Miracle-dz/UniFAR-FTUs huggingface dataset:
SG1-Functionalized Peptides as Precursors for Polymer−Peptide Conjugates: A Straightforward Approach

We report here a straightforward route to polymer−peptide conjugates via the convenient synthesis of SG1-functionalized peptides able to initiate nitroxide-mediated polymerization (NMP). The NMP initiator SG1-functionalized peptide (SG1-GGGWIKVAV) was prepared by solid-phase peptide synthesis (SPPS) using an automated synthesizer, with a last step consisting of reaction between the carboxylic acid function of the MAMA-SG1 (BlocBuilder) alkoxyamine with the peptide terminal amine in the presence of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as coupling agent. The resulting SG1-functionalized resin-attached peptide was used to perform the controlled NMP of styrene, leading after trifluoroacetic acid cleavage to the corresponding polystyrene−peptide conjugate. The latter was thoroughly characterized by UV spectrometry, gel permeation chromatography (GPC), 1H NMR, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS).
Inhibition of longevity regulator PAPP‐A modulates tissue homeostasis via restraint of mesenchymal stromal cells

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a secreted metalloprotease that increases insulin‐like growth factor (IGF) availability by cleaving IGF‐binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP‐A deletion extends lifespan and healthspan; however, the mechanism remains unclear. To clarify PAPP‐A’s role, we developed a PAPP‐A neutralizing antibody and treated adult mice with it. Transcriptomic profiling across tissues showed that anti‐PAPP‐A reduced IGF signaling and extracellular matrix (ECM) gene expression system wide. The greatest reduction in IGF signaling occurred in the bone marrow, where we found reduced bone, marrow adiposity, and myelopoiesis. These diverse effects led us to search for unifying mechanisms. We identified mesenchymal stromal cells (MSCs) as the source of PAPP‐A in bone marrow and primary responders to PAPP‐A inhibition. Mice treated with anti‐PAPP‐A had reduced IGF signaling in MSCs and dramatically decreased MSC number. As MSCs are (1) a major source of ECM and the progenitors of ECM‐producing fibroblasts, (2) the originating source of adult bone, (3) regulators of marrow adiposity, and (4) an essential component of the hematopoietic niche, our data suggest that PAPP‐A modulates bone marrow homeostasis by potentiating the number and activity of MSCs. We found that MSC‐like cells are the major source of PAPP‐A in other tissues also, suggesting that reduced MSC‐like cell activity drives the system‐wide reduction in ECM gene expression due to PAPP‐A inhibition. Dysregulated ECM production is associated with aging and drives age‐related diseases, and thus, this may be a mechanism by which PAPP‐A deficiency enhances longevity.
Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK

Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1–4 was detected in 8%–19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.
Myofibroblast dedifferentiation proceeds via distinct transcriptomic and phenotypic transitions

Myofibroblasts are the major cellular source of collagen, and their accumulation — via differentiation from fibroblasts and resistance to apoptosis — is a hallmark of tissue fibrosis. Clearance of myofibroblasts by dedifferentiation and restoration of apoptosis sensitivity has the potential to reverse fibrosis. Prostaglandin E2 (PGE2) and mitogens such as FGF2 have each been shown to dedifferentiate myofibroblasts, but — to our knowledge — the resultant cellular phenotypes have neither been comprehensively characterized or compared. Here, we show that PGE2 elicited dedifferentiation of human lung myofibroblasts via cAMP/PKA, while FGF2 utilized MEK/ERK. The 2 mediators yielded transitional cells with distinct transcriptomes, with FGF2 promoting but PGE2 inhibiting proliferation and survival. The gene expression pattern in fibroblasts isolated from the lungs of mice undergoing resolution of experimental fibrosis resembled that of myofibroblasts treated with PGE2 in vitro. We conclude that myofibroblast dedifferentiation can proceed via distinct programs exemplified by treatment with PGE2 and FGF2, with dedifferentiation occurring in vivo most closely resembling the former.
Amylin antibodies frequently display cross-reactivity with CGRP: characterization of eight amylin antibodies.

Amylin is a 37 amino acid endocrine hormone secreted from the pancreas in response to nutrient intake, acting centrally to promote meal ending satiation. With many studies linking amylin action to the nervous system, determining the distribution or expression of amylin in the nervous system is critical. However, amylin shares sequence identity and structural homology to the related neuropeptide calcitonin-gene related peptide (CGRP). This creates challenges in identifying selective amylin antibodies that do not cross-react with CGRP, especially in neural tissues, where CGRP is densely packed into secretory vesicles. Here, we characterized eight amylin antibodies to determine their ability to detect amylin and cross-react with rat or human αCGRP, using immunoblots and pre-absorption controls in rat pancreas. We observed that amylin antibodies frequently cross-reacted with αCGRP and are therefore not suitable for use in tissues which highly express CGRP. Prior work using these antibodies should be revisited in light of our findings.
A Naturally Heteroplasmic Clam Provides Clues about the Effects of Genetic Bottleneck on Paternal mtDNA

Abstract Mitochondrial DNA (mtDNA) is present in multiple copies within an organism. Since these copies are not identical, a single individual carries a heterogeneous population of mtDNAs, a condition known as heteroplasmy. Several factors play a role in the dynamics of the within-organism mtDNA population: among them, genetic bottlenecks, selection, and strictly maternal inheritance are known to shape the levels of heteroplasmy across mtDNAs. In Metazoa, the only evolutionarily stable exception to the strictly maternal inheritance of mitochondria is the doubly uniparental inheritance (DUI), reported in 100+ bivalve species. In DUI species, there are two highly divergent mtDNA lineages, one inherited through oocyte mitochondria (F-type) and the other through sperm mitochondria (M-type). Having both parents contributing to the mtDNA pool of the progeny makes DUI a unique system to study the dynamics of mtDNA populations. Since, in bivalves, the spermatozoon has few mitochondria (4–5), M-type mtDNA faces a tight bottleneck during embryo segregation, one of the narrowest mitochondrial bottlenecks investigated so far. Here, we analyzed the F- and M-type mtDNA variability within individuals of the DUI species Ruditapes philippinarum and investigated for the first time the effects of such a narrow bottleneck affecting mtDNA populations. As a potential consequence of this narrow bottleneck, the M-type mtDNA shows a large variability in different tissues, a condition so pronounced that it leads to genotypes from different tissues of the same individual not to cluster together. We believe that such results may help understanding the effect of low population size on mtDNA bottleneck.
Chasing breeding footprints through structural variations in Cucumis melo and wild relatives

Abstract Cucumis melo (melon or muskmelon) is an important crop in the family of the Cucurbitaceae. Melon is cross pollinated and domesticated at several locations throughout the breeding history, resulting in highly diverse genetic structure in the germplasm. Yet, the relations among the groups and cultivars are still incomplete. We shed light on the melonbreeding history, analyzing structural variations ranging from 50 bp up to 100 kb, identified from whole genome sequences of 100 selected melon accessions and wild relatives. Phylogenetic trees based on SV types completely resolve cultivars and wild accessions into two monophyletic groups and clustering of cultivars largely correlates with their geographic origin. Taking into account morphology, we found six mis-categorized cultivars. Unique inversions are more often shared between cultivars, carrying advantageous genes and do not directly originate from wild species. Approximately 60% of the inversion breaks carry a long poly A/T motif, and following observations in other plant species, suggest that inversions in melon likely resulted from meiotic recombination events. We show that resistance genes in the linkage V region are expanded in the cultivar genomes compared to wild relatives. Furthermore, particular agronomic traits such as fruit ripening, fragrance, and stress response are specifically selected for in the melon subspecies. These results represent distinctive footprints of selective breeding that shaped today’s melon. The sequences and genomic relations between land races, wild relatives, and cultivars will serve the community to identify genetic diversity, optimize experimental designs, and enhance crop development.
Transport Properties of Conductive Polyaniline Nanocomposites Based on Carbon Nanotubes

Intrinsically conducting polymers have been studied extensively due to their intriguing electronic and redox properties and numerous potential applications. To improve and extend their functions, the fabrication of multifunctional conducting polymer nanocomposites has attracted a great deal of attention with the advent of nanoscale dimension. In this paper we report the comparative study of nanocomposite synthesized by an in-situ oxidative polymerization of aniline monomer in the presence of functionalized multiwall carbon nanotubes (MWCNT) with that of pure polyaniline (PANI). Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and x-ray diffraction (XRD) are employed to characterize the pure PANI and the PANI-CNT nanocomposite. XRD and SEM reveal the homogeneous coating of PANI onto the CNT indicating that carbon nanotubes were well dispersed in polymer matrix. The interaction between the quinoid ring of PANI and the MWCNT causes PANI chains to be adsorbed at the surface of MWCNT, thus forming a tubular core surrounding the MWCNT was confirmed from FTIR. Nanocomposite shows high electrical conductivity compared to pure PANI. The enhancement in conductivity of the nanocomposite is due to the charge transfer effect from the quinoid rings of the PANI to the MWCNT. The effect of MWCNT on the transport properties of PANI in the form of the transport parameters such as charge localization length, most probable hopping distance and charge hopping energy in the temperature range 300-430 K was also studied.
Persistent viral shedding of human adenovirus type 7 in children with severe pneumonia

To understand host–pathogen interactions and develop effective prevention and control strategies for human adenovirus (HAdV), it is essential to explore the characteristics of HAdV shedding. Hospitalized children <14 years who had severe HAdV pneumonia were tested for HAdV DNA by quantitative real‐time PCR in nasopharyngeal aspirate (NPA). A total of 132 children were enrolled, including 102 patients with HAdV type 7 (HAdV‐7) infection and 12 patients with HAdV type 3 (HAdV‐3) infection. A total of 1372 qualified NPA samples were collected. There was a significant negative correlation between the viral load of HAdV and the course of the disease (Spearman r = −0.547, p = .000). HAdV‐7 load decreased at a rate of 0.089 log10 copies/mL per day (95% CI: −0.096 to −0.081; R 2 = 0.332), and the duration of viral shedding was predicted to be 96.9 days (y = 8.624–0.089x). However, HAdV‐3 load decreased more quickly (95% CI: – 0.229 to – 0.143; R 2 = 0.403), and the duration of viral shedding was 51.4 days (y = 9.558‐0.186x). The median viral load of the HAdV‐7 group at weeks 2 and 3, and more than 3 weeks postinfection was higher than that of the HAdV‐3 group. No significant differences in the duration of viral shedding were found in different gender, age (>2 vs. ≤2 years), and with or without underlying diseases groups. Viral shedding in children with severe HAdV pneumonia persisted, among which HAdV‐7 lasted longer than 3 months and the viral load decreased slowly than HAdV‐3.
CaWRKY28 Cys249 is required for interaction with CaWRKY40 in the regulation of pepper immunity to Ralstonia solanacearum.

WRKY transcription factors have been implicated in plant response to pathogens, but how WRKY-mediated networks are organized and operate to produce appropriate transcriptional outputs remains largely unclear. Here, we identify a member of the WRKY family from pepper (Capsicum annuum), CaWRKY28, that physically interacts with CaWRKY40, a positive regulator of pepper immunity and thermotolerance. We confirmed CaWRKY28/CaWRKY40 interaction by co-immunoprecipitation, bimolecular fluorescence complementation and microscale thermophoresis. Our findings supported that CaWRKY28 is a nuclear protein that acts as positive regulator in pepper responses to the pathogenic bacterium Ralstonia solanacearum infection. It performs its function not by directly modulating the W-box containing immunity related genes but by promoting CaWRKY40 via physical interaction to bind and activate its immunity related target genes including CaPR1, CaNPR1, CaDEF1 and CaABR1, but not its thermotolerance related target gene CaHSP24. All these data indicate that CaWRKY28 interacts with and potentiates CaWRKY40 in regulating immunity against R. solanacearum infection but not thermotolerance. Importantly, we discovered that CaWRKY28 Cys249, shared by CaWRKY28 and its orthologs probably only in the Solanaceae, is crucial for the CaWRKY28-CaWRKY40 interaction. These results highlight how CaWRKY28 associates with CaWRKY40 during the establishment of WRKY networks, and how CaWRKY40 achieves its functional specificity during pepper responses to R. solanacearum infection.
New particle formation in the presence of a strong biomass burning episode at a downwind rural site in PRD, China

ABSTRACT In order to characterise the features of particle pollution in the Pearl River Delta (PRD) region, a 1-month intensive campaign was conducted at the rural supersite (Kaiping) in the autumn of 2008. In total, 12 new particle formation (NPF) events are identified out of 30 campaign days. The results show that in the case of higher source and sink values, the result of the competition between source and sink is more likely the key limiting factor to determine the observation of NPF events at Kaiping. One episode with consecutive NPF events in the presence of strong biomass burning plume was observed between 10 and 15 November. The elevation of particle volume concentration (6.1 µm3/cm3/day) is due to the coaction by the local biomass burning and secondary transformation. Organics and sulphates are the major components in PM1, accounting for 42 and 35% of the mass concentration, respectively. In this study, a rough estimation is applied to quantify the contributions of diverse sources to the particle number concentration. On average, the primary emission and secondary formation provide 28 and 72% of particle number concentration and 21 and 79% of mass concentration, respectively.
Metal‐Dependent and Selective Crystallization of CAU‐10 and MIL‐53 Frameworks through Linker Nitration

Abstract The reaction of the V‐shaped linker molecule 5‐hydroxyisophthalic acid (H2L0), with Al or Ga nitrate under almost identical reaction conditions leads to the nitration of the linker and subsequent formation of metal–organic frameworks (MOFs) with CAU‐10 or MIL‐53 type structure of composition [Al(OH)(L)], denoted as Al‐CAU‐10‐L0, 2, 4, 6 or [Ga(OH)(L)], denoted as Ga‐MIL‐53‐L2. The Al‐MOF contains the original linker L0 as well as three different nitration products (L2, L4 and L4/6), whereas the Ga‐MOF mainly incorporates the linker L2. The compositions were deduced by 1H NMR spectroscopy and confirmed by Rietveld refinement. In situ and ex situ studies were carried out to follow the nitration and crystallization, as well as the composition of the MOFs. The crystal structures were refined against powder X‐ray diffraction (PXRD) data. As anticipated, the use of the V‐shaped linker results in the formation of the CAU‐10 type structure in the Al‐MOF. Unexpectedly, the Ga‐MOF crystallizes in a MIL‐53 type structure, which is usually observed with linear or slightly bent linker molecules. To study the structure directing effect of the in situ nitrated linker, pure 2‐nitrobenzene‐1,3‐dicarboxylic acid (m‐H2BDC‐NO2) was employed which exclusively led to the formation of [Ga(OH)(C8H3NO6)] (Ga‐MIL‐53‐m‐BDC‐NO2), which is isoreticular to Ga‐MIL‐53‐L2. Density Functional Theory (DFT) calculations confirmed the higher stability of Ga‐MIL‐53‐L2 compared to Ga‐CAU‐10‐L2 and grand canonical Monte Carlo simulations (GCMC) are in agreement with the observed water adsorption isotherms of Ga‐MIL‐53‐L2.
The Genetic Basis of Tomato Aroma

Tomato (Solanum lycopersicum L.) aroma is determined by the interaction of volatile compounds (VOCs) released by the tomato fruits with receptors in the nose, leading to a sensorial impression, such as “sweet”, “smoky”, or “fruity” aroma. Of the more than 400 VOCs released by tomato fruits, 21 have been reported as main contributors to the perceived tomato aroma. These VOCs can be grouped in five clusters, according to their biosynthetic origins. In the last decades, a vast array of scientific studies has investigated the genetic component of tomato aroma in modern tomato cultivars and their relatives. In this paper we aim to collect, compare, integrate and summarize the available literature on flavour-related QTLs in tomato. Three hundred and fifty nine (359) QTLs associated with tomato fruit VOCs were physically mapped on the genome and investigated for the presence of potential candidate genes. This review makes it possible to (i) pinpoint potential donors described in literature for specific traits, (ii) highlight important QTL regions by combining information from different populations, and (iii) pinpoint potential candidate genes. This overview aims to be a valuable resource for researchers aiming to elucidate the genetics underlying tomato flavour and for breeders who aim to improve tomato aroma.
Management of Non-Colorectal Digestive Cancers with Microsatellite Instability

Simple Summary Microsatellite instability (MSI) is an established predictive biomarker for immune checkpoint inhibitors with potential prognostic value in different types of tumors. Its prevalence and clinical utility vary in gastrointestinal cancers. In this review, we will discuss the role of MSI status in the management of non-colorectal cancers of the digestive system and address ongoing research work and mechanistic rationale(s) for future studies in this field. Abstract Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial

Supplemental Digital Content is available in the text. OBJECTIVES: We explored the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against central venous catheter-associated deep venous thrombosis in critically ill children. DESIGN: Post hoc analysis of a Bayesian phase 2b randomized clinical trial. SETTING: Seven PICUs. PATIENTS: Children less than 18 years old with newly inserted central venous catheter. INTERVENTIONS: Enoxaparin started less than 24 hours after insertion of central venous catheter and adjusted to anti-Xa level of 0.2–0.5 international units/mL versus usual care. MEASUREMENTS AND MAIN RESULTS: Of 51 children randomized, 24 were infants less than 1 year old. Risk ratios of central venous catheter-associated deep venous thrombosis with prophylaxis with enoxaparin were 0.98 (95% credible interval, 0.37–2.44) in infants and 0.24 (95% credible interval, 0.04–0.82) in older children greater than or equal to 1 year old. Infants and older children achieved anti-Xa level greater than or equal to 0.2 international units/mL at comparable times. While central venous catheter was in situ, endogenous thrombin potential, a measure of thrombin generation, was 223.21 nM.min (95% CI, 8.78–437.64 nM.min) lower in infants. Factor VIII activity, a driver of thrombin generation, was also lower in infants by 45.1% (95% CI, 15.7–74.4%). Median minimum platelet count while central venous catheter was in situ was higher in infants by 39 × 103/mm3 (interquartile range, 17–61 × 103/mm3). Central venous catheter:vein ratio was not statistically different. Prophylaxis with enoxaparin was less efficacious against central venous catheter-associated deep venous thrombosis at lower factor VIII activity and at higher platelet count. CONCLUSIONS: The relatively lesser contribution of thrombin generation on central venous catheter-associated thrombus formation in critically ill infants potentially explains the age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin.