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ABSTRACTIntroductionAntiplatelets and oral anticoagulants are commonly used to treat patients with various cardiovascular and cerebrovascular diseases. However, the primary concern for clinicians remains the risk of bleeding, thus necessitating the development of new therapies. Milvexian is a new anticoagulant that inhibits factor XIa, preventing the pathological formation of thrombi without increasing bleeding risk.Areas coveredThis drug evaluation examines the pharmacokinetic properties of milvexian and provides information on its pharmacodynamics and clinical efficacy in treating some cerebrovascular conditions.Expert opinionMilvexian shows a good pharmacokinetic profile with low renal elimination rates, justifying its use in patients with a high degree of renal impairment, and without relevant drug-drug interactions. In patients affected by acute non-cardioembolic ischemic stroke or high-risk transient ischemic stroke, milvexian, in addition to dual antiplatelet therapy, seems to have a positive efficacy profile without any safety concerns, especially in terms of intracranial hemorrhage. Two phase 3 trials are ongoing to investigate the efficacy and safety of milvexian for preventing cardioembolic and non-cardioembolic ischemic stroke.

Introduction: Mechanical thrombectomy (MT) is the standard treatment for acute ischemic stroke (AIS) due to anterior large vessel occlusion (LVO). Despite successful recanalization, some patients remain disabled after 3 months. Mechanisms that can cause futile recanalization (FR) are still largely unknown. We investigated if stress hyperglycemia might be associated with FR.Patients and methods: This is a retrospective analysis of consecutive patients with successful recanalization treated in four participating centers between January 2021 and December 2022. According to the modified Rankin scale (mRS) status at 3 months, patients were divided into two groups: FR, if mRS score >2, and useful recanalization (UR), if mRS score ⩽2. Stress hyperglycemia was estimated by the glucose-to-glycated hemoglobin ratio (GAR) index.Results: A total of 691 subjects were included. At 3 months, 403 patients (58.3%) were included in the FR group, while the remaining 288 patients (41.7%) were included in the UR group. At the multivariate analysis, variables independently associated with FR were the following: age (OR 1.04, 95% CI 1.02–1.06, p< 0.001), GAR index (OR 1.08, 95% CI 1.03–1.14, p= 0.003), NIHSS at admission (OR 1.16, 95% CI 1.11–1.22; p< 0.001), and procedure length (OR 1.01, 95% CI 1.00–1.02; p= 0.009). We observed that the model combining age, GAR index, NIHSS at admission, and procedure length had good predictive accuracy (AUC 0.78, 95% CI 0.74–0.81).Conclusions: Stress hyperglycemia predicts FR in patients with successful recanalization after MT. Further studies should explore if managing stress hyperglycemia may reduce futile recanalization. Additionally, we recommend paying close attention to AIS patients with a GAR index greater than 24.8 who exhibit a high risk of FR.

There is a growing interest in the search for metal-based therapeutics for protein misfolding disorders such as Alzheimer’s disease (AD). A novel and largely unexplored class of metallodrugs is constituted by paddlewheel diruthenium complexes, which exhibit unusual water solubility and stability and unique coordination modes to proteins. Here, we investigate the ability of the complexes [Ru2Cl(DPhF)(O2CCH3)3]·H2O (1), [Ru2Cl(DPhF)2(O2CCH3)2]·H2O (2), and K2[Ru2(DPhF)(CO3)3]·3H2O (3) (DPhF–= N,N′-diphenylformamidinate) to interfere with the amyloid aggregation of the Aβ1–42peptide. These compounds differ in charge and steric hindrance due to the coordination of a different number of bulky ligands. The mechanisms of action of the three complexes were studied by employing a plethora of physicochemical and biophysical techniques as well as cellular assays. All these studies converge on different mechanisms of inhibition of amyloid fibrillation: complexes 1and 2show a clear inhibitory effect due to an exchange ligand process in the Ru2unit aided by aromatic interactions. Complex 3shows no inhibition of aggregation, probably due to its negative charge in solution. This study demonstrates that slight variations in the ligands surrounding the bimetallic core can modulate the amyloid aggregation inhibition and supports the use of paddlewheel diruthenium complexes as promising therapeutics for Alzheimer’s disease.

ABSTRACTIntroductionRestless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated.Areas coveredThe present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options.Expert opinionα2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 (1), the only known peptide acting through this mechanism. The new peptides, notably 3and 9, showed lower IC50values than 1. When incorporated into tumor-targeted biodegradable nanoparticles, these exhibited cytotoxicity against three different CRC cell lines. Notably, NPs/9caused a significant increase in p53 levels associated with a strong increment of its main downstream target p21 inducing apoptosis. Also, the combined treatment of 9with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.

ABSTRACTIntroductionThe drug most frequently used for thrombolysis in cases of acute ischemic stroke (AIS) is alteplase. However, there is moderate-to-high-quality evidence that tenecteplase has similar or higher efficacy and safety. With improved pharmacokinetic properties over alteplase, tenecteplase could be a significant advantage in treating AIS.Areas CoveredAfter conducting an extensive search on Scopus and PubMed, this manuscript reviews and compares the pharmacokinetic properties of alteplase and tenecteplase. Additionally, it provides information on pharmacodynamics, clinical efficacy, safety, tolerability, and drug–drug interactions.Expert opinionThe pharmacokinetic profile of alteplase and tenecteplase is derived from studies in patients with acute myocardial infarction. Thanks to its pharmacokinetic properties, tenecteplase is the drug closest to being the ideal fibrinolytic for AIS. Its longer half-life enables a single-bolus administration, which is particularly useful in emergencies. Tenecteplase has proven to have a good efficacy and safety profile in randomized clinical trials. Although we are awaiting the results of the ongoing phase 3 randomized clinical trials, we believe that tenecteplase has the potential to revolutionize the treatment of AIS through thrombolysis.

The physical and chemical properties of paddlewheel diruthenium compounds are highly dependent on the nature of the ligands surrounding the bimetallic core. Herein, we compare the ability of two diruthenium compounds, [Ru2Cl(D-p-FPhF)(O2CCH3)3]·H2O (1) (D-p-FPhF–= N,N′-bis(4-fluorophenyl)formamidinate) and K3[Ru2(O2CO)4]·3H2O (2), to act as inhibitors of amyloid aggregation of the Aβ1–42peptide and its peculiar fragments, Aβ1–16and Aβ21–40. A wide range of biophysical techniques has been used to determine the inhibition capacity against aggregation and the possible mechanism of action of these compounds (Thioflavin T fluorescence and autofluorescence assays, UV–vis absorption spectroscopy, circular dichroism, nuclear magnetic resonance, mass spectrometry, and electron scanning microscopy). Data show that the most effective inhibitory effect is shown for compound 1. This compound inhibits fiber formation and completely abolishes the cytotoxicity of Aβ1–42. The antiaggregatory capacity of this complex can be explained by a binding mechanism of the dimetallic units to the peptide chain along with π–π interactions between the formamidinate ligand and the aromatic side chains. The results suggest the potential use of paddlewheel diruthenium complexes as neurodrugs and confirm the importance of the steric and charge effects on the properties of diruthenium compounds.

A 3 year monitoring programme, realized in a citizen science context, from 2014 until 2016, allowed us to gather information on the prevalent quantities and qualities of anthropogenic waste in five Mediterranean coastal areas within the Pelagos Sanctuary, three of them located in Liguria, near La Spezia Gulf, and the other two in Tuscany. Here, we present results concerning the Polymeric Articles’ abundances registered during the survey. Moreover, we show the results of the first study devoted to describe and quantify the anthropogenic content of the nest of a pair of Northern Gannets (Morus bassanus), a pelagic bird that, starting from some years, has been reproducing regularly in La Spezia Gulf. This breeding is atypical for this species, as is associated with artificial structures such as piers, floating docks, or boats; the material used in the construction of the nest reflects the “anthropogenic” link with the chosen location and objects of polymeric origin in particular abound. We detect the existence of a correlation between the most abundant types of Anthropogenic Marine Debris found in the Northern Gannet’ nest (fragments of polypropylene nets) and one of the productive activities of the zones.

BackgroundIn addition to other stroke-related deficits, the risk of seizures may impact driving ability after stroke.MethodsWe analysed data from a multicentre international cohort, including 4452 adults with acute ischaemic stroke and no prior seizures. We calculated the Chance of Occurrence of Seizure in the next Year (COSY) according to the SeLECT2.0prognostic model. We considered COSY<20% safe for private and <2% for professional driving, aligning with commonly used cut-offs.ResultsSeizure risks in the next year were mainly influenced by the baseline risk-stratified according to the SeLECT2.0score and, to a lesser extent, by the poststroke seizure-free interval (SFI). Those without acute symptomatic seizures (SeLECT2.00–6 points) had low COSY (0.7%–11%) immediately after stroke, not requiring an SFI. In stroke survivors with acute symptomatic seizures (SeLECT2.03–13 points), COSY after a 3-month SFI ranged from 2% to 92%, showing substantial interindividual variability. Stroke survivors with acute symptomatic status epilepticus (SeLECT2.07–13 points) had the highest risk (14%–92%).ConclusionsPersonalised prognostic models, such as SeLECT2.0, may offer better guidance for poststroke driving decisions than generic SFIs. Our findings provide practical tools, including a smartphone-based or web-based application, to assess seizure risks and determine appropriate SFIs for safe driving.

Digital transformation refers to an organization’s or company’s shift to digital management techniques, which alter organizational behavior and corporate culture and need the introduction of new digital management tools. By the opinion of the author, the gap between present management education that based on the traditional schemes of organizations, cultures are constrained in vertical silos, and the needs of the new digital ecosystems, mainly horizontal, clients’ needs-driven, internationally, and interculturally integrated, is growing and should be rapidly changed. Digital transformation is changing the way how organizations interact with customers, suppliers, and partners. The article presents the author’s viewpoint on the interpretation and analysis of the approaches used in the field of business management education. Preparation of a new generation of leaders requires restructuring of business management education, considering the growing importance of information technologies and implementation of integrated and multidisciplinary approaches to management education and training programs. In this context, the author proposes a conceptual approach to the designing of a university curriculum in the field of business management education and training, which is aimed at meeting the needs of modern managers in knowledge and competencies toward the process of digital transformation.

Development of an anatomically accurate 3-dimensional (3D) digital model of the human larynx derived from published literature and radiographic imaging. The laryngeal framework was segmented from a computed tomography (CT) angiogram of a healthy 29-year-old female. Data derived from published anatomical studies were compiled to provide additional anatomical detail to each structure. Anatomical details beyond the resolution of the imaging study or which could not be elucidated from the study were refined according to descriptions in the anatomic literature. The 3D model was refined by the medical illustrator, and its mesh was reformatted to optimize online viewing and manipulation. Due to the small size of the laryngeal muscles, there was no attempt to segment these muscles using radiographic imaging. All intrinsic laryngeal muscles were generated de novo , as were the superior laryngeal nerve and recurrent laryngeal nerve. CT imaging was utilized to generate meshes of the hyoid bone, epiglottis, thyroid cartilage, cricoid cartilage, and thyrohyoid membrane. Additionally, the airway space was segmented to provide size and spatial location to the vallecula, false vocal folds, true vocal folds, piriform sinus, subglottis, and a scaffold for the mucosa. These meshes were processed to limit radiographic artifact and serve as a foundation for the construction of the remainder of the laryngeal anatomy. The model was uploaded to a 3D repository, which can be accessed here (https://shorturl.at/nJPYZ). The larynx is a highly specialized organ essential for speech, swallowing, and airway protection. This study describes a digital 3D model of the larynx, created by combining radiographic imaging with critical review of anatomic literature. Utilizing the expertise of neuroradiology, laryngeal surgery, and medical illustration, we highlight surgically-relevant anatomic relationships and important aspects to consider during laryngeal surgery. [ABSTRACT FROM AUTHOR]

Development of an anatomically accurate 3-dimensional (3D) digital model of the human nasopharynx, oropharynx, and hypopharynx derived from published literature and radiographic imaging. Muscles of the pharynx, including the palatopharyngeus, superior, middle, and inferior constrictor, salpingopharyngeus and stylopharyngeus were manually segmented from a head and neck CT angiogram of a healthy 29-year-old female. Data derived from published anatomical studies were compiled to provide additional anatomical detail to each muscle. The eustachian tube and supporting structures, adjacent supporting structures, and adjacent major neurovasculature were also segmented. These anatomical details were then incorporated into the model by a 3D medical illustrator. A total of 6 muscles were segmented from CT angiography data as were the hyoid bone, thyroid and cricoid cartilage, epiglottis, skull base, course of the eustachian tube, and nearby major arteries and veins. Meshes were further refined in digital 3D space based on data from peer-reviewed anatomical studies. The left trigeminal, glossopharyngeal, and hypoglossal nerves were incorporated into the model to highlight important anatomical relationships relevant for surgery. Finally, the model was uploaded to a publicly available 3D repository, which can be accessed here (https://shorturl.at/qJO16). The pharynx is a complex 3D structure that plays a critical role in swallowing, speaking, and airway protection. By combining radiographic data with published anatomical descriptions, and through the collaboration between neuroradiology, head and neck surgery, and medical illustration, we developed an anatomically accurate, detailed 3D model of the pharynx for education and training purposes. [ABSTRACT FROM AUTHOR]

Development of an anatomically accurate, digital, 3-dimensional (3D) model of the masticator space, including the muscles of mastication and temporomandibular joint, by combining data from radiographic imaging and published literature, and augmenting this with medical illustration. The present study involved the manual segmentation of the muscles of mastication, namely the masseter, temporalis, medial pterygoid, and lateral pterygoid muscles, as well as the buccinator muscle from a head and neck CT angiogram of a healthy 29-year-old female. The skull base, supporting structures, and adjacent major arteries were also segmented from the same study. The segmentation was then refined based on a compilation of data from published anatomical studies, which were utilized to provide additional anatomical detail for each muscle. Published studies were also used to incorporate structures unable to be segmented by this imaging technique, specifically major cranial nerves and the temporomandibular joint. The resulting anatomical details were subsequently incorporated into a 3D model by a professional medical illustrator. A total of 5 left-sided muscles were segmented from CT angiography data and were incorporated with segmentations of the skull base and mandible. Meshes were further refined in digital 3D space based on data from peer-reviewed anatomical studies. The left temporomandibular joint, sphenomandibular ligament, and stylomandibular ligament, as well as the left trigeminal nerve and maxillary artery and its branches were incorporated into the model to highlight important surgical anatomical relationships. Finally, the model was uploaded to a publicly available 3D repository, available at https://shorturl.at/hnrVZ. This 3D study serves to demonstrate, in a layered fashion, the complex anatomy of the muscles of mastication, including their relationship with important cranial base and neurovascular structures relevant to common surgical procedures and approaches to the infratemporal fossa. Moreover, it serves as an adjunct to the other studies published in this issue. [ABSTRACT FROM AUTHOR]

Using published literature and radiographic imaging, this study aims to develop an anatomically accurate 3-dimensional (3D) digital model of the human parotid gland, submandibular gland, facial nerve, and adjacent anatomy. The model is available for viewing at https://shorturl.at/uzADZ. The left parotid and submandibular glands, parotid ducts, retromandibular vein, external carotid artery, and its relevant branches were segmented from a computed tomography (CT) angiography study of a healthy female. The object segmentations were exported and refined based on a literature review of relevant anatomical structures. These structures were incorporated into the head and neck model to ensure compatibility with other anatomical structures, such as the mandible and skull base. Following the segmentation of the parotid and submandibular glands, the parotid gland was divided into superficial and deep lobes based on the course of the retromandibular vein. The facial nerve and its branches were added according to the most common anatomical variants. The internal maxillary artery and its first-order branches were identified; when below the resolution of the patient's imaging study, these branches were added according to the most commonly described anatomical variants. This applies to all other neurovascular structures depicted in the final renders. This study demonstrates the critical anatomic landmarks related to surgery of the parotid and submandibular glands, with particular emphasis on vascular structures including the maxillary and facial arteries, the common facial vein, external jugular vein, and retromandibular vein, as well as the facial nerve (CN VII), great auricular nerve, auriculotemporal nerve, lingual nerve, and hypoglossal nerve. The associated 3D model can serve as a helpful tool for improving the understanding of anatomical relationships, particularly in the parotid space. [ABSTRACT FROM AUTHOR]

This article traces the history of Joan of Arc through her brief life that includes leading an army in defense of France at the age of 17 and ending with her death at the stake at the age of 19. In her activities, St Joan reported that she was guided by voices and visions in which she communicated with venerated spiritual figures such as St Michael and St Margaret. Questions have arisen about the nature of these experiences, and various medical and psychiatric diagnoses have been offered by contemporary experts. In our effort to evaluate the diagnostic proposals, we have examined the incidence of voices and visions in the Middle Ages, and we have followed that with a review of nonpathologic voice-hearing in our own era. We then move on to an analysis of some proposed medical and psychiatric diagnoses, all of which we find unconvincing. With this background, we argue that St Joan does not warrant a medical or psychiatric diagnosis. Such a conclusion, however, leaves us with another issue, that of Joan's achievements. How do we understand an adolescent being able to lead an army? Addressing this question proves more difficult than deciding whether St Joan warrants a diagnosis. In addition to her achievements in the war against Britain, Joan of Arc stands out as both the most documented person in Western civilization up until her era, and as the only person who has been both condemned and canonized by the Catholic Church.

Neurodegenerative diseases are often associated with an uncontrolled amyloid aggregation. Hence, many studies are oriented to discover new compounds that are able to modulate self-recognition mechanisms of proteins involved in the development of these pathologies. Herein, three metal-complexes able to release carbon monoxide (CORMs) were analyzed for their ability to affect the self-aggregation of the amyloidogenic fragment of nucleophosmin 1, corresponding to the second helix of the three-helix bundle located in the C-terminal domain of the protein, i.e., NPM1264–277, peptide. These complexes were two cymantrenes coordinated to the nucleobase adenine (Cym-Ade) and to the antibiotic ciprofloxacin (Cym-Cipro) and a Re(I)-compound containing 1,10-phenanthroline and 3-CCCH2NHCOCH2CH2-6-bromo-chromone as ligands (Re-Flavo). Thioflavin T (ThT) assay, UV–vis absorption and fluorescence spectroscopies, scanning electron microscopy (SEM), and electrospray ionization mass spectrometry (ESI-MS) indicated that the three compounds have different effects on the peptide aggregation. Cym-Adeand Cym-Ciproact as aggregating agents. Cym-Adeinduces the formation of NPM1264–277fibers longer and stiffer than that formed by NPM1264–277alone; irradiation of complexes speeds the formation of fibers that are more flexible and thicker than those found without irradiation. Cym-Ciproinduces the formation of longer fibers, although slightly thinner in diameter. Conversely, Re-Flavoacts as an antiaggregating agent. Overall, these results indicate that metal-based CORMs with diverse structural features can have a different effect on the formation of amyloid fibers. A proper choice of ligands attached to metal can allow the development of metal-based drugs with potential application as antiamyloidogenic agents.

IMPORTANCE: Acute symptomatic seizures occurring within 7 days after ischemic stroke may be associated with an increased mortality and risk of epilepsy. It is unknown whether the type of acute symptomatic seizure influences this risk. OBJECTIVE: To compare mortality and risk of epilepsy following different types of acute symptomatic seizures. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data acquired from 2002 to 2019 from 9 tertiary referral centers. The derivation cohort included adults from 7 cohorts and 2 case-control studies with neuroimaging-confirmed ischemic stroke and without a history of seizures. Replication in 3 separate cohorts included adults with acute symptomatic status epilepticus after neuroimaging-confirmed ischemic stroke. The final data analysis was performed in July 2022. EXPOSURES: Type of acute symptomatic seizure. MAIN OUTCOMES AND MEASURES: All-cause mortality and epilepsy (at least 1 unprovoked seizure presenting >7 days after stroke). RESULTS: A total of 4552 adults were included in the derivation cohort (2547 male participants [56%]; 2005 female [44%]; median age, 73 years [IQR, 62-81]). Acute symptomatic seizures occurred in 226 individuals (5%), of whom 8 (0.2%) presented with status epilepticus. In patients with acute symptomatic status epilepticus, 10-year mortality was 79% compared with 30% in those with short acute symptomatic seizures and 11% in those without seizures. The 10-year risk of epilepsy in stroke survivors with acute symptomatic status epilepticus was 81%, compared with 40% in survivors with short acute symptomatic seizures and 13% in survivors without seizures. In a replication cohort of 39 individuals with acute symptomatic status epilepticus after ischemic stroke (24 female; median age, 78 years), the 10-year risk of mortality and epilepsy was 76% and 88%, respectively. We updated a previously described prognostic model (SeLECT 2.0) with the type of acute symptomatic seizures as a covariate. SeLECT 2.0 successfully captured cases at high risk of poststroke epilepsy. CONCLUSIONS AND RELEVANCE: In this study, individuals with stroke and acute symptomatic seizures presenting as status epilepticus had a higher mortality and risk of epilepsy compared with those with short acute symptomatic seizures or no seizures. The SeLECT 2.0 prognostic model adequately reflected the risk of epilepsy in high-risk cases and may inform decisions on the continuation of antiseizure medication treatment and the methods and frequency of follow-up.

Ruthenium(II) complexes with a three-legged piano-stool structure based on an arene ring, an N-heterocyclic carbene (NHC)-carbene ligand with a peracetylated glucose moiety and two chlorides or one bidentate ligand, were prepared and characterized by spectroscopy and crystallography. In one case, the sugar substituent is replaced by an ethyl. The chirality of the sugar results in the formation of two diastereomers that interconvert through rotations around the Ccarbene–Ru and Carene–Ru bonds. In water, the complexes undergo a series of equilibrium hydrolysis steps involving the Ru–Cl bonds. The Ru–arene bond and the sugar acetyls are also partially hydrolyzed, and the selectivity of the process is governed by the nature of the arene and the pH of the solution. The reactivity of the compounds was studied against model nucleophiles and biological macromolecules. In the former case, mass experiments demonstrated a variety of binding modes with a trend reflecting the stability in aqueous environment. In the latter case, protein crystallography was used to characterize the preferential binding sites of one of the complexes. The X-ray structure of the adduct formed upon reaction of one representative complex with hen egg white lysozyme contains a Ru center, which retains the carbene ligand, close to the side chain of Asp119. In the adduct with bovine pancreatic ribonuclease, there are two protein molecules in the asymmetric unit. In one molecule, two Ru centers are located close to the side chains of His105 and of His119, which is the protein active site. In the second molecule, only one Ru center was found in the proximity of the side chain of His105. The Ru complexes also interact with calf-thymus DNA, although without displacing the intercalating probe EB. Finally, the complexes are essentially inactive against the human ovarian carcinoma A2780 cells, the cisplatin-resistant A2780cis cells, and the human embryonic kidney HEK293T cells.

Due to their unique coordination structure, dirhodium paddlewheel complexes are of interest in several research fields, like medicinal chemistry, catalysis, etc. Previously, these complexes were conjugated to proteins and peptides for developing artificial metalloenzymes as homogeneous catalysts. Fixation of dirhodium complexes into protein crystals is interesting to develop heterogeneous catalysts. Porous solvent channels present in protein crystals can benefit the activity by increasing the probability of substrate collisions at the catalytic Rh binding sites. Toward this goal, the present work describes the use of bovine pancreatic ribonuclease (RNase A) crystals with a pore size of 4 nm (P3221 space group) for fixing [Rh2(OAc)4] and developing a heterogeneous catalyst to perform reactions in an aqueous medium. The structure of the [Rh2(OAc)4]/RNase A adduct was investigated by X-ray crystallography: the metal complex structure remains unperturbed upon protein binding. Using a number of crystal structures, metal complex accumulation over time, within the RNase A crystals, and structures at variable temperatures were evaluated. We also report the large-scale preparation of microcrystals (∼10–20 μm) of the [Rh2(OAc)4]/RNase A adduct and cross-linking reaction with glutaraldehyde. The catalytic olefin cyclopropanation reaction and self-coupling of diazo compounds by these cross-linked [Rh2(OAc)4]/RNase A crystals were demonstrated. The results of this work reveal that these systems can be used as heterogeneous catalysts to promote reactions in aqueous solution. Overall, our findings demonstrate that the dirhodium paddlewheel complexes can be fixed in porous biomolecule crystals, like those of RNase A, to prepare biohybrid materials for catalytic applications.

Human milk is the ideal source of nutrition for most infants, but significant gaps remain in our understanding of human milk biology. As part of addressing these gaps, the Breastmilk Ecology: Genesis of Infant Nutrition (BEGIN) Project Working Groups 1–4 interrogated the state of knowledge regarding the infant–human milk–lactating parent triad. However, to optimize the impact of newly generated knowledge across all stages of human milk research, the need remained for a translational research framework specific to the field. Thus, with inspiration from the simplified environmental sciences framework of Kaufman and Curl, Working Group 5 of the BEGIN Project developed a translational framework for science in human lactation and infant feeding, which includes 5 nonlinear, interconnected translational stages, T1: Discovery; T2: Human health implications; T3: Clinical and public health implications; T4: Implementation; and T5: Impact. The framework is accompanied by 6 overarching principles: 1) Research spans the translational continuum in a nonlinear, nonhierarchical manner; 2) Projects engage interdisciplinary teams in continuous collaboration and cross talk; 3) Priorities and study designs incorporate a diverse range of contextual factors; 4) Research teams include community stakeholders from the outset through purposeful, ethical, and equitable engagement; 5) Research designs and conceptual models incorporate respectful care for the birthing parent and address implications for the lactating parent; 6) Research implications for real-world settings account for contextual factors surrounding the feeding of human milk, including exclusivity and mode of feeding. To demonstrate application of the presented translational research framework and its overarching principles, 6 case studies are included, each illustrating research gaps across all stages of the framework. Applying a translational framework approach to addressing gaps in the science of human milk feeding is an important step toward the aligned goals of optimizing infant feeding across diverse contexts as well as optimizing health for all.

The molecular mechanism of how human serum transferrin (hTF) recognizes cisplatin at the atomic level is still unclear. Here, we report the molecular structure of the adduct formed upon the reaction of hTF with cisplatin. Pt binds the side chain of Met256 (at the N-lobe), without altering the protein overall conformation.

The paddlewheel [Ru2Cl(O2CCH3)4] complex was previously reported to react with the model protein hen egg white lysozyme (HEWL), forming adducts with two diruthenium moieties bound to Asp101 and Asp119 side chains upon the release of one acetate. To study the effect of the equatorial ligands on the reactivity with proteins of diruthenium compounds, X-ray structures of the adducts formed when HEWL reacts with [Ru2Cl(D-p-FPhF)(O2CCH3)3] [D-p-FPhF = N,N′-bis(4-fluorophenyl)formamidinate] under different conditions were solved. [Ru2Cl(D-p-FPhF)(O2CCH3)3] is bonded through their equatorial positions to the Asp side chains. Protein binding occurs cis or trans to D-p-FPhF. Lys or Arg side chains or even main-chain carbonyl groups can coordinate to the diruthenium core at the axial site. Data help to understand the reactivity of paddlewheel diruthenium complexes with proteins, providing useful information for the design of new artificial diruthenium-containing metalloenzymes with potential applications in the fields of catalysis, biomedicine, and biotechnology.

Background: Rehabilitation is currently the best available treatment for post-stroke disability. There is, however, great variability in the proportion of patients accessing rehabilitation across high-income countries suggesting that factors not explained by facilities availability or guidelines diversity may intervene in decision-making. Objectives: To evaluate which factors are associated with appropriate post-stroke rehabilitation referrals in a tertiary stroke unit setting. Methods: Retrospective single-center cohort study including patients admitted to the Stroke Unit of the “Santa Maria della Misericordia” University Hospital, Udine (IT) from January 1st to December 31st, 2019. Information regarding stroke severity (National Institute of Health Stroke Scale), functional assessment (modified Rankin scale [mRS] and Barthel index [BI]), length of hospital stay, and rehabilitation pathway was collected. Outcome was defined as referral to the appropriate rehabilitation pathway. Appropriateness was assessed comparing patient clinical information at discharge against local criteria for intensive vs. extensive rehabilitation. A mixed-linear effect model was built to explore NIHSS, mRS, and BI variation over time. Multivariable logistic regression was used to estimate the adjusted-odds ratio (OR) and 95% confidence interval (CI 95%) of appropriate assignment to rehabilitation pathways. Results: 288 patients were included in the study (age 73.1 years, males 57.9%) and in 75.7%, the rehabilitation pathway assignment was appropriate. NIHSS at discharge was lower compared to admission but no effect of rehabilitation assignment was evident, while mRS scores at discharge and at three months were 2.6 (CI 95% 2.2; 3.0) and 2.1 (CI 95% 1.8; 2.5) higher compared to admission (p&lt; 0.0001). Rehabilitation assignment effect on mRS was time dependent, resulting in an additional − 0.6 (CI 95% − 1.0; − 0.2) lowering at discharge for those appropriately assigned (p= 0.003), with a trend for significance at three months (p= 0.08). BI score was higher at discharge (p&lt; 0.0001), and appropriate assignment was associated with higher scores (p= 0.01). Multivariate analysis showed that the OR of appropriate rehabilitation pathway assignment were reduced by higher mRS (0.60 [CI 95% 0.48; 0.76], p&lt; 0.0001) and increased by higher NIHSS (1.11 [CI 95% 1.04; 1.19], p= 0.001) scores at discharge. The latter finding might be explained by the rehabilitation assessment focus on post-stroke motor symptoms captured by NIHSS. Conclusions: Higher mRS and lower NIHSS levels at discharge were independent predictors for inappropriate rehabilitation assignment after stroke in our cohort. These findings may reflect a therapeutic bias toward patients with higher post-stroke disability in a rehabilitation framework heavily tilted on post-stroke motor symptoms.

ObjectiveInvestigate MRI evidence of anterior cruciate ligament (ACL) healing, patient-reported outcomes and knee laxity in patients with acute ACL rupture managed non-surgically with the Cross Bracing Protocol (CBP).MethodsEighty consecutive patients within 4 weeks of ACL rupture were managed with CBP (knee immobilisation at 90° flexion in brace for 4 weeks, followed by progressive increases in range-of-motion until brace removal at 12 weeks, and physiotherapist-supervised goal-oriented rehabilitation). MRIs (3 months and 6 months) were graded using the ACL OsteoArthritis Score (ACLOAS) by three radiologists. Mann-Whitney U tests compared Lysholm Scale and ACL quality of life (ACLQOL) scores evaluated at median (IQR) of 12 months (7–16 months) post-injury, and χ2tests compared knee laxity (3-month Lachman’s test and 6-month Pivot-shift test), and return-to-sport at 12 months between groups (ACLOAS grades 0–1 (continuous±thickened ligament and/or high intraligamentous signal) versus ACLOAS grades 2–3 (continuous but thinned/elongated or complete discontinuity)).ResultsParticipants were aged 26±10 years at injury, 39% were female, 49% had concomitant meniscal injury. At 3 months, 90% (n=72) had evidence of ACL healing (ACLOAS grade 1: 50%; grade 2: 40%; grade 3: 10%). Participants with ACLOAS grade 1 reported better Lysholm Scale (median (IQR): 98 (94–100) vs 94 (85–100)) and ACLQOL (89 (76–96) vs 70 (64–82)) scores, compared with ACLOAS grades 2–3. More participants with ACLOAS grade 1 had normal 3-month knee laxity (100% vs 40%) and returned to pre-injury sport (92% vs 64%), compared with participants with an ACLOAS grades 2–3. Eleven patients (14%) re-injured their ACL.ConclusionAfter management of acute ACL rupture with the CBP, 90% of patients had evidence of healing on 3-month MRI (continuity of the ACL). More ACL healing on 3-month MRI was associated with better outcomes. Longer-term follow-up and clinical trials are needed to inform clinical practice.

The proliferation of Internet of Things (IoT) devices has revolutionized multiple sectors, promising significant societal benefits. With an estimated 29 billion IoT devices expected to be interconnected by 2030, these devices span from common household items to advanced sensors and applications across various domains. However, the extensive scale of IoT networks has introduced security challenges, including vulnerabilities, cyber-attacks, and a lack of standardized protocols. In response to evolving threats, machine learning techniques, particularly for malware detection, have made significant strides. This survey focuses on a less-explored aspect of IoT security: the potential of energy-based attack detection. We aim to provide an up-to-date, comprehensive understanding of this approach by analyzing the existing body of research. We explore the diverse landscape of machine learning methodologies employed in IoT security, emphasizing the energy-based approach as a valuable tool for detecting and mitigating attacks. Furthermore, this survey underscores the significance of power consumption analysis in identifying deviations from expected behavior, enabling the detection of ongoing attacks or security vulnerabilities. Our survey offers insights into the state-of-the-art techniques, methodologies, and advancements in energy-based attack detection for IoT devices. By presenting a structured roadmap through the literature, research methodology, and in-depth discussion, we aim to aid researchers, practitioners, and policymakers in enhancing IoT security. This survey’s unique contribution lies in bridging the gap in the literature regarding energy-based approaches and underscoring their potential for fortifying IoT security. Future research in this direction promises to significantly enhance the safety and resilience of the IoT landscape.

A new mineral paratobermorite with the ideal crystal-chemical formula Ca4(Al0.5Si0.5)2Si4O16(OH)·2H2O·(Ca·3H2O) is a member of the tobermorite group within the tobermorite supergroup. It was found at the Bazhenovskoe chrysotile asbestos deposit, Central Urals, Russia, in cavities of grossular rodingite in association with prehnite, pectolite, thomsonite-Ca, and calcite. Paratobermorite occurs as well-shaped prismatic to acicular crystals up to 1 × 1.5 × 8 mm3typically assembled in spray- or bush-like radial clusters or open-work aggregates up to 1.5 cm across, which form interrupted crusts up to 3 × 5 cm2. Paratobermorite is transparent, colorless, pale yellowish, pale beige, or pinkish, with a vitreous luster. The mineral is brittle, with the (001) perfect cleavage. The Mohs hardness is ca. 3½. Dmeas= 2.51 (2) and Dcalc= 2.533 g/cm3. Paratobermorite is optically biaxial (+), α = 1.565 (2), β = 1.566 (2), γ = 1.578 (2), 2 Vmeas= 25 (10)° and 2 Vcalc= 32° (589 nm). Optical orientation is: X= c, Y= b, Z= a. The chemical composition of paratobermorite (electron microprobe, H2O by selective sorption from gaseous products of heating) is Na2O 0.40, K2O 0.28, CaO 36.60, MnO 0.04, BaO 0.07, Al2O36.46, SiO242.32, H2O 14.10, total 100.27 wt%. The empirical formula calculated on the basis of 22 O atoms per formula unit and (O,OH)17·5H2O is Na0.09K0.04Ca4.72Al0.92Si5.09O15.69(OH)1.31·5H2O. Like other members of the tobermorite supergroup, paratobermorite displays OD character, with two MDO (maximum degree of order) structures: one (MDO1), with non-standard space group F2/d11 and the second (MDO2), just corresponding to the structure-type of the new mineral, with non-standard space group C1121/m;its unit-cell parameters obtained from single-crystal X‑ray diffraction data are: a= 11.2220(4), b= 7.3777(2), c= 22.9425(8) Å, γ = 89.990(3)°, V= 1899.46(10) Å3, and Z= 4; polytype 2M. The structure of paratobermorite is solved on a single crystal, R= 8.36%. Like structures of other “tobermorites 11 Å,” it is based on the complex layer built of a sheet of sevenfold Ca-centered polyhedra with wollastonite-type chains of Ttetrahedra attached to the Ca-sheet from both sides. The tetrahedral (T) sites T1 and T2 are fully occupied by Si, while alternating T3 and T4 sites are filled by Al and Si in the ratio 1:1. The chains of tetrahedra belonging to neighboring complex layers share common oxygen vertices of the bridging T3,4 tetrahedra to form xonotlite-type ribbons [Si6O17]∞. The heteropolyhedral Ca-T-O scaffolding appears as a microporous quasi-framework with wide channels, which contain additional Ca atoms and H2O molecules. The complex Ca-T-O layers in paratobermorite (so-called “complex modules of type A”) significantly differ in topology (mutual arrangement of Ttetrahedra and Ca polyhedra) from the complex Ca-T-O layers in tobermorite (“complex modules of type B”). IR spectrum confirms the presence of nonequivalent H2O molecules and nonequivalent T-O-Tangles involving Tatoms of two neighboring wollastonite-type chains. Due to the original topological type of the structure and the presence of significant amount of Al, which substitutes Si, paratobermorite can be considered as a novel microporous material, a perspective cation-exchanger.

The objective of this study was to develop an anatomically accurate three-dimensional (3D) digital model of the soft palate, derived from patient imaging data and peer-reviewed gross and microscopic anatomical studies, and to provide this model publically for educational purposes. A head and neck CT angiography study of a healthy 29-year-old female was segmented by a neuroradiologist and a head and neck cancer surgeon into 3D objects. Peer-reviewed anatomical literature was queried to provide additional anatomical details. These details were then incorporated into the model with the assistance of a 3D medical illustrator. Tissue segmentation derived from CTA provided baseline anatomical structures to model the 5 paired muscles of the soft palate, the paired eustachian tubes, and relevant bony architecture. Twelve peer-reviewed anatomical studies contained sufficient anatomical descriptions to guide refinement of these structures in digital 3D space. The final modeled objects were finalized by a medical illustrator and then uploaded to a publicly available 3D model repository. The soft palate is a dynamic 3D structure that plays an important role in essential functions such as breathing, swallowing, and speaking. By combining tissue segmentation from a normal neck CTA with published anatomical literature, and utilizing multidisciplinary expertise, we developed an anatomically accurate, detailed 3D model of the soft palate, which can serve as a powerful teaching aid for this complex region. [ABSTRACT FROM AUTHOR]

Combining published literature, radiographic imaging, and medical illustration, this study aimed to develop an anatomically accurate 3-dimensional (3D) digital model of the human tongue, and to make this model publicly available for education and training purposes. The intrinsic and extrinsic muscles of the tongue were manually segmented from a head and neck CT angiogram of a healthy 29-year-old female. Data derived from published anatomical studies were compiled to provide additional anatomical detail to each tongue muscle. These anatomical details were then incorporated into a model by a 3D medical illustrator. A total of nine muscles were segmented for this study, along with the mandible and the hyoid bone. 3D meshes of the extrinsic muscles of the tongue, intrinsic muscles of the tongue, and the mylohyoid were created from CT angiography segmentation data. These meshes were refined in digital 3D space based off data from peer-reviewed anatomical studies. The final model was then uploaded to a publicly available 3D model repository. The tongue is a complex 3D organ with important roles in swallowing, speaking, and airway protection. By combining radiographic data with published anatomical descriptions, and through the collaboration between neuroradiology, head and neck surgery, and medical illustration, we developed an anatomically accurate, detailed 3D model of the oral tongue, which may serve as a powerful anatomy teaching aid. [ABSTRACT FROM AUTHOR]

The interaction with proteins of metal-based drugs plays a crucial role in their transport, mechanism, and activity. For an active MLncomplex, where L is the organic carrier, various binding modes (covalent and non-covalent, single or multiple) may occur and several metal moieties (M, ML, ML2, etc.) may interact with proteins. In this study, we have evaluated the interaction of [VIVO(malt)2] (bis(maltolato)oxidovanadium(IV) or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme (HEWL) by electrospray ionization mass spectrometry, electron paramagnetic resonance, and X-ray crystallography. The multiple binding of different V-containing isomers and enantiomers to different sites of HEWL is observed. The data indicate both non-covalent binding of cis-[VO(malt)2(H2O)] and [VO(malt)(H2O)3]+and covalent binding of [VO(H2O)3–4]2+and cis-[VO(malt)2] and other V-containing fragments to the side chains of Glu35, Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate. Our results suggest that the multiple and variable interactions of potential VIVOL2drugs with proteins can help to better understand their solution chemistry and contribute to define the molecular basis of the mechanism of action of these intriguing molecules.

Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell, https://resilience.ccr.cancer.gov/), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n= 38), infusion products for chimeric antigen receptor T cell therapies (n= 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n= 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBPknockouts in murine and human donor CD8+T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibpknockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibpknockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors.

X-ray diffraction data demonstrate that the adduct formed upon the reaction of dirhodium(II,II) tetraacetate with RNase A reacts with imidazole, leading to the formation of an unexpected product with the imidazole that binds the dirhodium center at an equatorial site rather than an axial site. The origin of this result has been dissected using quantum-chemical calculations.