A lithium-aluminium heterobimetallic dimetallocene.

Homobimetallic dimetallocenes exhibiting two identical metal atoms sandwiched between two η5 bonded cyclopentadienyl rings is a narrow class of compounds, with representative examples being dizincocene and diberyllocene. Here we report the synthesis and structural characterization of a heterobimetallic dimetallocene, accessible through heterocoupling of lithium and aluminylene fragments with pentaisopropylcyclopentadienyl ligands. The Al-Li bond features a high ionic character and profits from attractive dispersion interactions between the isopropyl groups of the cyclopentadienyl ligands. A key synthetic step is the isolation of a cyclopentadienylaluminylene monomer, which also enables the structural characterization of this species. In addition to their structural authentication by single-crystal X-ray diffraction analysis, both compounds were characterized by multinuclear NMR spectroscopy in solution and in the solid state. Furthermore, reactivity studies of the lithium-aluminium heterobimetallic dimetallocene with an N-heterocyclic carbene and different heteroallenes were performed and show that the Al-Li bond is easily cleaved.

Spectroscopic Identification of Trifluorosilylphosphinidene and Isomeric Phosphasilene and Silicon Trifluorophosphine Complex.

The perfluorinated silylphosphinidene, F3SiP, in the triplet ground state is generated by the reaction of laser-ablated silicon atoms with PF3 in solid neon and argon matrices. The reactions proceed with the initial formation of a silicon trifluorophosphine complex, F3PSi, in the triplet ground state, and a more stable inserted phosphasilene, FPSiF2, in the singlet ground state upon deposition. The trifluorosilylphosphinidene was formed through F-migration reactions of FPSiF2 and F3PSi following a two-state mechanism under irradiation with visible light (λ = 470 nm) and full arc light (λ > 220 nm), respectively. High-level quantum-chemical methods support the identification of F3PSi, FPSiF2, and F3SiP by matrix-isolation IR spectroscopy.

A multi-center interventional study to assess pharmacokinetics, effectiveness, and tolerability of prolonged-release tacrolimus after pediatric kidney transplantation: study protocol for a prospective, open-label, randomized, two-phase, two-sequence, single dose, crossover, phase III b trial.

Background: Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra- and inter-individual bioavailability. Non-adherence to immunosuppressants is associated with rejection after kidney transplantation, which is the main cause of long-term graft loss. Once-daily formulations have been shown to significantly improve adherence compared to twice-daily dosing. Envarsus®, the once-daily prolonged-release formulation of tacrolimus, offers the same therapeutic efficacy as the conventional twice-daily immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile, and a reduced peak to trough, which may reduce CNI-related toxicity. Envarsus® has been approved as an immunosuppressive therapy in adults following kidney or liver transplantation but has not yet been approved in children. The objective of this study is to evaluate the pharmacokinetic profile, efficacy, and tolerability of Envarsus® in children and adolescents aged ≥ 8 and ≤ 18 years to assess its potential role as an additional option for immunosuppressive therapy in children after kidney transplantation. Methods/design: The study is designed as a randomized, prospective crossover trial. Each patient undergoes two treatment sequences: sequence 1 includes 4 weeks of Envarsus® and sequence 2 includes 4 weeks of Prograf®. Patients are randomized to either group A (sequence 1, followed by sequence 2) or group B (sequence 2, followed by sequence 1). The primary objective is to assess equivalency between total exposure (of tacrolimus area under the curve concentration (AUC0-24)), immediate-release tacrolimus (Prograf®) therapy, and prolonged-release tacrolimus (Envarsus®) using a daily dose conversion factor of 0.7 for prolonged- versus immediate-release tacrolimus. Secondary objectives are the assessment of pharmacodynamics, pharmacogenetics, adherence, gut microbiome analyses, adverse events (including tacrolimus toxicity and biopsy-proven rejections), biopsy-proven rejections, difference in estimated glomerular filtration rate (eGFR), and occurrence of donor-specific antibodies (DSAs). Discussion: This study will test the hypothesis that once-daily prolonged-release tacrolimus (Envarsus®) is bioequivalent to twice-daily intermediate-release tacrolimus after pediatric kidney transplantation and may reduce toxicity and facilitate medication adherence. This novel concept may optimize immunosuppressive therapy for more stable graft function and increased graft survival by avoiding T-cell mediated and/or antibody-mediated rejection due to improved adherence. In addition, the study will provide data on the pharmacodynamics and pharmacogenetics of prolonged-release tacrolimus in children and adolescents. Clinical Trial Registration: EUDRA-CT 2019-003710-13 and ClinicalTrial.gov, identifier NCT06057545.

Quantification of midostaurin in plasma and serum by stable isotope dilution liquid chromatography-tandem mass spectrometry: Application to a cohort of patients with acute myeloid leukemia.

OBJECTIVES: Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors. METHODS: A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections. RESULTS: Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens. CONCLUSION: In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

Predicting subgroup treatment effects for a new study: Motivations, results and learnings from running a data challenge in a pharmaceutical corporation.

We present the motivation, experience, and learnings from a data challenge conducted at a large pharmaceutical corporation on the topic of subgroup identification. The data challenge aimed at exploring approaches to subgroup identification for future clinical trials. To mimic a realistic setting, participants had access to 4 Phase III clinical trials to derive a subgroup and predict its treatment effect on a future study not accessible to challenge participants. A total of 30 teams registered for the challenge with around 100 participants, primarily from Biostatistics organization. We outline the motivation for running the challenge, the challenge rules, and logistics. Finally, we present the results of the challenge, the participant feedback as well as the learnings. We also present our view on the implications of the results on exploratory analyses related to treatment effect heterogeneity.

Cerebrospinal fluid concentrations of posaconazole in paediatric leukaemia patients.

BACKGROUND: Little is known about the distribution of posaconazole in brain tissue and CSF. We therefore analysed trough concentrations of posaconazole in paediatric leukaemia patients in non-inflamed CSF. PATIENTS AND METHODS: The study included paediatric patients <18 years of age with acute leukaemia in remission who underwent repeat therapeutic lumbar punctures as part of their anti-leukaemia treatment. CSF and blood were obtained 20-24 h after dosing, and posaconazole was measured by LC-MS/MS. RESULTS: Six patients (median age: 10 years; range, 6-14) with acute lymphatic (three) or acute myeloid (three) leukaemia were included who received posaconazole gastroresistant tablets at weight-banded doses (five) or the oral solution (one). In contrast to 14 control samples, posaconazole was detectable in all 11 samples of treated patients. CSF concentrations ranged from 8.3 to 42 ng/mL with a median CSF concentration of 13.6 ng/mL. Concurrent serum concentrations were between 965 and 5177 ng/mL with a median of 1716 ng/mL. CONCLUSIONS: Trough concentrations of posaconazole in the CSF after systemic administration were low but detectable in all subjects. Concurrent serum concentrations were in the target range for prophylaxis and treatment in 100% and 90%, respectively.

Catalyst-Free Trifluoromethoxylation of Silyl Enol Ethers and Allyl Silanes with Bis(trifluoromethyl)peroxide.

Radical trifluoromethoxylation is an attractive approach to prepare compounds featuring the important OCF3 group, however most existing methods have focused on aromatic substrates. Here, we report novel methodologies with alkenyl substrates employing bis(trifluoromethyl)peroxide (BTMP) as a practical and comparatively atom economical trifluoromethoxylating reagent. With silyl enol ether substrates, switching reaction solvent allows for the synthesis of either α-(trifluoromethoxy)ketone products or unprecedented alkenyl-OCF3 species. Furthermore, allyl silanes have been employed as substrates for the first time, affording allyl(trifluoromethyl)ether products in good yields. In each case, the methods operate at room temperature without large excesses of the alkene substrate while, in contrast to previous radical trifluoromethoxylation reactions, no catalyst, light or other activators are required.

Personality Traits and Physical Activity: Insights from German University Students.

This study explores the intriguing relationship between personality traits, self-rated fitness (SRF), and physical activity (PA) variables among German university students (N = 4244) and sheds light on the impact of personality on adherence to PA guidelines. Employing an online cross-sectional study, the short-form of the Big Five Inventory-2 assessed five domains of personality traits (Extraversion, Negative Emotionality, Agreeableness, Conscientiousness, and Open-Mindedness). PA, including sitting time, was assessed using the International Physical Activity Questionnaire (short-form). SRF and muscle-strengthening activities (MSA) were assessed with one item each. Multiple linear and logistic regression analyses examined associations of individual personality trait domains and all domains combined with SFR, PA variables, and adherence to PA guidelines, controlling for sociodemographic, behavioral, and (mental) health covariates. Most reliably, Extraversion and Conscientiousness revealed positive associations with PA variables, while Negative Emotionality yielded inverse relationships with PA variables. For instance, each unit increase in Extraversion corresponded to an additional 17 min of weekly MSA. On the contrary, daily sitting time was unrelated to personality. Of note, high Open-Mindedness was associated with lower odds for adhering to current PA guidelines. The findings have implications for developing targeted interventions that promote a physically active lifestyle and support students' well-being and academic success.

Precise cooperative sulfur placement leads to semi-crystallinity and selective depolymerisability in CS2/oxetane copolymers.

CS2 promises easy access to degradable sulfur-rich polymers and insights into how main-group derivatisation affects polymer formation and properties, though its ring-opening copolymerisation is plagued by low linkage selectivity and small-molecule by-products. We demonstrate that a cooperative Cr(III)/K catalyst selectively delivers poly(dithiocarbonates) from CS2 and oxetanes while state-of-the-art strategies produce linkage scrambled polymers and heterocyclic by-products. The formal introduction of sulfur centres into the parent polycarbonates results in a net shift of the polymerisation equilibrium towards, and therefore facilitating, depolymerisation. During copolymerisation however, the catalyst enables near quantitative generation of the metastable polymers in high sequence selectivity by limiting the lifetime of alkoxide intermediates. Furthermore, linkage selectivity is key to obtain semi-crystalline materials that can be moulded into self-standing objects as well as to enable chemoselective depolymerisation into cyclic dithiocarbonates which can themselves serve as monomers in ring-opening polymerisation. Our report demonstrates the potential of cooperative catalysis to produce previously inaccessible main-group rich materials with beneficial chemical and physical properties.

Bilateral lung transplantation for pediatric pulmonary arterial hypertension: perioperative management and one-year follow-up.

Background: Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes. Methods: Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020. Results: Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic (n = 4) or heritable PAH (n = 4), PAH associated with congenital heart disease (n = 2), pulmonary veno-occlusive disease (n = 1), and pulmonary capillary hemangiomatosis (n = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months). Conclusion: LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading.

Storage of halved strawberry fruits affects aroma, phytochemical content and gene expression, and is affected by pre-harvest factors.

Introduction: Strawberry fruit are highly valued for their aroma which develops during ripening. However, they have a short shelf-life. Low temperature storage is routinely used to extend shelf-life for transport and storage in the supply chain, however cold storage can also affect fruit aroma. Some fruit continue to ripen during chilled storage; however, strawberries are a non-climacteric fruit and hence ripening postharvest is limited. Although most strawberry fruit is sold whole, halved fruit is also used in ready to eat fresh fruit salads which are of increasing consumer demand and pose additional challenges to fresh fruit storage. Methods: To better understand the effects of cold storage, volatilomic and transcriptomic analyses were applied to halved Fragaria x ananassa cv. Elsanta fruit stored at 4 or 8°C for up to 12 days over two growing seasons. Results and discussion: The volatile organic compound (VOC) profile differed between 4 or 8°C on most days of storage. Major differences were detected between the two different years of harvest indicating that aroma change at harvest and during storage is highly dependent on environmental factors during growth. The major component of the aroma profile in both years was esters. Over 3000 genes changed in expression over 5 days of storage at 8°C in transcriptome analysis. Overall, phenylpropanoid metabolism, which may also affect VOCs, and starch metabolism were the most significantly affected pathways. Genes involved in autophagy were also differentially expressed. Expression of genes from 43 different transcription factor (TF) families changed in expression: mostly they were down-regulated but NAC and WRKY family genes were mainly up-regulated. Given the high ester representation amongst VOCs, the down-regulation of an alcohol acyl transferase (AAT) during storage is significant. A total of 113 differentially expressed genes were co-regulated with the AAT gene, including seven TFs. These may be potential AAT regulators.

Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake.

Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel's antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy.

Homing and Nest Recognition in Nocturnal Blue Petrels: What Scent May Attract Birds to their Burrows?

Hypogean petrels return to the same nest burrow to breed on remote islands during the summer months. Their nocturnal behavior at the colony, strong musky odor and olfactory anatomy suggest an important role of olfaction in homing behavior and nest recognition. Behavioral experiments showed that olfactory cues are sufficient to allow nest identification, suggesting a stabile chemical signature emanating from burrows and facilitating nest recognition. However, the chemical nature and sources of this odor remain unknown. To better understand the nest odor composition, we analyzed volatile organic compounds (VOCs) of nests of blue petrels (Halobaena caerulea) derived from three different odor sources: nest air, nest material and feather samples. We also compared, during two successive years, VOCs from burrows with an incubating breeder on the nest, and burrows used during the breeding season by blue petrels but shortly temporally unoccupied by breeders. We found that the nest air odor was mainly formed by the owners' odor, which provided an individual chemical label for nests that appeared stabile over the breeding season. These findings, together with the previous homing behavioral studies showing an essential role of the sense of smell in blue petrels, strongly suggest that the scent emanating from burrows of blue petrels provides the information that facilitates nest recognition and homing.

Phosphanyl-substituted tin half-sandwich complexes.

Phosphanyl-substituted tin(ii) half sandwich complexes are reported. Due to the Lewis acidic tin center and Lewis basic phosphorous atom they form head-to-tail dimers. Their properties and reactivities were investigated both experimentally and theoretically. Furthermore, related transition metal complexes of these species are presented.

On pyridine chloronium cations.

We present the first solid-state structural evidence of mono- and bis(pyridine)chloronium cations. The latter was synthesized from a mixture of pyridine, elemental chlorine and sodium tetrafluoroborate in propionitrile at low temperatures. The mono(pyridine) chloronium cation was realized with the less reactive pentafluoropyridine, using ClF, AsF5, and C5F5N in anhydrous HF. During the course of this study, we also investigated pyridine dichlorine adducts and found a surprising disproportionation reaction of chlorine that depended on the substitutional pattern of the pyridine. Electron richer dimethylpyridine (lutidine) derivatives favor full disproportionation into a positively and a negatively charged chlorine atom which forms a trichloride monoanion, while unsubstituted pyridine forms a 1 : 1 py·Cl2 adduct.

Mycophenolic acid directly protects podocytes by preserving the actin cytoskeleton and increasing cell survival.

Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF's active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p < 0.05) affected expression of 351 genes in podocytes. Gene Ontology term enrichment analysis particularly clustered terms related to actin and inflammation-related cell death. Indeed, quantification of the actin cytoskeleton of BSA treated podocytes revealed a significant increase of thickness and number of actin filaments after treatment with MPA. Further, MPA significantly reduced TNFα and cycloheximide induced cell death. MPA has a substantial effect on the transcriptome of podocytes in vitro, particularly including functional clusters related to non-immune cell dependent mechanisms. This may provide a molecular basis for direct beneficial effects of MPA on the structural integrity and survival of podocytes under pro-inflammatory conditions.

Smartphone-assisted training with education for patients with hip and/or knee osteoarthritis (SmArt-E): study protocol for a multicentre pragmatic randomized controlled trial.

INTRODUCTION: Hip and knee osteoarthritis are associated with functional limitations, pain and restrictions in quality of life and the ability to work. Furthermore, with growing prevalence, osteoarthritis is increasingly causing (in)direct costs. Guidelines recommend exercise therapy and education as primary treatment strategies. Available options for treatment based on physical activity promotion and lifestyle change are often insufficiently provided and used. In addition, the quality of current exercise programmes often does not meet the changing care needs of older people with comorbidities and exercise adherence is a challenge beyond personal physiotherapy. The main objective of this study is to investigate the short- and long-term (cost-)effectiveness of the SmArt-E programme in people with hip and/or knee osteoarthritis in terms of pain and physical functioning compared to usual care. METHODS: This study is designed as a multicentre randomized controlled trial with a target sample size of 330 patients. The intervention is based on the e-Exercise intervention from the Netherlands, consists of a training and education programme and is conducted as a blended care intervention over 12 months. We use an app to support independent training and the development of self-management skills. The primary and secondary hypotheses are that participants in the SmArt-E intervention will have less pain (numerical rating scale) and better physical functioning (Hip Disability and Osteoarthritis Outcome Score, Knee Injury and Osteoarthritis Outcome Score) compared to participants in the usual care group after 12 and 3 months. Other secondary outcomes are based on domains of the Osteoarthritis Research Society International (OARSI). The study will be accompanied by a process evaluation. DISCUSSION: After a positive evaluation, SmArt-E can be offered in usual care, flexibly addressing different care situations. The desired sustainability and the support of the participants' behavioural change are initiated via the app through audio-visual contact with their physiotherapists. Furthermore, the app supports the repetition and consolidation of learned training and educational content. For people with osteoarthritis, the new form of care with proven effectiveness can lead to a reduction in underuse and misuse of care as well as contribute to a reduction in (in)direct costs. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00028477. Registered on August 10, 2022.

COVID-19 in pediatric lung transplant recipients: Clinical course and outcome.

BACKGROUND: COVID-19 causes high morbidity and mortality in adult lung transplant (LTX) recipients. Data on COVID-19 in children after LTX is limited. We report the clinical presentation and outcome of SARS-CoV-2 infection in 19 pediatric LTX recipients. METHODS: Between March 2020 and June 2022, SARS-CoV-2 testing was performed on all pediatric LTX patients with COVID-19 symptoms or contact with a SARS-CoV-2 infected person. Positive patients were prospectively evaluated for symptoms, treatment and outcome. Vaccination status and immune response were recorded. RESULTS: Nineteen out of 51 pediatric LTX recipients had a SARS-CoV-2 infection. Mean age was 12.3 years (IQR 9-17), 68% were female, 84% had preexisting comorbidities. Mean time between LTX and SARS-CoV-2 infection was 4.8 years (IQR 2-6). No patients experienced severe COVID-19: 11% were asymptomatic, and 89% had mild symptoms, primarily rhinitis (74%), fever (47%), and cough (37%). One SARS-CoV-2 positive patient was hospitalized due to combined fungal and bacterial infection. Mean duration of symptoms was 10.5 days (IQR 3-16), whereas mean period of positivity by antigen test was 21 days (IQR 9-27, p = 0.013). Preventive antiviral therapy was initiated in 3 patients. After a mean follow-up of 2.5 months (IQR 1.1-2.4), no patient reported persistent complaints related to COVID-19. Lung function tests remained stable. CONCLUSIONS: Unlike adult LTX recipients, children and adolescents are at low risk for severe COVID-19, even with risk factors beyond immunosuppression. Our findings cast doubt on the necessity of excessive isolation for these patients and should reassure clinicians and caregivers of LTX patients.

Comparative transcriptomic profiling of peach and nectarine cultivars reveals cultivar-specific responses to chilled postharvest storage.

Introduction: Peach (Prunus persica (L.) Batsch,) and nectarine fruits (Prunus persica (L.) Batsch, var nectarine), are characterized by a rapid deterioration at room temperature. Therefore, cold storage is widely used to delay fruit post-harvest ripening and extend fruit commercial life. Physiological disorders, collectively known as chilling injury, can develop typically after 3 weeks of low-temperature storage and affect fruit quality. Methods: A comparative transcriptomic analysis was performed to identify regulatory pathways that develop before chilling injury symptoms are detectable using next generation sequencing on the fruits of two contrasting cultivars, one peach (Sagittaria) and one nectarine, (Big Top), over 14 days of postharvest cold storage. Results: There was a progressive increase in the number of differentially expressed genes between time points (DEGs) in both cultivars. More (1264) time point DEGs were identified in 'Big Top' compared to 'Sagittaria' (746 DEGs). Both cultivars showed a downregulation of pathways related to photosynthesis, and an upregulation of pathways related to amino sugars, nucleotide sugar metabolism and plant hormone signal transduction with ethylene pathways being most affected. Expression patterns of ethylene related genes (including biosynthesis, signaling and ERF transcription factors) correlated with genes involved in cell wall modification, membrane composition, pathogen and stress response, which are all involved later during storage in development of chilling injury. Discussion: Overall, the results show that common pathways are activated in the fruit of 'Big Top' nectarine and 'Sagittaria' peach in response to cold storage but include also differences that are cultivar-specific responses.

Glia from the central and peripheral nervous system are differentially affected by paclitaxel chemotherapy via modulating their neuroinflammatory and neuroregenerative properties.

Glia are critical players in defining synaptic contacts and maintaining neuronal homeostasis. Both astrocytes as glia of the central nervous system (CNS), as well as satellite glial cells (SGC) as glia of the peripheral nervous system (PNS), intimately interact with microglia, especially under pathological conditions when glia regulate degenerative as well as regenerative processes. The chemotherapeutic agent paclitaxel evokes peripheral neuropathy and cognitive deficits; however, the mechanisms underlying these diverse clinical side effects are unclear. We aimed to elucidate the direct effects of paclitaxel on the function of astrocytes, microglia, and SGCs, and their glia-glia and neuronal-glia interactions. After intravenous application, paclitaxel was present in the dorsal root ganglia of the PNS and the CNS of rodents. In vitro, SGC enhanced the expression of pro-inflammatory factors and reduced the expression of neurotrophic factor NT-3 upon exposure to paclitaxel, resulting in predominantly neurotoxic effects. Likewise, paclitaxel induced a switch towards a pro-inflammatory phenotype in microglia, exerting neurotoxicity. In contrast, astrocytes expressed neuroprotective markers and increasingly expressed S100A10 after paclitaxel exposure. Astrocytes, and to a lesser extent SGCs, had regulatory effects on microglia independent of paclitaxel exposure. Data suggest that paclitaxel differentially modulates glia cells regarding their (neuro-) inflammatory and (neuro-) regenerative properties and also affects their interaction. By elucidating those processes, our data contribute to the understanding of the mechanistic pathways of paclitaxel-induced side effects in CNS and PNS.