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Objective. Therapeutic approach of osteoarthritis (OA) still represents a challenge in clinical practice. The aim of the study is to assess the efficacy of far infrared (FIR) emitting plaster in the treatment of knee OA. Design. This is a randomized, single-blind, placebo-controlled, parallel group with equal randomization (1:1), clinical trial. Patients affected by knee OA were randomly allocated to 1 of 2 treatment groups, either placebo plaster or far infrared emitting plaster. Primary endpoint was to assess pain improvement from baseline to 1 months posttreatment in the visual analogue score (VAS). Secondary end point was to evaluate pain score after 1 week of treatment and to compare ultrasonographic findings after 1 month of treatment. Results. Each group comprised 30 (in the FIR group) and 30 (in the placebo group) completers. VAS scores of the placebo and the FIR group were significantly lower at 1 week post-treatment (95% confidence interval CI = -1.14 to 0.31; PConclusions. Far infrared emitting plaster could be considered an effective non-pharmacological choice for the therapeutic management of knee OA.

Abstract Understanding the effects of consolidating inorganic mineral treatments on carbonate stones of cultural heritage, and on the nature and distribution of newly formed products within the matrix, poses a significant challenge in Heritage Science and Conservation Science. Existing analytical methods often fail to deliver spatial and compositional insights into the newly formed crystalline phases with the appropriate high lateral resolution. In this study, we explore the capabilities and limitations of synchrotron radiation (SR) micro-X-ray powder diffraction (μXRPD) mapping combined with micro-X-ray fluorescence (μXRF) to give insight into compounds formed following the application of ammonium oxalate (AmOx) and diammonium phosphate-based (DAP) solutions on porous carbonate stone. Ultimately, the integration of μXRPD mapping and μXRF analysis proved itself a powerful asset in providing precise qualitative and quantitative data on the newly formed phases, in the case of both calcium oxalates (CaOxs) and calcium phosphates (CaPs), and their complex stratigraphic distribution, thus opening a new route for applications to a more comprehensive study of inorganic treatments applied to carbonate substrates.

A self-assembled tetrameric water cluster stabilized by [ReCl6]2− anions and [H4biim]2+ cations occurs in the new compound [H4biim][ReCl6]·4H2O, which exhibits a weak ferromagnetic coupling between the Re(IV) centers through an unusual ReIV–Cl⋯(H2O)⋯Cl–ReIV pathway. [ABSTRACT FROM AUTHOR]

The preparation, crystal structures and magnetic properties of the copper(II) complexes of formula [Cu(pyim)(tcm)2]n (1), [Cu(bpy)(tcm)2]n (2), [Cu4(bpz)4(tcm)8] (3), {[Cu(terpy)(tcm)]·tcm}n (4) and {[Cu2(tppz)(tcm)4]·3/2H2O}n (5) [pyim = 2-(2-pyridyl)imidazole, tcm = tricyanomethanide, bpy = 2,2′-bipyridine, bpz = 2,2′-bipyrazine, terpy = 2,2′:6′,2″-terpyridine and tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine] are reported. Complexes 1, 2 and 4 are uniform copper(II) chains with single- (1 and 4) and double-(2) µ-1,5-tcm bridges with values of the intrachain copper–copper separation of 7.489(1) (1), 7.520(1) and 7.758(1) (2) and 7.469(1) Å (4). Each copper atom in 1, 2 and 4 is five-coordinate with bidentate pyim (1)/bpy (2) and tridentate terpy (4) ligands and nitrile-nitrogen atoms from bridging (1, 2 and 4) and terminal (1) tcm groups building a distorted square pyramidal surrounding. The structure of 3 is made up of neutral centrosymmetric rectangles of (2,2′-bipyrazine)copper(II) units at the corners, the edges being built by single- and double-µ-1,5-tcm bridges with copper–copper separations of 7.969(1) and 7.270(1) Å, respectively. Five- and six-coordinated copper atoms with distorted square pyramidal and elongated octahedral environments occur in 3. Compound 5 is a neutral copper(II) chain with regular alternating bis-tridentate tppz and double µ-1,5-tcm bridges, the intrachain copper–copper distances being 6.549(7) and 7.668(1) Å, respectively. The two crystallographically independent copper atoms in 5 have an elongated octahedral geometry with three tppz nitrogen atoms and a nitrile-nitrogen atom from a bridging tcm group in the equatorial positions, and two nitrile nitrogen atoms from a terminal and a bridging tcm ligand occupying the axial sites. The investigation of the magnetic properies of 1–5 in the temperature range 1.9–295 K has shown the occurrence of weak ferro- [J = +0.11(1) cm−1 (2)] and antiferromagnetic interactions [J = −0.093(1) (1), −0.083(1) (4), −0.04(1) and 1.21(1) cm−1 (3)] across the µ-1,5-tcm bridges and intermediate antiferromagnetic coupling [−J = 37.4(1) cm−1 (5)] through bis-tridentate tppz. The values of the magnetic interactions are analyzed through simple orbital symmetry considerations and compared with those previously reported for related systems. [ABSTRACT FROM AUTHOR]

Background: Substance use among adolescents is common and associated with significant consequences, including depression. Adolescents can experience myriad problems related to early onset substance use and depression, making further understanding of this comorbidity necessary. Method: Participants were a subset from a large-scale performance improvement project and consisted of adolescents aged 12–18 who screened positive for depression during their routine medical or psychiatric appointment and who then completed the substance use assessment Car, Relax, Alone, Forget, Friends, Trouble Version 2.1 (CRAFFT). Participants with problematic substance use had a CRAFFT score ≥2. Results: A total of 621 participants were included in this study, and 105 (16.9%) reported problematic substance use. Compared with participants without problematic substance use, those with problematic use were more likely to have moderate to severe depression and anxiety, as well as significantly higher irritability, impulsivity, suicidal propensity, and suicidal thoughts scores. Controlling for age at screening, sex, race, and ethnicity, problematic substance use remained a significant predictor of depression severity, impulsivity, suicidal propensity, and suicidal thoughts. Limitations: Participants were from a large, metropolitan area of the Southwest United States who must have screened positive for depression, so results may not generalize. Because all participants were underage, they may have been wary in responding to the substance use assessment accurately. Conclusions: By using a large, diverse sample in a real-world clinical setting, findings strengthen the association between problematic substance use and depression and depression-associated symptoms among adolescents, highlighting the need for early detection and universal depression screening.

Abstract Disasters and other emergency events have complex effects on human systems, particularly if the events are severe or prolonged. When these types of events happen in rural communities, the resources of the local public health, healthcare, and emergency response organizations can be quickly depleted or overwhelmed. Planning for emergencies can help to mitigate their impact. Model-based systems engineering (MBSE) methods, including computer simulations, can provide insight on how best to prepare for these events and to explore the effects of varying approaches and resource utilization. To best apply these methods for improving disaster management in rural settings, a synthesis of the current body of evidence in this field is needed. The objective of this scoping review was to provide a descriptive overview of the application of computer simulation based on MBSE approaches to disaster preparedness and response for rural healthcare systems. Six studies met inclusion criteria, and varied in terms of MBSE method used, healthcare setting, and disaster type and context considered. We identified a gap in the research regarding the application of MBSE approaches to support rural healthcare disaster preparedness planning efforts. Model-based systems engineering and systems thinking, therefore, represent novel methods for developing tools and computational simulations that could assist rural communities better prepare for disasters.

Objective: This study aimed to (a) describe an annual prevention-focused, community-based oral health outreach program in rural Zambia, (b) assess its oral health outcomes using demographic and oral health variables, and c) identify milestones resulting from program activities. Methods: A retrospective analysis of demographic and oral health data from a single site between 2007–2014 and 2018–2019 was conducted. Demographic variables included sex and age, while clinical outcomes encompassed pain, untreated caries, and treatment urgency. Bivariate and multivariable analyses were performed, adjusting for sex and age categories. Information on community development was obtained from the Ministry of Health and local community representatives. Results: Data from 5,791 subjects were analyzed. The prevalence of pain, untreated caries, and highest treatment urgency category decreased consistently across year categories. Both bivariate and multivariable analyses showed statistically significant differences in clinical outcomes between year categories (p < 0.001). In addition, the percentage of male participants and younger age categories increased during the study period. Key program milestones included the installation of two boreholes for clean water, the development of a local community oral health volunteer program, the establishment of an educational pipeline by the Dental Training School for residents, and the construction of a maternal/oral health center with district and ministry oversight. Conclusion: The observed decrease in treatment urgency scores, presence of pain, and untreated caries are consistent with the prevention-seeking behavior of program participants. The increasing participation and changing demographic patterns over time suggest a growing demand for oral health services among males and younger individuals. The positive oral health outcomes and development of a maternal child/oral health facility exemplify a program design aligned with community needs and appropriate care delivery.

Abstract Aims In healthy subjects, adrenergic stimulation augments left ventricular (LV) long‐axis shortening and lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise in HFpEF would further impair passive LV filling in early‐mid diastole, during conduit flow from pulmonary veins. Methods and results Twenty HFpEF patients (67.8 ± 9.8 years; 11 women), diagnosed using 2007 ESC recommendations, underwent ramped semi‐supine bicycle exercise to submaximal target heart rate (∼100 bpm) or symptoms. Seventeen asymptomatic subjects (64.3 ± 8.9 years; 7 women) were controls. Simultaneous LA and LV volumes were measured from pyramidal 3D‐echocardiographic full‐volume datasets acquired from an apical window at baseline and during stress, together with brachial arterial pressure. LA conduit flow was computed from the increase in LV volume from its minimum at end‐systole to the last frame before atrial contraction (onset of the P wave), minus the reduction in LA volume during the same time interval; the difference was integrated and expressed as average flow rate, according to a published formula. The slope of single‐beat preload recruitable stroke work (PRSW) quantified LV inotropic state. 3D LV torsion (rotation of the apex minus rotation of the base divided by LV length) was also measurable, both at rest and during stress, in 10 HFpEF patients and 4 controls. There were divergent responses in conduit flow rate, which increased by 40% during exercise in controls (+17.8 ± 37.3 mL/s) but decreased by 18% in patients with HFpEF (−9.6 ± 42.3 mL/s) (P = 0.046), along with congruent changes (+1.77 ± 1.13°/cm vs. −1.94 ± 2.73°/cm) in apical torsion (P = 0.032). Increments of conduit flow rate and apical torsion during stress correlated with changes in PRSW slope (P = 0.003 and P = 0.006, respectively). Conclusions In HFpEF, conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with changes in LV inotropic state and torsion, contributing to impaired stroke volume reserve. Conduit flow is measurable using 3D‐echocardiographic full‐volume atrio‐ventricular datasets, and as a marker of LV relaxation can contribute to the diagnosis of HFpEF.

Abstract Three‐dimensional echocardiography can elucidate the phasic functions of the left atrium if a simultaneous acquisition of a pyramidal full‐volume dataset, as gathered from the apical window and containing the entire left atrial and left ventricular cardiac sections, is obtained. Hence, conduit can be quantified as the integral of net, diastolic, instantaneous difference between synchronized atrial and ventricular volume curves, beginning at minimum ventricular cavity volume and ending just before atrial contraction. Increased conduit can reflect increased downstream suction, as conduit would track the apex‐to‐base intracavitary pressure gradient existing, in early diastole, within the single chamber formed by the atrium and the ventricle, when the mitral valve is open. Such a gradient increases in response to adrenergic stimulation or during exercise and mediates an increment in passive flow during early diastole, with the ventricle being filled from the atrial reservoir and, simultaneously, from blood drawn from the pulmonary veins. In this context conduit, and even more conduit flow rate, expressed in ml/sec, can be viewed as an indirect marker of left ventricular relaxation. It is well known, however, that a large amount of conduit (in relative terms) is also supposed to contribute to LV stroke volume in conditions of increased resistance to LV filling, when diastolic function significantly worsens. Stiffening of the atrio‐ventricular complex implies increments in LA pressure more pronounced in late systole, causing markedly elevated “v” waves, independently of the presence of mitral insufficiency. The combination of increased atrio‐ventricular stiffness and conduit flow is associated with an elevation of the right ventricular pulsatile relative to resistive load that negatively impacts on exercise capacity and survival in these patients. Atrial conduit is an “intriguing” parameter that conveys a noninvasive picture of the complex atrioventricular coupling condition in diastole and its backward effects on the right side of the heart and the pulmonary circulation. Given the easiness associated with its correctly performed quantification in the imaging laboratory, I am sure that conduit will survive the competitive access to the list of valuable parameters capable of deciphering, although not necessarily simplifying, the complex diastolic scenario in health and disease.

In this work, we describe the complex formation and radiochemistry of the cyclen-based chelator DOTI-Me bearing four methylimidazole arms. Radiolabeling properties were evaluated for 52g Mn, 64 Cu, 68 Ga, 111 In, 161 Tb, and 177 Lu, and DOTI-Me showed distinct differences to the structurally related H 4 DOTA. While radiochemical conversions (RCCs) for 52g Mn and 111 In were comparable to those of H 4 DOTA, DOTI-Me was not suited for 68 Ga. Conversely, quantitative RCCs were achieved for 64 Cu at ambient temperature, while elevated temperatures were required for complexation with H 4 DOTA. For 161 Tb and 177 Lu, good but not quantitative RCCs were obtained with DOTI-Me. With the exemption of 68 Ga 3+ , radiolabeled complexes showed high stability in ligand challenge experiments and in human serum. X-ray analysis of the nonradioactive complexes revealed the formation of 8-coordinate Mn 2+ and In 3+ DOTI-Me complexes. Cu 2+ adopted a unique distorted square-pyramidal 2 + 3 with the neutral DOTI-Me ligand and a Jahn-Teller distorted 4 + 2 coordination geometry for the diprotonated H 2 DOTI-Me 2+ cation, respectively. For Zn 2+ , the complex with HDOTI-Me + showed a distorted 4 + 3 pentagonal bipyramidal geometry. Summarizing, the ligand DOTI-Me may be an interesting alternative to H 4 DOTA for 52g Mn, 64 Cu, 111 In, 161 Tb, and 177 Lu, covering diagnostic as well as therapeutic radionuclides. Further studies of targeted radiopharmaceuticals based on the DOTI-Me scaffold in combination with the set of radiometals presented herein are thus warranted.

Androgen insensitivity syndrome (AIS) is one of the most common Disorders of Sexual Differentiation (DSDs). AIS is characterized by an X-linked recessive inheritance pattern associated with variants in the androgen receptor (AR) gene that affects the masculinization process in individuals with XY karyotype. Here, we report a neonatal case of a very early diagnosis of complete AIS due to a novel variant in the AR gene. In the present case, after the clinical evaluation, the infant has undergone the following tests: biochemical analyses, including newborn screening workflow, karyotype analysis, and Next-Generation Sequencing (NGS) panel of 50 genes involved in DSDs. The NGS analysis identified a missense variant, c.2108C>A, in the AR gene. According to a cytogenetic analysis, the patient presented a 46, XY karyotype, thus the resulting hemizygote for the AR gene variant. The variant is not currently described in the literature nor in the ClinVar database. However, according to computational models, the variant could have a pathogenetic effect. This clinical case reveals a novel variant of the AR gene with a possible pathogenetic effect associated with AIS and highlights the importance of a multidisciplinary approach for the timely diagnosis and appropriate follow-up of the patient.

The neutral holmium(III) oxalate octadecahydrate {[Ho 2 (ox) 3 (H 2 O) 6 ]·12H 2 O} n of mixed hexagonal/decagonal (6 3 ·10 3 ) 3D net topology shows important changes in the magnetocaloric efficiency upon dehydration/rehydration by heating and water vapor exposition to give the holmium(III) oxalate decahydrate {[Ho 2 (ox) 3 (H 2 O) 6 ]·4H 2 O} n of hexagonal (6 3 ) 2D net topology through the intermediacy of the elusive amorphous anhydrous compound {Ho 2 (ox) 3 } n .

Up to approximately 70% of cancer survivors report persistent deficits in memory, attention, speed of information processing, multi-tasking, and mental health functioning, a series of symptoms known as "brain fog." The severity and duration of such effects can vary depending on age, cancer type, and treatment regimens. In particular, every year, hundreds of thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors and brain metastases originating from extracranial tumors. Besides its potential benefits in the control of tumor progression, recent studies indicate that RT reprograms the brain tumor microenvironment inducing increased activation of microglia and astrocytes and a consequent general condition of neuroinflammation that in case it becomes chronic could lead to a cognitive decline. Furthermore, radiation can induce endothelium reticulum (ER) stress directly or indirectly by generating reactive oxygen species (ROS) activating compensatory survival signaling pathways in the RT-surviving fraction of healthy neuronal and glial cells. In particular, the anomalous accumulation of misfolding proteins in neuronal cells exposed to radiation as a consequence of excessive activation of unfolded protein response (UPR) could pave the way to neurodegenerative disorders. Moreover, exposure of cells to ionizing radiation was also shown to affect the normal proteasome activity, slowing the degradation rate of misfolded proteins, and further exacerbating ER-stress conditions. This compromises several neuronal functions, with neuronal accumulation of ubiquitinated proteins with a consequent switch from proteasome to immunoproteasome that increases neuroinflammation, a crucial risk factor for neurodegeneration. The etiology of brain fog remains elusive and can arise not only during treatment but can also persist for an extended period after the end of RT. In this review, we will focus on the molecular pathways triggered by radiation therapy affecting cognitive functions and potentially at the origin of so-called "brain fog" symptomatology, with the aim to define novel therapeutic strategies to preserve healthy brain tissue from cognitive decline., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marino, Bedeschi, Vaccari, Cambiaghi and Tesei.)

This study investigates a mechanistic link of bacterial biofilm-mediated host-pathogen interaction leading to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. We report that periprosthetic breast tissue of participants with symptoms associated with BII had increased abundance of biofilm and biofilm-derived oxylipin 10-HOME compared with participants with implants who are without symptoms (non-BII) and participants without implants. S. epidermidis biofilm was observed to be higher in the BII group compared with the non-BII group and the normal tissue group. Oxylipin 10-HOME was found to be immunogenically capable of polarizing naive CD4+ T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of CD4+Th1 subtype was observed in the periprosthetic breast tissue and blood of people in the BII group. Mice injected with 10-HOME also had increased Th1 subtype in their blood, akin to patients with BII, and demonstrated fatigue-like symptoms. The identification of an oxylipin-mediated mechanism of immune activation induced by local bacterial biofilm provides insight into the possible pathogenesis of the implant-associated immune symptoms of BII.

LAT1 (SLC7A5) is one of the most studied membrane transporters due to its relevance to physiology in supplying essential amino acids to brain and fetus, and to pathology being linked to nervous or embryo alterations; moreover, LAT1 over-expression is always associated with cancer development. Thus, LAT1 is exploited as a pro-drug vehicle and as a target for anti-cancer therapy. We here report the identification of a new substrate with pathophysiological implications, i.e., Cu-histidinate, and an unconventional uniport mechanism exploited for the Cu-histidinate transport. Crystals of the monomeric species Cu(His) 2 were obtained in our experimental conditions and the actual transport of the complex was evaluated by a combined strategy of bioinformatics, site-directed mutagenesis, radiolabeled transport, and mass spectrometry analysis. The LAT1-mediated transport of Cu(His) 2 may have profound implications for both the treatment of copper dysmetabolism diseases, such as the rare Menkes disease, and of cancer as an alternative to platinum-based therapies., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals, even relative to risk of developing breast cancer, remains unclear. Here, we performed a comprehensive analysis of the microbiota of the normal breast tissue, which was analyzed in relation to the microbial composition of the tumor and adjacent normal tissue., Methods: The study cohorts included 403 cancer-free women (who donated normal breast tissue cores) and 76 breast cancer patients (who donated tumor and/or adjacent normal tissue samples). Microbiome profiling was obtained by sequencing the nine hypervariable regions of the 16S rRNA gene (V1V2, V2V3, V3V4, V4V5, V5V7, and V7V9). Transcriptome analysis was also performed on 190 normal breast tissue samples. Breast cancer risk score was assessed using the Tyrer-Cuzick risk model., Results: The V1V2 amplicon sequencing resulted more suitable for the analysis of the normal breast microbiome and identified Lactobacillaceae (Firmicutes phylum), Acetobacterraceae, and Xanthomonadaceae (both Proteobacteria phylum) as the most abundant families in the normal breast. However, Ralstonia (Proteobacteria phylum) was more abundant in both breast tumors and histologically normal tissues adjacent to malignant tumors. We also conducted a correlation analysis between the microbiome and known breast cancer risk factors. Abundances of the bacterial taxa Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp. were associated with age (p < 0.0001), racial background (p < 0.0001), and parity (p < 0.0001). Finally, transcriptome analysis of normal breast tissues showed an enrichment in metabolism- and immune-related genes in the tissues with abundant Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp., whereas the presence of Ralstonia in the normal tissue was linked to dysregulation of genes involved in the carbohydrate metabolic pathway., Conclusions: This study defines the microbial features of normal breast tissue, thus providing a basis to understand cancer-related dysbiosis. Moreover, the findings reveal that lifestyle factors can significantly affect the normal breast microbial composition., (© 2023. The Author(s).)

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world's population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. ( R / S )- RC - 752 emerged as the most interesting compound for S1R affinity ( K i S1R = 6.2 ± 0.9) and functional antagonist activity. Furthermore, it showed no cytotoxic effect in two normal human cell lines or in an in vivo zebrafish model and was stable after incubation in mouse plasma. ( R / S )- RC - 752 was then evaluated in two animal models of NP: the formalin test and the spinal nerve ligation model. The results clearly demonstrated that compound ( R / S )- RC - 752 effectively alleviated pain in both animal models, thus providing the proof of concept of its efficacy as an antinociceptive agent.

Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-d-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone- and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.

While in the past technology has mostly been utilized to store information about the structural configuration of proteins and molecules for research and medical purposes, Artificial Intelligence is nowadays able to learn from the existing data how to predict and model properties and interactions, revealing important knowledge about complex biological processes, such as aging. Modern technologies, moreover, can rely on a broader set of information, including those derived from the next-generation sequencing (e.g., proteomics, lipidomics, and other omics), to understand the interactions between human body and the external environment. This is especially relevant as external factors have been shown to have a key role in aging. As the field of computational systems biology keeps improving and new biomarkers of aging are being developed, artificial intelligence promises to become a major ally of aging research., Competing Interests: Authors NM, GP, and AS, were employed by the company Women’s Brain Project (WBP). Authors EB, QV, and AZ were employed by the company Insilico Medicine Hong Kong Ltd. Author ES was employed by company Bayer Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marino, Putignano, Cappilli, Chersoni, Santuccione, Calabrese, Bischof, Vanhaelen, Zhavoronkov, Scarano, Mazzotta and Santus.)

In recent years, the food industry has become increasingly involved in researching vegetable fats and oils with appropriate mechanical properties (ease of transport, processing, and storage) and a specific lipidic composition to ensure healthy products for consumers. The chemical-physical behavior of these matrices depends on their composition in terms of single fatty acids (FA). However, as we demonstrate in this work, these properties, as well as the absorption, digestion and uptake in humans of specific FAs, are also largely determined by their regiosomerism within the TriAcylGlycerols (TAG) moieties ( sn -1,2,3 positions). The goal of this work is to study for the first time vegetable fats obtained directly from a sample of natural cocoa butter (CB) through a process that manipulates the distribution of FAs but not their nature. Even if the initial percentage of each FA in the mixture remains the same, CB derivatives seem to show improved chemical-physical features. In order to understand which factors account for their physical and chemical characteristics, and to check whether or not the obtained new matrices could be considered as valid alternatives to other vegetable fats (e.g., palm oil (PO)), we carried out an experimental investigation at both the macroscopic and molecular level including: (i) Differential Scanning Calorimetry (DSC) analyses to examine thermal features; (ii) rheological testing to explore mechanical properties; (iii) powder X-ray diffraction (PXRD) to evaluate the solid-state phases of the obtained fats; and (iv) 1 H and 13 C Nuclear Magnetic Resonance (NMR, 1D and 2D) spectroscopy to rapidly analyze fatty acid composition including regioisomeric distribution on the glycerol backbone. These last results open up the possibility of using NMR spectroscopy as an alternative to the chromatographic techniques routinely employed for the investigation of similar matrices.

Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk., (Published by Oxford University Press 2022. This work is written by US Government employees and is in the public domain in the US.)

Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles' heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer.

Microbiota studies have reported changes in the microbial composition of the breast upon cancer development. However, results are inconsistent and limited to the later phases of cancer development (after diagnosis). We analyzed and compared the resident bacterial taxa of histologically normal breast tissue (healthy, H, n  = 49) with those of tissues donated prior to (prediagnostic, PD, n  = 15) and after (adjacent normal, AN, n  = 49, and tumor, T, n  = 46) breast cancer diagnosis ( n total = 159). DNA was isolated from tissue samples and submitted for Illumina MiSeq paired-end sequencing of the V3-V4 region of the 16S gene. To infer bacterial function in breast cancer, we predicted the functional bacteriome from the 16S sequencing data using PICRUSt2. Bacterial compositional analysis revealed an intermediary taxonomic signature in the PD tissue relative to that of the H tissue, represented by shifts in Bacillaceae , Burkholderiaceae , Corynebacteriaceae , Streptococcaceae , and Staphylococcaceae . This compositional signature was enhanced in the AN and T tissues. We also identified significant metabolic reprogramming of the microbiota of the PD, AN, and T tissue compared with the H tissue. Further, preliminary correlation analysis between host transcriptome profiling and microbial taxa and genes in H and PD tissues identified altered associations between the human host and mammary microbiota in PD tissue compared with H tissue. These findings suggest that compositional shifts in bacterial abundance and metabolic reprogramming of the breast tissue microbiota are early events in breast cancer development that are potentially linked with cancer susceptibility. IMPORTANCE The goal of this study was to determine the role of resident breast tissue bacteria in breast cancer development. We analyzed breast tissue bacteria in healthy breast tissue and breast tissue donated prior to (precancerous) and after (postcancerous) breast cancer diagnosis. Compared to healthy tissue, the precancerous and postcancerous breast tissues demonstrated differences in the amounts of breast tissue bacteria. In addition, breast tissue bacteria exhibit different functions in pre-cancerous and post-cancerous breast tissues relative to healthy tissue. These differences in function are further emphasized by altered associations of the breast tissue bacteria with gene expression in the human host prior to cancer development. Collectively, these analyses identified shifts in bacterial abundance and metabolic function (dysbiosis) prior to breast tumor diagnosis. This dysbiosis may serve as a therapeutic target in breast cancer prevention.

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer's disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer's, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida's digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida's application, achieved a 75% ROC-AUC (receiver operating characteristic - area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline., Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00284-3., Competing Interests: Conflict of interestES is Director of AI and Machine Learning at Bayer. A.S.C. is an official employee of Biogen International and works as Head of Stakeholder Engagement for Alzheimer disease at Biogen. She is also co-founder and CEO of the Women’s Brain Project., (© The Author(s) 2022.)

The construction of shelters on plants by arthropods might influence other organisms via changes in colonization, community richness, species composition, and functionality. Arthropods, including beetles, caterpillars, sawflies, spiders, and wasps often interact with host plants via the construction of shelters, building a variety of structures such as leaf ties, tents, rolls, and bags; leaf and stem galls, and hollowed out stems. Such constructs might have both an adaptive value in terms of protection (i.e., serve as shelters) but may also exert a strong influence on terrestrial community diversity in the engineered and neighboring hosts via colonization by secondary occupants. Although different traits of the host plant (e.g., physical, chemical, and architectural features) may affect the potential for ecosystem engineering by insects, such effects have been, to a certain degree, overlooked. Further analyses of how plant traits affect the occurrence of shelters may therefore enrich our understanding of the organizing principles of plant-based communities. This data set includes more than 1000 unique records of ecosystem engineering by arthropods, in the form of structures built on plants. All records have been published in the literature, and span both natural structures (91% of the records) and structures artificially created by researchers (9% of the records). The data were gathered between 1932 and 2021, across more than 50 countries and several ecosystems, ranging from polar to tropical zones. In addition to data on host plants and engineers, we aggregated data on the type of constructs and the identity of inquilines using these structures. This data set highlights the importance of these subtle structures for the organization of terrestrial arthropod communities, enabling hypotheses testing in ecological studies addressing ecosystem engineering and facilitation mediated by constructs. There are no copyright restrictions and please cite this paper when using the data in publications., (© 2022 The Ecological Society of America.)

Background: Family with sequence similarity 83 member A (FAM83A) presents oncogenic properties in several cancers including breast cancer. Recently, we reported FAM83A overexpression in normal breast tissues from women at high risk of breast cancer. We now hypothesize that FAM83A is a key factor in breast cancer initiation., Methods: Immunohistochemical staining was used to evaluate FAM83A protein levels in both a normal breast tissue microarray (TMA, N = 411) and a breast tumor TMA (N = 349). EGFR staining and its correlation with FAM83A expression were also assessed. Lentivirus-mediated manipulation of FAM83A expression in primary and hTERT-immortalized breast epithelial cells was employed. Biological and molecular alterations upon FAM83A overexpression/downregulation and FAM83A's interaction partners were investigated., Results: TMA analysis revealed a 1.5-fold increase in FAM83A expression level in breast cancer cases as compared with normal breast tissues (p < 0.0001). FAM83A protein expression was directly correlated with EGFR level in both normal and breast cancer tissues. In in vitro assays, exogenous expression of FAM83A in either primary or immortalized breast epithelial cells promoted cell viability and proliferation. Additionally, Ingenuity Pathway Analysis (IPA) revealed that FAM83A overexpression in primary cells affected the expression of genes involved in cellular morphology and metabolism. Mass spectrometry analysis identified DDX3X and LAMB3 as potential FAM83A interaction partners in primary cells, while we detected FAM83A interaction with cytoskeleton reorganization factors, including LIMA1, MYH10, PLEC, MYL6 in the immortalized cells., Conclusions: This study shows that FAM83A promotes metabolic activation in primary breast epithelial cells and cell proliferation in both primary and immortalized cells. These findings support its role in early breast oncogenesis., (© 2022. The Author(s).)

Background: Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N = 146, median age = 39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina's HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation., Results: Transcriptomic analysis identified 69 differentially expressed genes between women at high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. Majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR < 0.01) and primary epithelial cells (p < 0.05) from high-risk breasts. Moreover, 1698 DNA methylation changes were identified in high-risk breast tissues (FDR < 0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p < 0.05, r ≤ 0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified., Conclusions: Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues, and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches., (© 2022. The Author(s).)

The Komen Tissue Bank is the only biorepository in the world for normal breast tissues from women. Below we report the acquisition and processing of breast tissue from volunteer donors and describe an experimental and analysis pipeline to generate a single-cell atlas. This atlas is based on single-cell RNA-seq and is useful to derive breast epithelial cell subcluster-specific gene expression signatures, which can be applied to breast cancer gene expression data to identify putative cell-of-origin. For complete details on the use and execution of this protocol, please refer to Bhat-Nakshatri et al. (2021)., Competing Interests: Authors have no conflict of interest to disclose., (© 2021 The Authors.)

The cobalt substituted polyoxotungstate [Co 6 (H 2 O) 2 (α-B-PW 9 O 34 ) 2 (PW 6 O 26 )] 17- (Co6) displays fast electron transfer (ET) kinetics to photogenerated Ru III (bpy) 3 3+ , 4 to 5 orders of magnitude faster than the corresponding ET observed for cobalt oxide nanoparticles. Mechanistic evidence has been acquired indicating that: (i) the one-electron oxidation of Co6 involves Co(II) aquo or Co(II) hydroxo groups (abbreviated as Co6(II)-OH 2 and Co6(II)-OH, respectively, whose speciation in aqueous solution is associated to a pK a of 7.6), and generates a Co(III)-OH moiety (Co6(III)-OH), as proven by transient absorption spectroscopy; (ii) at pH>pK a , the Co6(II)-OH→Ru III (bpy) 3 3+ ET occurs via bimolecular kinetics, with a rate constant k close to the diffusion limit and dependent on the ionic strength of the medium, consistent with reaction between charged species; (iii) at pH a , the process involves Co6(II)-OH 2 →Co6(III)-OH transformation and proceeds via a multiple-site, concerted proton electron transfer (CPET) where water assists the transfer of the proton, as proven by the absence of effect of buffer base concentrations on the rate of the ET and by a H/D kinetic isotope in a range of 1.2-1.4. The reactivity of water is ascribed to its organization on the surface of the polyanionic scaffold through hydrogen bond networking involving the Co(II)-OH 2 group., (© 2021 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Two novel copper(II) complexes of formulas {[Cu(4-Hmpz) 4 ][Cu(4-Hmpz) 2 (µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' )(ClO 4 ) 2 ]} n ( 1 ) and {[Cu(3,4,5-Htmpz) 4 ] 2 [Cu(3,4,5-Htmpz) 2 (µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' )(H 2 O)(ClO 4 )] 2 [Cu 2 (3,4,5-Htmpz) 4 (µ-ox- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' )]}(ClO 4 ) 4 ·6H 2 O ( 2 ) have been obtained by using 4-methyl-1 H -pyrazole (4-Hmpz) and 3,4,5-trimethyl-1 H -pyrazole (3,4,5-Htmpz) as terminal ligands and oxalate (ox) as the polyatomic inverse coordination center. The crystal structure of 1 consists of perchlorate counteranions and cationic copper(II) chains with alternating bis(pyrazole)(µ 3 - κ 2 O 1 , O 2 : κO 2' : κO 1' -oxalato)copper(II) and tetrakis(pyrazole)copper(II) fragments. The crystal structure of 2 is made up of perchlorate counteranions and cationic centrosymmetric hexanuclear complexes where an inner tetrakis(pyrazole)(µ- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' -oxalato)dicopper(II) entity and two outer mononuclear tetrakis(pyrazole)copper(II) units are linked through two mononuclear aquabis(pyrazole)(µ 3 - κ 2 O 1 , O 2 : κO 2' : κO 1' -oxalato)copper(II) units. The magnetic properties of 1 and 2 were investigated in the temperature range 2.0-300 K. Very weak intrachain antiferromagnetic interactions between the copper(II) ions through the µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' center occur in 1 [ J = -0.42(1) cm -1 , the spin Hamiltonian being defined as H = - J∑ S 1,i · S 2,i +1 ], whereas very weak intramolecular ferromagnetic [ J = +0.28(2) cm -1 ] and strong antiferromagnetic [ J' = -348(2) cm -1 ] couplings coexist in 2 which are mediated by the µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' and µ-ox- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' centers, respectively. The variation in the nature and magnitude of the magnetic coupling for this pair of oxalato-centered inverse copper(II) complexes is discussed in the light of their different structural features, and a comparison with related oxalato-centered inverse copper(II)-pyrazole systems from the literature is carried out.

Gastrointestinal (GI) endoscopy is the gold standard in the detection and treatment of early and advanced GI cancers. However, conventional endoscopic techniques are technically demanding and require visual-spatial skills and significant hands-on experience. GI endoscopy simulators represent a valid solution to allow doctors to practice in a pre-clinical scenario. From the first endoscopy mannequin, developed in 1969, several simulation platforms have been developed, ranging from purely mechanical systems to more complex mechatronic devices and animal-based models. Considering the recent advancement of technologies (e.g., artificial intelligence, augmented reality, robotics), simulation platforms can now reach high levels of realism, representing a valid and smart alternative to standard trainee/mentor learning programs. This is particularly true nowadays, when the current demographic trend and the most recent pandemic demand, more than ever, the ability to cope with many patients. This review offers a broad view of the technology available for GI endoscopy training, including platforms currently in the market and the relevant advancements in this research and application field. Additionally, new training needs and new emerging technologies are discussed to understand where medical education is heading.