberculosis preventive treatment. Re-testing of people with indeterminate results is probably not indicated, since indeterminate results seldom revert to positive.

BRCA1/2 reversion mutations in a pan-cancer cohort.

Tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency-causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan-cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell-free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events-BRCA1 (n = 3), BRCA2 (n = 18)-including eight pure deletions, one single-nucleotide variant, six multinucleotide variants, and six deletion-insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology-mediated end-join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

Phytochrome C and Low Temperature Promote the Protein Accumulation and Red Light Signaling of Phytochrome D.

Light affects almost every aspect of plant development. It is perceived by photoreceptors, among which phytochromes (PHY) are responsible for monitoring the red and far-red spectrum. Arabidopsis thaliana possesses five phytochrome genes (phyA-E). Whereas functions of phyA and phyB are extensively studied, our knowledge on other phytochromes is still rudimentary. To analyze phyD function we expressed it at high levels in different phytochrome-deficient genetic backgrounds. Overexpressed phyD-YFP can govern effective light signaling but only at low temperature and in cooperation with functional phyC. Under these conditions, phyD-YFP accumulates to high levels and opposite to phyB, this pool is stable in light. By comparing the photoconvertible phyD-YFP and phyB levels and their signaling in continuous and pulsed irradiation, we showed that phyD-YFP is a less efficient photoreceptor than phyB. This conclusion is supported by the facts that only a part of the phyD-YFP pool is photoconvertible and thermal reversion of phyD-YFP is faster than that of phyB. Our data suggest that the temperature-dependent function of phyD is based on the amount of phyD protein and not on its Pfr stability, as described for phyB. We also found that phyD-YFP and phyB-GFP associate with strongly overlapping genomic locations and mediate similar changes in gene expression, however the efficiency of phyD-YFP is lower. Based on these data we propose that under certain conditions, synergistic interaction of phyD and phyC can substitute phyB function in seedlings and in adult plants, thus increases the ability of plants to respond more flexibly to environmental changes.

Mutation of wbtJ, a N-formyltransferase involved in O-antigen synthesis, results in biofilm formation, phase variation and attenuation in Francisella tularensis.

Two clinically important subspecies, Francisella tularensis subsp. tularensis (type A) and F. tularensis subsp. holarctica (type B) are responsible for most tularaemia cases, but these isolates typically form a weak biofilm under in vitro conditions. Phase variation of the F. tularensis lipopolysaccharide (LPS) has been reported in these subspecies, but the role of variation is unclear as LPS is crucial for virulence. We previously demonstrated that a subpopulation of LPS variants can constitutively form a robust biofilm in vitro, but it is unclear whether virulence was affected. In this study, we show that biofilm-forming variants of both fully virulent F. tularensis subspecies were highly attenuated in the murine tularaemia model by multiple challenge routes. Genomic sequencing was performed on these strains, which revealed that all biofilm-forming variants contained a lesion within the wbtJ gene, a formyltransferase involved in O-antigen synthesis. A ΔwbtJ deletion mutant recapitulated the biofilm, O-antigen and virulence phenotypes observed in natural variants and could be rescued through complementation with a functional wbtJ gene. Since the spontaneously derived biofilm-forming isolates in this study were a subpopulation of natural variants, reversion events to the wbtJ gene were detected that eliminated the phenotypes associated with biofilm variants and restored virulence. These results demonstrate a role for WbtJ in biofilm formation, LPS variation and virulence of F. tularensis.

Multidrug Resistance Reversed by Maleimide Interactions. A Biological and Synthetic Overview for an Emerging Field.

Multidrug Resistance (MDR) can be considered one of the most frightening adaptation types in bacteria, fungi, protozoa, and eukaryotic cells. It allows the organisms to survive the attack of many drugs used in the daily basis. This force the development of new and more complex, highly specific drugs to fight diseases. Given the high usage of medicaments, poor variation in active chemical cores, and self-medication, the appearance of MDR is more frequent each time, and has been established as a serious medical and social problem. Over the years it has been possible the identification of several genes and proteins responsible for MDR and with that the development of blockers of them to reach MDR reversion and try to avoid a global problem. These mechanisms also have been observed in cancer cells, and several calcium channel blockers have been successful in MDR reversion, and the maleimide can be found included in them. In this review we explore the history, mechanisms, reversion efforts, and we specifically focused on the maleimide synthesis as MDR-reversers in co-administration, as well as their biological applications in a urge to expand the available information and explore a very plausible MDR reversion source.

Phytochrome B phosphorylation expanded: site-specific kinases are identified.

The phytochrome B (phyB) photoreceptor is a key participant in red and far-red light sensing, playing a dominant role in many developmental and growth responses throughout the whole life of plants. Accordingly, phyB governs diverse signaling pathways, and although our knowledge about these pathways is constantly expanding, our view about their fine-tuning is still rudimentary. Phosphorylation of phyB is one of the relevant regulatory mechanisms, and - despite the expansion of the available methodology - it is still not easy to examine. Phosphorylated phytochromes have been detected using various techniques for decades, but the first phosphorylated phyB residues were only identified in 2013. Since then, concentrated attention has been turned toward the functional role of post-translational modifications in phyB signaling. Very recently in 2023, the first kinases that phosphorylate phyB were identified. These discoveries opened up new research avenues, especially by connecting diverse environmental impacts to light signaling and helping to explain some long-term unsolved problems such as the co-action of Ca2+ and phyB signaling. This review summarizes our recent views about the roles of the identified phosphorylated phyB residues, what we know about the enzymes that modulate the phospho-state of phyB, and how these recent discoveries impact future investigations.

Cold-adapted live attenuated MERS-CoV vaccine strain remains attenuated in mice after multiple passages in Vero cells at 37 °C.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic disease affecting camels and humans. The live attenuated vaccine represents a candidate human vaccine because it can induce strong immune responses in immunized hosts. The attenuated vaccine strain of the highly pathogenic virus can also be used to produce a cell-based vaccine in the BSL2 GMP facility. In this study, we evaluated the reversion potential of pathogenicity to pathogenic wild-type virus to ensure the safety of the live attenuated vaccine strain. We passaged our previously developed cold-adapted live attenuated MERS-CoV vaccine strain at 22 °C (EMC2012-CA22°C) in Vero cells at 37 °C as often as 15 times to determine the potential of pathogenicity reversion in hDPP4 (human dipeptidyl peptidase 4)-transgenic mice, K18-hDPP4. The serial passage of EMC2012-CA22°C in Vero cells at 37 °C up to 15 times did not result in pathogenicity reversion to wild-type MERS-CoV. In K18-hDPP4 mice infected with this virus, no weight loss or mortality was observed, and no virus was detected in tissues such as the lung, kidney, brain, and nasal turbinate. In addition, mice immunized with this virus produced a robust neutralizing antibody response and were fully protected from lethal challenge with wild-type MERS-CoV. The cold-adapted attenuated MERS-CoV vaccine strain (EMC2012-CA22°C) was not reverted to wild-type pathogenic virus after 15 passages in Vero cells at 37 °C.

Effect of erenumab on the reversion from chronic migraine to episodic migraine in an Asian population: A post hoc analysis of the DRAGON study.

BACKGROUND: Erenumab is a fully human monoclonal antibody that selectively targets the calcitonin gene-related peptide receptor. It has been proven to be safe and efficacious in patients with episodic migraine (EM) and chronic migraine (CM) as demonstrated in phase 2 and 3 clinical trials including patients from Europe, Japan, and the United States. Reversion from CM to EM, as indicated by a reduction in the frequency of headache days, is an important indicator for efficacy outcome, though it has not been analyzed widely in patients with CM to date. OBJECTIVE: Primary results of the DRAGON study demonstrated the efficacy and safety of erenumab in patients with CM from China and other Asian countries. This post hoc analysis evaluated the rate of reversion from CM to EM in the overall population and in subgroups of patients defined by baseline demographic and clinical characteristics (age, body mass index, gender, prior preventive treatment failure, medication overuse status, and disease duration). METHODS: Reversion from CM to EM was defined as a reduction in headache frequency to < 45 headache days over the 12 weeks of the double-blind treatment period. In addition, migraine-related disability and disease impact on functional impairment were assessed within each treatment group in reverters and non-reverters using the Headache Impact Test-6 (HIT-6), Migraine Physical Function Impact Diary (MPFID), and modified Migraine Disability Assessment (mMIDAS). RESULTS: Overall, 557 patients with CM were randomized to monthly erenumab 70 mg (n = 279) or placebo (n = 278), of whom 52.3% (146 of 279) treated with erenumab reverted from CM to EM compared to 41.0% (114 of 278) in the placebo group (odds ratio [OR] 1.59, 95% confidence interval: 1.1-2.2; p = 0.007). Treatment with erenumab resulted in a greater mean change (standard error) from baseline in the HIT-6 total score for reverters versus non-reverters compared to placebo (erenumab: -9.5 [0.6] vs. -5.1 [0.5]; placebo: -8.9 [0.7] vs. -4.9 [0.5]). A similar pattern was observed for mMIDAS score in erenumab treatment groups versus placebo (erenumab: -22.1 [1.2] vs. -6.3 [1.8]; placebo: -19.9 [1.3] vs. -7.9 [1.6]). Substantial improvements were reported in MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores in reverters versus non-reverters in erenumab treatment groups (MPFID-PI: -5.9 [0.3] vs. -1.9 [0.6]; MPFID-EA: -7.9 [0.4] vs. -3.4 [0.6]) and in placebo (MPFID-PI: -5.4 [0.4] vs. -1.0 [0.5]; MPFID-EA: -7.1 [0.5] vs. -3.2 [0.5]). CONCLUSIONS: This analysis demonstrated that a greater proportion of patients treated with erenumab reverted from CM to EM compared to patients treated with placebo. The reversion from CM to EM was reflected by the greater improvements in patient-reported outcomes in the erenumab group.

Harnessing the Photoperformance of N-Methyl-Quinolinone for Gated Photo-Driven Cyclability and Reversible Photoligation.

[2π + 2π]-photocycloadditions and their ability to trigger controlled and reversible photoligation through disparate wavelengths provide an attractive platform to unlock advanced functionalities in soft materials. Yet, among the limited amount of functional motifs enabling reversible photoreactions, cyclability is often overlooked due to poor reaction yield and orthogonality. In this study, the advantageous photocharacteristics of the previously underexplored N-methyl-quinolinone photoresponsive motif are leveraged to create a covalent gated system, enabling controlled formation and cleavage of covalent bonds on demand. A systematic evaluation of individual cycloadditions and reversions on the molecular scale, including reaction rates, conversions, and photoproducts, allows identification of the required conditions for generating controlled photoreactions with a remarkable degree of cyclability; while, maintaining high reaction yields. Ultimately, these controlled and cyclable reactions are translated to a macromolecular scale, showcasing a comparable performance in initiating reversible photoligation, as observed at the molecular level. In addition, it is also shown that this progressive methodology can be leveraged to gain a comprehensive understanding of cyclability and clarify the factors contributing to its decreasing yield. Overall, unlocking the potential of quinolinone derivatives through this step-by-step approach lays the foundation for the development of highly controlled and responsive polymer materials with unprecedented potential.

Nonlinear association between remnant cholesterol and reversion from impaired fasting glucose to normoglycemia: a multicenter cohort study.

BACKGROUND: Remnant cholesterol (RC), a potent atherogenic lipid, has been shown to be strongly correlated with insulin resistance and the pathogenesis of diabetes mellitus. However, the relationship between RC and normoglycemia reversal in individuals with impaired fasting glucose (IFG) is crucial and remains unclear. This investigation, which aimed to clarify this association, is important for understanding and potentially improving the management of diabetes. METHOD: This study, which included 15,019 IFG participants from 11 Chinese cities between 2010 and 2016, was conducted with a rigorous research process. Cox regression analysis revealed intriguing findings regarding the relationship between RC and normoglycemia reversal in individuals with IFG. Potential nonlinear associations were further explored via smooth curve-fitting techniques and 4-knot restricted cubic spline functions, ensuring a comprehensive analysis. To examine the validity of the results, an array of subgroup and sensitivity analyses were conducted, further bolstering the robustness of the findings. RESULTS: By the end of the 2.89-year median follow-up period, 6,483 of the 15,019 IFG participants (43.17%) had reverted to normoglycemia. The findings, which reveal that increased RC levels are inversely associated with the likelihood of normoglycemia reversal, are novel and significant. According to the fully adjusted Cox proportional hazards model analysis, an increase of one standard deviation in RC was associated with a 20% decrease in the likelihood of normoglycemia reversal among IFG participants (HR: 0.80, 95% CI: 0.77-0.82). A nonlinear association between RC and normoglycemia reversal was observed, with an inflection point at 41.37 mg/dL. This suggests that the growth rate of the likelihood of reversion decreased and stabilized after the inflection point was reached. Moreover, significant interactions were observed between the age groups, providing a more nuanced understanding of this complex relationship. CONCLUSION: Among Chinese adults with IFG, RC exhibited a negative nonlinear relationship with the probability of normoglycemia reversal. When RC levels reached or exceeded 41.38 mg/dL, the probability of achieving normoglycemia progressively diminished and subsequently stabilized. Maintaining RC levels below 41.38 mg/dL can significantly improve the probability of normoglycemia reversal among individuals with IFG, especially those aged 60 years or older.

Differing biophysical properties underpin the unique signaling potentials within the plant phytochrome photoreceptor families.

Many aspects of photoperception by plants and microorganisms are initiated by the phytochrome (Phy) family of photoreceptors that detect light through interconversion between red light- (Pr) and far-red light-absorbing (Pfr) states. Plants synthesize a small family of Phy isoforms (PhyA to PhyE) that collectively regulate photomorphogenesis and temperature perception through redundant and unique actions. While the selective roles of these isoforms have been partially attributed to their differing abundances, expression patterns, affinities for downstream partners, and turnover rates, we show here from analysis of recombinant Arabidopsis chromoproteins that the Phy isoforms also display distinct biophysical properties. Included are a hypsochromic shift in the Pr absorption for PhyC and varying rates of Pfr to Pr thermal reversion, part of which can be attributed to the core photosensory module in each. Most strikingly, PhyB combines strong temperature dependence of thermal reversion with an order-of-magnitude faster rate to likely serve as the main physiological thermosensor, whereby thermal reversion competes with photoconversion. In addition, comparisons of Pfr occupancies for PhyA and PhyB under a range of red- and white-light fluence rates imply that low-light environments are effectively sensed by PhyA, while high-light environments, such as full sun, are effectively sensed by PhyB. Parallel analyses of the Phy isoforms from potato and maize showed that the unique features within the Arabidopsis family are conserved, thus indicating that the distinct biophysical properties among plant Phy isoforms emerged early in Phy evolution, likely to enable full interrogation of their light and temperature environments.

Ningalins, Pyrrole-Bearing Metabolites Isolated from Didemnum spp. Synthesis and MDR-Reversion Activity in Cancer Therapy.

Multi-Drug Resistance (MDR) is one of the most frequent problems observed in the course of cancer chemotherapy. Cells under treatment, tend to develop survival mechanisms to drug-action thus generating drug-resistance. One of the most important mechanism to get it is the over expression of P-gp glycoprotein, which acts as an efflux-pump releasing the drug outside of the cancer cell. A strategy for a succesfull treatment consists in the co-administration of one compound that acts against P-gp and another which acts against the cell during chemotherapy. Ningalins are pyrrole-containing naturally occurring compounds isolated mainly from the marine tunicate Didemnum spp and also they are some of the top reversing agents in MDR treatment acting on P-gp. Considering the relevance displayed for some of these isolated alkaloids or their core as a drug for co-administration in cancer therapy, all the total synthesis described to date for the members of ningalins family are reviewed herein.

Directed energy deposition of 18NiM300 steel: effect of process and post processing conditions on microstructure and properties.

This current study investigates the effect of Direct Energy Deposition (DED) process conditions on the properties and microstructure of M300 maraging steel samples. The investigation centers on two key factors: laser power and deposition environment. The microstructure of this tool steel is analyzed by computing the Primary Cellular Arm Spacing. The findings revealed a significant influence of both inert atmosphere and laser power on cooling conditions. These different cooling rates influence the phase content as demonstrated by X-Ray Diffraction and Electron Backscatter Diffraction measurements. It was demonstrated the presence of different content of residual austenite at cell boundaries. These distinct microstructural features caused variations in the hardness values of the printed samples. Furthermore, a direct aging heat treatment was implemented, that was chosen from Differential Scanning Calorimetry measurements results. This heat treatment proves effective in achieving consistent hardness increases and eliminated the differences among samples built in different process conditions. This outcome suggests the possibility of selecting the most economically viable DED parameters for optimal results.

This study innovatively explores how DED process conditions impact M300 maraging steel microstructure, revealing crucial insights for optimizing properties and achieving consistent results, ensuring economically viable applications.

Predictors and outcomes of fluctuations in the clinical dementia rating scale.

INTRODUCTION: Reversion, or change in cognitive status from impaired to normal, is common in aging and dementia studies, but it remains unclear what factors predict reversion. METHODS: We investigated whether reverters, defined as those who revert from a Clinical Dementia Rating® (CDR®) scale score of 0.5 to CDR 0) differed on cognition and biomarkers from unimpaired participants (always CDR 0) and impaired participants (converted to CDR > 0 and had no reversion events). Models evaluated relationships between biomarker status, apolipoprotein E (APOE) ε4 status, and cognition. Additional models described predictors of reversion and predictors of eventual progression to CDR > 0. RESULTS: CDR reversion was associated with younger age, better cognition, and negative amyloid biomarker status. Reverters that eventually progressed to CDR > 0 had more visits, were older, and were more likely to have an APOE ε4 allele. DISCUSSION: CDR reversion occupies a transitional phase in disease progression between cognitive normality and overt dementia. Reverters may be ideal candidates for secondary prevention Alzheimer's disease (AD) trials. HIGHLIGHTS: Reverters had more longitudinal cognitive decline than those who remained cognitively normal. Predictors of reversion: younger age, better cognition, and negative amyloid biomarker status. Reverting from CDR 0.5 to 0 is a risk factor for future conversion to CDR > 0. CDR reversion may be a transitional phase in Alzheimer's Disease progression. CDR reverters may be ideal for Alzheimer's disease secondary prevention trials.

Reversed Corneal Fibroblasts Therapy Restores Transparency of Mouse Cornea after Injury.

Cell-based therapies using corneal stromal stem cells (CSSC), corneal keratocytes, or a combination of both suppress corneal scarring. The number of quiescent keratocytes in the cornea is small; it is difficult to expand them in vitro in quantities suitable for transplantation. This study examined the therapeutic effect of corneal fibroblasts reversed into keratocytes (rCF) in a mouse model of mechanical corneal injury. The therapeutic effect of rCF was studied in vivo (slit lamp, optical coherence tomography) and ex vivo (transmission electron microscopy and immunofluorescence staining). Injection of rCF into the injured cornea was accompanied by recovery of corneal thickness, improvement of corneal transparency, reduction of type III collagen in the stroma, absence of myofibroblasts, and the improvement in the structural organization of collagen fibers. TEM results showed that 2 months after intrastromal injection of cells, there was a decrease in the fibril density and an increase in the fibril diameter and the average distance between collagen fibrils. The fibrils were well ordered and maintained the short-range order and the number of nearest-neighbor fibrils, although the averaged distance between them increased. Our results demonstrated that the cell therapy of rCF from ReLEx SMILe lenticules promotes the recovery of transparent corneal stroma after injury.