Correction for 'Kinetics of the mechanically induced ibuprofen-nicotinamide co-crystal formation by in situ X-ray diffraction' by Lucia Casali et al., Phys. Chem. Chem. Phys., 2024, 26, 22041-22048, https://doi.org/10.1039/D4CP01457J.

This work focuses on the allotropic phase transformation occurring in Co powders at high temperature. First, we studied the phase transformation kinetics in Co powders that are exposed to a temperature of 750 K while being stirred. Then, we investigated the phase transformation kinetics in Co powders that are ball milled at the same temperature. We observe that the mechanical processing induces a significant intensification of the phase transformation, which we relate to the effects of individual impacts occurring during the mechanical processing. We developed an analytical kinetic model that provides a reliable description of the phase transformation kinetics while accounting for the discontinuous nature of ball milling. We not only explain the observed intensification on a sound phenomenological basis, but also define an intensification index to measure the extent of intensification. The results can be extended to other cases where ball milling intensifies a transformation process.

The synthesis of amide moieties, essential components in both pharmaceuticals and agrochemicals, traditionally involves environmentally hazardous and polluting processes. This study presents a novel mechanochemical method to form amide bond using 1,1'-oxalyl diimidazole (ODI) as activating agent, and evaluates its applicability in synthesizing agrochemicals such as Mepronil, Flutolanil, and Fluxapyroxad at gram-scale. The mechanochemical kinetics underlying the synthesis of the three mentioned compounds was also investigated. The new method was compared with the similar 1,1'-carbonyl diimidazole (CDI)-mediated mechanochemical amidation previously reported. Results demonstrate that ODI-mediated synthesis outperforms in the case of deactivated acids. Energetic considerations and technical process parameters are also discussed to provide quantitative technology assessment. A comprehensive analysis by green chemistry metrics with CHEM21 and DOZNTM 3.0 toolkits, underscores the potential benefits of the mechanochemical approach, compared with the solvent-based protocols for the preparation of marketed agrochemicals.

This work addresses a key challenge in scaling up mechanochemical synthesis: deriving a kinetic model when unpredictable formation and intricate interaction of multiple crystalline phases occur during solid-state transformations. Reaction kinetics translate our understanding of chemical processes into mathematical rate expressions used for reactor design and evaluation, thus representing a challenge to be addressed for the scale up at the industrial level. Choosing co-crystallization of chloro-3-sulfamoylbenzoic acid (CSBA) and isonicotinamide (INA) as a model system, at first we employ time-resolved in situ powder X-ray diffraction (PXRD) and multivariate curve resolution-Alternating Least Squares (MCR-ALS) analysis to quantify and resolve the evolution of crystalline intermediates under varying methanol-assisted conditions. Our data show that even small changes in the amount of methanol can dramatically alter the kinetic profile, stabilise transient phases (including some that were previously unreported) and alter the overall reaction pathway. We then demonstrate the robust deconvolution of overlapping phases and the extraction of quantitative rate parameters that rationalize the observed behaviour by integrating kinetic modelling as a soft-hard constraint in the MCR-ALS workflow. The validation of the established MCR-ALS workflow is achieved by applying a phenomenological kinetic modelling tailored to rationalize the mechanochemical reaction rates. These results establish a broadly applicable platform for analysing and controlling the complex phase evolution, along with the derivation of a kinetic model instrumental to mechanochemical process development and scaling up, thereby supporting the transition of sustainable solid-state syntheses from the laboratory to industry.

The mechanical processing of Co powders by ball milling is known to induce a phase transformation between the two allotropic forms of Co with hexagonal close-packed and face-centred cubic crystalline structures. The same phase transformation can be also activated and driven by gradual heating or isothermal annealing. For this reason, it is reasonable to expect that temperature plays an important role also during the mechanical processing. In this work, we investigate exactly how temperature affects the phase transformation behaviour by ball milling Co powders at different milling frequencies and temperatures between 300 K and 500 K. Unexpectedly, we find that, regardless of the milling frequency, any temperature increases results in a decrease of the phase transformation rate. We tentatively explain the experimental findings by considering thermally activated recovery processes.

We report a deuterium kinetic isotope effect (KIE) in the mechanically driven formation and polymorphic transformation of a hydrogen-bonded organic salt, monitored in situ by synchrotron powder X-ray diffraction and Raman spectroscopy. Surprisingly, no measurable KIE is observed in the salt formation step (which necessarily involves H transfer), whereas a pronounced KIE emerges in the subsequent polymorphic transformation (involving only supramolecular rearrangement). Deuteration delays the onset of the polymorphic transformation and slows the transformation rate, with the fully deuterated system showing an approximately 3-fold decrease in rate and partially deuterated mixtures exhibiting intermediate kinetics. An impact-based kinetic model captures the isotope-dependent trends, while solid-state DFT including vibrational contributions does not indicate an isotope-dependent change in relative phase stability, supporting a primarily kinetic origin of the KIE. These results identify partial deuteration as a practical handle for tuning the solid-state reactivity.

Background: Growth Differentiation Factor 15 (GDF15) has been described as influencing skeletal physiology. Nevertheless, no systematic appraisal of the effect of GDF15 on skeletal muscle tissues has been developed to the present day. Objective: The aim of the present work was to review the evidence on the topic. Methods: In this preregistered systematic review (https://osf.io/wa8xr), articles were retrieved from MEDLINE/PubMed, EMBASE, and WebOfScience. Inclusion criteria comprised studies on humans or animal models, assessment of peripheral or local tissue GDF15 concentrations, as well as the direct expression of GDF15 in skeletal muscle, and direct or indirect correlates of GDF15 with physical activity/ sarcopenia/trophism/ function. Results: A total of 646 studies were retrieved, and 144 finally included. Molecular inducers or inhibitors of GDF15 in skeletal muscle tissues were described. GDF15 was reported to promote skeletal muscle health, metabolic homeostasis, and overall physical conditioning. In pathology, GDF15 seems to be correlated to the degree of muscle impairment and mitochondrial stress. GDF15 has also been described as having the potential to stratify patients based on clinical prognosis and functional outcome. Conclusion: A hormetic hypothesis for GDF15 on skeletal muscle was proposed. In fact, GDF15 exhibited beneficial effects when expressed at high levels facing acute stressors (i.e., “myoprotection”). Conversely, GDF15 exhibited maladaptive effects, such as chronic low-grade inflammation, when chronically expressed in pathological processes (e.g., obesity, aging). GDF15 may be a potential molecular target for disease-modifying interventions. The current review underscores the need for further research on GDF15 to elucidate its therapeutic potential across different pathological states. The study protocol, registered before data collection and analysis, can be retrieved at https://osf.io/wa8xr. It should be noted that the study deviated from the protocol after peer review, including other electronic databases beyond MEDLINE/PubMed alone.

In epigenetic analysis, the identification of differentially methylated regions (DMRs) typically involves the detection of consecutive CpGs groups that show significant changes in their average methylation levels. However, the methylation state of a genomic region can also be characterized by a mixture of patterns (epialleles) with variable frequencies, and the relative proportions of such patterns can provide insights into its mechanisms of formation. Traditional methods based on bisulfite conversion and high-throughput sequencing, such as Illumina, owing to the read size (150 bp) allow epiallele frequency analysis only in high CpG density regions, limiting differential methylation studies to just 50% of the human methylome. Nanopore sequencing, with its long reads, enables the analysis of epiallele frequency across both high and low CpG density regions. Here, we introduce a novel computational approach, PoreMeth2, an R library that integrates epiallelic diversity and methylation frequency changes from nanopore data to identify DMRs, providing insights into their possible mechanisms of formation, and annotate them to genic and regulatory elements. We apply PoreMeth2 to cancer and glial cell data sets, providing evidence of its advance over other state-of-the-art methods and demonstrating its ability to distinguish epigenomic alterations with a strong impact on gene expression from those with weaker effects on transcriptional activity.

Fibromyalgia (FM) is a complex and multifaceted condition characterized by a range of clinical symptoms, including widespread pain and a strong association with migraine headaches. Recent findings have underscored the role of oxidative stress and transient receptor potential ankyrin 1 (TRPA1) channel in migraine and FM. However, the precise mechanisms underlying the comorbidity between migraine and FM are unclear. Periorbital mechanical allodynia (PMA), which recapitulates one of the major symptoms of migraine, and the feed-forward mechanism driven by reactive oxygen species and TRPA1, were investigated in a reserpine-induced FM model in C57BL/6J mice, employing pharmacological interventions and genetic approaches. Reserpine-treated mice developed PMA (which was alleviated by antimigraine drugs) and increased endoneurial macrophages and oxidative stress markers in the trigeminal nerve tissues (neuroinflammation). These responses were absent upon macrophage depletion and by pharmacological inhibition or global genetic deletion of the TRPA1 channel. Furthermore, selective silencing of TRPA1 in Schwann cells attenuated both reserpine-induced PMA and neuroinflammation, while selective silencing of TRPA1 in sensory neurons reduced PMA but not neuroinflammation. In reserpine-treated mice, Schwann cell TRPA1 promoted NADPH oxidase 1-mediated reactive oxygen species generation and macrophage density increase in the mouse trigeminal nerve, which sustains PMA. Targeting TRPA1 channels in Schwann cells could offer a novel therapeutic strategy for FM-related headaches.

Cutaneous squamous cell carcinoma (cSCC) stands as the second most prevalent non-melanoma skin cancer worldwide, comprising approximately 20

This work addresses a long standing question in the field of mechanochemistry, namely the role of mesostructure in the initiation of self-propagating high-temperature reactions in exothermic chemical systems, commonly referred to as ignition. In an attempt to find robust evidence in this regard, we compare the ignition behaviour of equimolar Al-Ni powder mixtures and equimolar Al-Ni multilayers. To achieve the best possible control of experimental conditions and allowing high reproducibility, we used elemental powders sieved in the range between 20 μm and 44 μm, and multilayers with bi-layer thickness between 10 nm and 800 nm. We carried out systematic ball milling experiments involving pristine powder mixtures and multilayers as well as a mix of pristine material and material prone to ignition suitably prepared. Experimental findings suggest that pristine powder mixtures and multilayers with bi-layer thickness of 240 nm have analogous ignition behaviour. Along the same lines, data suggest that pristine powder mixtures undergo ignition when they attain a mesostructure similar to that of multilayers with bi-layer thickness of 10 nm.

Post-COVID-19 (PC) and post-COVID-19 vaccination (PCV) syndromes are considered emergent multidisciplinary disorders. PC/PCV small fiber neuropathy (SFN) was rarely described and its association with undifferentiated arthritis (UA) was never defined. We aimed to evaluate PC/PCV-UA associated with the recent onset of severe lower limb paresthesia, compare SFN positive (+) to negative (-) patients, and evaluate changes in biomarkers in SFN+ during treatments. Nineteen PC/PCV-UA-patients with possible SFN underwent skin biopsy at the Usl Tuscany Center (Florence) early arthritis outpatient clinic from September 2021 to March 2024. Eight selected SFN+ were compared to ten SFN- patients. In SFN+ patients, baseline joint ultrasound (US), electromyography (EMG), optical coherence tomography (OCT), and skin biopsy were repeated at six months. Moreover, SFN+ patients were clinically assessed by a 0-10 numeric rating scale for neurological symptoms and DAS28/ESR up to 12 months follow-up. SFN+ patients showed a lower intraepidermal nerve fiber density at histopathological examination of skin biopsies and a higher frequency of OCT and EMG abnormalities in comparison to SFN- patients. In SFN+ patients, US and DAS28/ESR significantly improved, while intraepidermal nerve fiber density did not significantly change at the six-month follow-up. Fatigue, motor impairment, burning pain, brain fog, and sensitivity disorders decreased at long-term follow-up (12 months).

BACKGROUND:Perineural invasion (PNI) is a complex molecular process histologically represented by the presence of tumor cells within the peripheral nerve sheath and defined when infiltration into the 3 nerve sheath layers can be clearly identified. Several molecular pathways have been implicated in cSCC. PNI is a well-recognized risk factor in cutaneous squamous cell carcinoma (cSCC) and its accurate assessment represents a challenging field in pathology daily practice. SUMMARY:As a highly intricate and dynamic process, PNI involves a contingent on bidirectional signaling interactions between the tumor and various nerve components, such as Schwann cells and neurons. The current staging systems recommend the identification of PNI as a dichotomous variable (presence vs. absence) to identify a subgroup of high-risk patients. However, recent further insights revealed that the evaluation of morphological PNI-related features in cSCC may enhance the prognostic stratification of patients and may optimize the current staging guidelines for recurrence risk assessment and improvement of patient selection for postoperative adjuvant treatments. Furthermore, recent emerging biomarkers could redefine early PNI detection. KEY MESSAGES:This review provides updated insights into cSCC with PNI, focusing on molecular and cellular pathogenic processes, and aims to increase knowledge on prognostic relevant PNI-related histological features.

BACKGROUND AND PURPOSE:Fibromyalgia is a complex clinical disorder with an unknown aetiology, characterized by generalized pain and co-morbid symptoms such as anxiety and depression. An imbalance of oxidants and antioxidants is proposed to play a pivotal role in the pathogenesis of fibromyalgia symptoms. However, the precise mechanisms by which oxidative stress contributes to fibromyalgia-induced pain remain unclear. The transient receptor potential ankyrin 1 (TRPA1) channel, known as both a pain sensor and an oxidative stress sensor, has been implicated in various painful conditions. EXPERIMENTAL APPROACH:The feed-forward mechanism that implicates reactive oxygen species (ROS) driven by TRPA1 was investigated in a reserpine-induced fibromyalgia model in C57BL/6J mice employing pharmacological interventions and genetic approaches. KEY RESULTS:Reserpine-treated mice developed pain-like behaviours (mechanical/cold hypersensitivity) and early anxiety-depressive-like disorders, accompanied by increased levels of oxidative stress markers in the sciatic nerve tissues. These effects were not observed upon pharmacological blockade or global genetic deletion of the TRPA1 channel and macrophage depletion. Furthermore, we demonstrated that selective silencing of TRPA1 in Schwann cells reduced reserpine-induced neuroinflammation (NADPH oxidase 1-dependent ROS generation and macrophage increase in the sciatic nerve) and attenuated fibromyalgia-like behaviours. CONCLUSION AND IMPLICATIONS:Activated Schwann cells expressing TRPA1 promote an intracellular pathway culminating in the release of ROS and recruitment of macrophages in the mouse sciatic nerve. These cellular and molecular events sustain mechanical and cold hypersensitivity in the reserpine-evoked fibromyalgia model. Targeting TRPA1 channels on Schwann cells could offer a novel therapeutic approach for managing fibromyalgia-related behaviours.

Background and PurposeRetinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).Experimental ApproachBoth neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.ResultshNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.Conclusions and ImplicationsOur data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.

Mechanochemistry is drawing attention from the pharmaceutical industry given its potential for sustainable material synthesis and manufacture. Scaling mechanochemical processes to industrial level remains a challenge due to an incomplete understanding of their underlying mechanisms. We here show how time-resolved in situ powder X-ray diffraction data, coupled with analytical kinetic modelling, provides a powerful approach to gain mechanistic insight into mechanochemical reactions. By using the ibuprofen-nicotinamide co-crystal mechanosynthesis as a benchmark system, we investigate the behaviour of the solids involved and identify the factors that promote the reaction. As mechanochemical mechanisms become increasingly clear, it promises to become a breakthrough in the industrial preparation of advanced pharmaceuticals.

This study investigates the mechanochemical reaction of hydrogen isotope exchange between solid benzoic acid and liquid heavy water. The systematic change of milling conditions revealed that the reaction rate scales with the milling frequency and the mass of the milling balls. The ball size being always the same, faster reactions stem from the use of higher milling frequencies and heavier balls. The kinetic curves are described by a kinetic model that accounts for the statistical, deformational and chemical factors involved in mechanochemical transformations. The results indicate that the reaction is driven by the generation of a new interface area caused by the deformation of the solid reactants.

This themed collection includes a collection of articles on the fundamental basis of mechanochemical reactivity.