Mechanisms of Ligand Hyperfine Coupling in Transition-Metal Complexes: σ and π Transmission Pathways.

Theoretical interpretation of hyperfine interactions was pioneered in the 1950s-1960s by the seminal works of McConnell, Karplus, and others for organic radicals and by Watson and Freeman for transition-metal (TM) complexes. In this work, we investigate a series of octahedral Ru(III) complexes with aromatic ligands to understand the mechanism of transmission of the spin density from the d-orbital of the metal to the s-orbitals of the ligand atoms. Spin densities and spin populations underlying ligand hyperfine couplings are analyzed in terms of π-conjugative or σ-hyperconjugative delocalization vs spin polarization based on symmetry considerations and restricted open-shell vs unrestricted wave function analysis. The transmission of spin density is shown to be most efficient in the case of symmetry-allowed π-conjugative delocalization, but when the π-conjugation is partially or fully symmetry-forbidden, it can be surpassed by σ-hyperconjugative delocalization. Despite a lower spin population of the ligand in σ-hyperconjugative transmission, the hyperfine couplings can be larger because of the direct involvement of the ligand s-orbitals in this delocalization pathway. We demonstrate a quantitative correlation between the hyperfine couplings of aromatic ligand atoms and the characteristics of the metal-ligand bond modulated by the trans substituent, a hyperfine trans effect.

Amyloid precursor protein induces reactive astrogliosis.

AIM: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. METHODS: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. RESULTS: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. CONCLUSIONS: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

Paramagnetic Effects in NMR Spectroscopy of Transition-Metal Complexes: Principles and Chemical Concepts.

ConspectusMagnetic resonance techniques represent a fundamental class of spectroscopic methods used in physics, chemistry, biology, and medicine. Electron paramagnetic resonance (EPR) is an extremely powerful technique for characterizing systems with an open-shell electronic nature, whereas nuclear magnetic resonance (NMR) has traditionally been used to investigate diamagnetic (closed-shell) systems. However, these two techniques are tightly connected by the electron-nucleus hyperfine interaction operating in paramagnetic (open-shell) systems. Hyperfine interaction of the nuclear spin with unpaired electron(s) induces large temperature-dependent shifts of nuclear resonance frequencies that are designated as hyperfine NMR shifts (δHF).Three fundamental physical mechanisms shape the total hyperfine interaction: Fermi-contact, paramagnetic spin-orbit, and spin-dipolar. The corresponding hyperfine NMR contributions can be interpreted in terms of through-bond and through-space effects. In this Account, we provide an elemental theory behind the hyperfine interaction and NMR shifts and describe recent progress in understanding the structural and electronic principles underlying individual hyperfine terms.The Fermi-contact (FC) mechanism reflects the propagation of electron-spin density throughout the molecule and is proportional to the spin density at the nuclear position. As the imbalance in spin density can be thought of as originating at the paramagnetic metal center and being propagated to the observed nucleus via chemical bonds, FC is an excellent indicator of the bond character. The paramagnetic spin-orbit (PSO) mechanism originates in the orbital current density generated by the spin-orbit coupling interaction at the metal center. The PSO mechanism of the ligand NMR shift then reflects the transmission of the spin polarization through bonds, similar to the FC mechanism, but it also makes a substantial through-space contribution in long-range situations. In contrast, the spin-dipolar (SD) mechanism is relatively unimportant at short-range with significant spin polarization on the spectator atom. The PSO and SD mechanisms combine at long-range to form the so-called pseudocontact shift, traditionally used as a structural and dynamics probe in paramagnetic NMR (pNMR). Note that the PSO and SD terms both contribute to the isotropic NMR shift only at the relativistic spin-orbit level of theory.We demonstrate the advantages of calculating and analyzing the NMR shifts at relativistic two- and four-component levels of theory and present analytical tools and approaches based on perturbation theory. We show that paramagnetic NMR effects can be interpreted by spin-delocalization and spin-polarization mechanisms related to chemical bond concepts of electron conjugation in π-space and hyperconjugation in σ-space in the framework of the molecular orbital (MO) theory. Further, we discuss the effects of environment (supramolecular interactions, solvent, and crystal packing) and demonstrate applications of hyperfine shifts in determining the structure of paramagnetic Ru(III) compounds and their supramolecular host-guest complexes with macrocycles.In conclusion, we provide a short overview of possible pNMR applications in the analysis of spectra and electronic structure and perspectives in this field for a general chemical audience.

Swedish Alzheimer's disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways.

Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition.

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

Inhibition of Chk1 stimulates cytotoxic action of platinum-based drugs and TRAIL combination in human prostate cancer cells.

Checkpoint kinase 1 (Chk1) plays an important role in regulation of the cell cycle, DNA damage response and cell death, and represents an attractive target in anticancer therapy. Small-molecule inhibitors of Chk1 have been intensively investigated either as single agents or in combination with various chemotherapeutic drugs and they can enhance the chemosensitivity of numerous tumor types. Here we newly demonstrate that pharmacological inhibition of Chk1 using potent and selective inhibitor SCH900776, currently profiled in phase II clinical trials, significantly enhances cytotoxic effects of the combination of platinum-based drugs (cisplatin or LA-12) and TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in human prostate cancer cells. The specific role of Chk1 in the drug combination-induced cytotoxicity was confirmed by siRNA-mediated silencing of this kinase. Using RNAi-based methods we also showed the importance of Bak-dependent mitochondrial apoptotic pathway in the combined anticancer action of SCH900776, cisplatin and TRAIL. The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL.

Emotion regulation shows an age- and sex-specific moderating effect on the relationship between chronic stress and cognitive performance.

Despite the extensive knowledge about the effects of chronic stress on cognition, the underlying mechanisms remain unclear. We conducted a cross-sectional moderation analysis on a population-based sample of 596 adults to examine the age- and sex-specific role of emotion regulation (ER) in the relationship between chronic stress and cognitive performance using validated self-report questionnaires. While women showed no direct or moderated relationship between stress and cognition, men displayed a distinct age-related pattern where stress was negatively associated with poorer cognitive performance at older ages, and the onset of this relationship was detected earlier in men with ER problems. These results showed that suppression of emotions and lack of executive control of ER amplify the negative consequences of chronic stress and suggest that there are sex-specific differences in the decline of ability to cope with long-term exposure to stressors.

Effect of respiratory muscle endurance training on performance and respiratory function in professional cyclists during the off-season.

BACKGROUND: The study aimed to analyze the effect of respiratory muscle endurance training (RMT) on performance and respiratory function in professional road cyclists during the off-season period. METHODS: Twenty professional road cyclists from the Czech Republic were divided into the control (CON) (N.=10) and the RMT (N.=10) groups. Cyclists from the RMT group accomplished 30 sessions over 10 weeks. Performance in the incremental cycling test and respiratory capacity via test were assessed before and after 10 weeks in both groups. The comparison between and within the groups was performed, together with effect size and delta % (P<0.05). RESULTS: Significant effects on respiratory function during the exercise, on lung volume utilization at 90% of VO2max (TV-90%) and maximal voluntary ventilation (MVV) were found in RMT compared to the CON group, with a moderate effect size (0.71 and 0.61), and improvements of 13% and 14%, respectively. Parameters of performance in the cycling protocol and respiratory function at rest presented better values in the RMT group, however with no significance and in minor magnitude. CONCLUSIONS: Using RMT during off-season benefits professional road cyclists by improving the major efficiency of respiratory function during progressive efforts. Therefore, the protocol of RMT could be used as an ergogenic aid during this period in order to maintain respiratory adaptations, optimizing the pre-season training. Adjustments can be made to improve the parameters outcomes.

The Impact of ortho-substituents on Bonding in Silver(I) and Halogen(I) Complexes of 2-Mono- and 2,6-Disubstituted Pyridines: An In-Depth Experimental and Theoretical Study.

The coordination nature of 2-mono- and 2,6-disubstituted pyridines with electron-withdrawing halogen and electron-donating methyl groups for [N-X-N]+ (X=I, Br) complexations have been studied using 15 N NMR, X-ray crystallography, and Density Functional Theory (DFT) calculations. The 15 N NMR chemical shifts reveal iodine(I) and bromine(I) prefer to form complexes with 2-substituted pyridines and only 2,6-dimethylpyridine. The crystalline halogen(I) complexes of 2-substituted pyridines were characterized by using X-ray diffraction analysis, but 2,6-dihalopyridines were unable to form stable crystalline halogen(I) complexes due to the lower nucleophilicity of the pyridinic nitrogen. In contrast, the halogen(I) complexes of 2,6-dimethylpyridine, which has a more basic nitrogen, are characterized by X-crystallography, which complements the 15 N NMR studies. DFT calculations reveal that the bond energies for iodine(I) complexes vary between -291 and -351 kJ mol-1 and for bromine between -370 and -427 kJ mol-1 . The bond energies of halogen(I) complexes of 2-halopyridines with more nucleophilic nitrogen are 66-76 kJ mol-1 larger than those of analogous 2,6-dihalopyridines with less nucleophilic nitrogen. The experimental and DFT results show that the electronic influence of ortho-halogen substituents on pyridinic nitrogen leads to a completely different preference for the coordination bonding of halogen(I) ions, providing new insights into bonding in halogen(I) chemistry.

The long-term effects of consecutive COVID-19 waves on mental health.

BACKGROUND: Although several studies have documented the impact of the COVID-19 pandemic on mental health, the long-term effects remain unclear. AIMS: To examine longitudinal changes in mental health before and during the consecutive COVID-19 waves in a well-established probability sample. METHOD: An online survey was completed by the participants of the COVID-19 add-on study at four time points: pre-COVID-19 period (2014-2015, n = 1823), first COVID-19 wave (April to May 2020, n = 788), second COVID-19 wave (August to October 2020, n = 532) and third COVID-19 wave (March to April 2021, n = 383). Data were collected via a set of validated instruments, and analysed with latent growth models. RESULTS: During the pandemic, we observed a significant increase in stress levels (standardised ß = 0.473, P < 0.001) and depressive symptoms (standardised ß = 1.284, P < 0.001). The rate of increase in depressive symptoms (std. covariance = 0.784, P = 0.014), but not in stress levels (std. covariance = 0.057, P = 0.743), was associated with the pre-pandemic mental health status of the participants. Further analysis showed that secondary stressors played a predominant role in the increase in mental health difficulties. The main secondary stressors were loneliness, negative emotionality associated with the perception of COVID-19 disease, lack of resilience, female gender and younger age. CONCLUSIONS: The surge in stress levels and depressive symptoms persisted across all three consecutive COVID-19 waves. This persistence is attributable to the effects of secondary stressors, and particularly to the status of mental health before the COVID-19 pandemic. Our findings reveal mechanisms underlying the surge in mental health difficulties during the COVID-19 waves, with direct implications for strategies promoting mental health during pandemics.

Targeting DNA-PK.

This chapter explores the multifaceted roles of DNA-PK with particular focus on its functions in non-homologous end-joining (NHEJ) DNA repair. DNA-PK is the primary orchestrator of NHEJ but also regulates other biologic processes. The growing understanding of varied DNA-PK biologic roles highlights new avenues for cancer treatment. However, these multiple roles also imply challenges, particularly in combination therapies, with perhaps a higher risk of clinical toxicities than was previously envisioned. These considerations underscore the need for compelling and innovative strategies to accomplish effective clinical translation.

Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.

PURPOSE: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. EXPERIMENTAL DESIGN: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models. RESULTS: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. CONCLUSIONS: Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.

Estimation of photosynthetic dynamics in forests from daily measured fluorescence and PRI data with adjustment for canopy shadow fraction.

We conducted year-long measurements of the photochemical reflectance index (PRI) and solar-induced fluorescence in the O2A oxygen band (SIFA) at a Norway spruce forest and a European beech forest to study relationships of these remote sensing variables to photosynthesis by trees in grown forest stands. Measured PRI and SIFA values were linked to changes in forest gross primary productivity (GPP) and light-use efficiency (LUE). Changes in the shadow fraction (αS) within tree crowns influenced PRI and fluorescence signals. In the spruce forest, the quantum yield of SIFA (FYSIFA) decreased around midday together with photosynthesis and GPP. Such decreases in FYSIFA were accompanied by an increase in the αS. In the beech forest, we detected an increase in FYSIFA together with a decrease in αS in the afternoon hours. The overall sensitivity of PRI to LUE was variable according to the season, presumably influenced by complex changes in photosynthetic pigments. PRI and FYSIFA showed weak correlations with canopy LUE; however, when considered together, the correlation was strengthened (R2 was 0.63 and 0.34 in spruce and beech forest, respectively). Our model predicting LUE dynamics includes a diurnal minimum of PRI and canopy αS to make allowances for seasonal changes in photosynthetic pigments and for diurnal variability of the shadow fraction in forests. The incorporation of these correcting factors allowed us to estimate LUE at R2 = 0.68 (spruce) and 0.53 (beech). The modeling equations appeared sensitive to the absorbed photosynthetically active radiation (APAR), but less sensitive to the GPP of these forests. Substituting pigments correction with introducing differential PRI (ΔPRI) into the model did not significantly improve the LUE estimation across the season. Our results show that the joint use of PRI and fluorescence improves LUE and GPP estimation accuracy in both daily and seasonal observations.

Germline multigene panel testing of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Quadratic Spin-Orbit Mechanism of the Electronic g-Tensor.

Understanding how the electronic g-tensor is linked to the electronic structure is desirable for the correct interpretation of electron paramagnetic resonance spectra. For heavy-element compounds with large spin-orbit (SO) effects, this is still not completely clear. We report our investigation of quadratic SO contributions to the g-shift in heavy transition metal complexes. We implemented third-order perturbation theory in order to analyze the contributions arising from frontier molecular spin orbitals (MSOs). We show that the dominant quadratic SO term─spin-Zeeman (SO2/SZ)─generally makes a negative contribution to the g-shift, irrespective of the particular electronic configuration or molecular symmetry. We further analyze how the SO2/SZ contribution adds to or subtracts from the linear orbital-Zeeman (SO/OZ) contribution to the individual principal components of the g-tensor. Our study suggests that the SO2/SZ mechanism decreases the anisotropy of the g-tensor in early transition metal complexes and increases it in late transition metal complexes. Finally, we apply MSO analysis to the investigation of g-tensor trends in a set of closely related Ir and Rh pincer complexes and evaluate the influence of different chemical factors (the nuclear charge of the central atom and the terminal ligand) on the magnitudes of the g-shifts. We expect our conclusions to aid the understanding of spectra in magnetic resonance investigations of heavy transition metal compounds.

Missorting of plasma miRNAs in aging and Alzheimer's disease.

The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.

Nature of NMR Shifts in Paramagnetic Octahedral Ru(III) Complexes with Axial Pyridine-Based Ligands.

In recent decades, transition-metal coordination compounds have been extensively studied for their antitumor and antimetastatic activities. In this work, we synthesized a set of symmetric and asymmetric Ru(III) and Rh(III) coordination compounds of the general structure (Na+/K+/PPh4+/LH+) [trans-MIIIL(eq)nL(ax)2]- (M = RuIII or RhIII; L(eq) = Cl, n = 4; L(eq) = ox, n = 2; L(ax) = 4-R-pyridine, R = CH3, H, C6H5, COOH, CF3, CN; L(ax) = DMSO-S) and systematically investigated their structure, stability, and NMR properties. 1H and 13C NMR spectra measured at various temperatures were used to break down the total NMR shifts into the orbital (temperature-independent) and hyperfine (temperature-dependent) contributions. The hyperfine NMR shifts for paramagnetic Ru(III) compounds were analyzed in detail using relativistic density functional theory (DFT). The effects of (i) the 4-R substituent of pyridine, (ii) the axial trans ligand L(ax), and (iii) the equatorial ligands L(eq) on the distribution of spin density reflected in the "through-bond" (contact) and the "through-space" (pseudocontact) contributions to the hyperfine NMR shifts of the individual atoms of the pyridine ligands are rationalized. Further, we demonstrate the large effects of the solvent on the hyperfine NMR shifts and discuss our observations in the general context of the paramagnetic NMR spectroscopy of transition-metal complexes.

Uptake and Effectiveness of Risk-Reducing Surgeries in Unaffected Female BRCA1 and BRCA2 Carriers: A Single Institution Experience in the Czech Republic.

Unnafected female carriers of BRCA1 and BRCA2 pathogenic/likely pathogenic variants (P/LPVs) are at higher risk of breast cancer (BC) and ovarian cancer (OC). In the retrospective single-institution study in the Czech Republic, we analyzed the rate, longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) on the incidence of BC and OC in BRCA1/2 carriers diagnosed between years (y) 2000 to 2020. The study included 496 healthy female BRCA1/2 carriers. The median follow-up was 6.0 years. RRM was performed in 156 (31.5%, mean age 39.3 y, range 22-61 y) and RRSO in 234 (47.2%, mean age 43.2 y, range 28-64 y) BRCA1/2 carriers. A statistically significant increase of RRM (from 12% to 29%) and RRSO (from 31% to 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, 95% CI 2.78- 146.02; p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (HR not defined due to 0% occurrence in the RRSO group, p < 0.001). Study results demonstrate a significant increase in the rate of prophylactic surgeries in BRCA1/2 healthy carriers after 2013 and the effectiveness of RRM and RRSO on the incidence of BC and OC in these populations.

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

Amyloid precursor protein induces reactive astrogliosis.

We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of reactive astrogliosis.