Concerning the dismal prognosis of chemoresistant patients with epithelial ovarian carcinoma (EOC), we aimed to follow up the findings of a previous whole-exome sequencing study using an orthogonal Sanger sequencing on the same patients and a separate set of 127 EOC patients (N = 177, all fresh frozen tumor samples). We focused on TP53 as a frequently mutated gene relevant for chemosensitivity, included KRAS as an additional therapeutically relevant target, complemented the study with transcript levels of both genes, and compared results with clinical parameters. All variants in TP53 and KRAS detected by exome sequencing were confirmed. KRAS mutated patients had significantly more frequent FIGO stages I or II (p = .002) and other than high-grade serous tumor subtypes (nonHGSCs) (p < .001), which was connected with lower KRAS transcript levels (p = .004). Patients with nonHGSC subtypes had less frequent TP53 mutations (p = .002). Carriers of TP53 variants disrupting the DNA binding loop had significantly longer platinum-free intervals than the rest (p = .037). Tumors bearing nonsense, frameshift, or splice site TP53 variants had a significantly lower TP53 transcript level, while those with missense variants had significantly higher levels than wild types (p < .001). The normalized intratumoral TP53 and KRAS transcript levels were correlated, and patients with co-mutated genes had poorer overall survival than others (p = .015). Protein levels of both genes significantly correlated with their respective transcripts (p = .028 and p = .001, respectively). Our study points to KRAS as a target for future therapy of nonHGSCs and reveals the prognostic value of TP53 variants in the DNA binding loop.

• Keywords
• Epithelial ovarian carcinoma, KRAS, TP53, platinum sensitivity, transcript expression, variant,
• MeSH
• Drug Resistance, Neoplasm genetics   MeSH
• Adult MeSH
• Carcinoma, Ovarian Epithelial * genetics   drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Tumor Suppressor Protein p53 * genetics   metabolism   MeSH
• Ovarian Neoplasms * genetics   drug therapy   pathology   mortality   MeSH
• Platinum * therapeutic use   pharmacology   MeSH
• Prognosis MeSH
• Proto-Oncogene Proteins p21(ras) * genetics   metabolism   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• KRAS protein, human MeSH Browser
• Tumor Suppressor Protein p53 * MeSH
• Platinum * MeSH
• Proto-Oncogene Proteins p21(ras) * MeSH
• TP53 protein, human MeSH Browser

Spinocerebellar ataxias (SCA) are rare neurodegenerative diseases affecting the cerebellum and its connections, leading to progressive motor disability and cognitive impairment as part of the cerebellar cognitive affective syndrome. Spatial navigation, cognitive function important for everyday movement, relies on spatial perspective taking-the ability to imagine the environment from different viewpoints. While animal and neuroimaging studies suggest a crucial role of the cerebellum in spatial navigation, research on patients with cerebellar disorders is lacking. This study aimed to investigate perspective taking in patients with SCA and Friedreich ataxia (FRDA) using two tests. The Perspective-Taking/Spatial Orientation Test (PTSOT) was administered to 30 SCA patients, 30 FRDA patients, and 34 healthy controls (HC). In addition, SCA and HC completed the Directional-approach Task and a comprehensive neuropsychological assessment. SCA patients performed significantly worse than HC on both perspective taking tests. FRDA patients performed better than SCA and differed from HC only in a subset of PTSOT measures. Perspective taking performance in SCA was associated with global cognition and multiple cognitive domains but not with cerebellar motor impairment. These findings are of potential clinical relevance, as spatial navigation deficits are known to negatively affect the mobility and independence of the affected individuals. Our findings expand the understanding of cognitive impairments in cerebellar diseases, adding spatial navigation to the spectrum of the cerebellar cognitive affective syndrome.

• Keywords
• Cerebellum, Cognition, Friedreich ataxia, Spatial navigation, Spatial perspective taking, Spinocerebellar ataxia,
• MeSH
• Adult MeSH
• Friedreich Ataxia * physiopathology   psychology   MeSH
• Cognition MeSH
• Cognitive Dysfunction physiopathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cerebellum physiopathology   MeSH
• Neuropsychological Tests MeSH
• Spatial Navigation * physiology   MeSH
• Spinocerebellar Ataxias * physiopathology   psychology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Dementia with Lewy bodies (DLB) is marked by multidomain cognitive impairments, with fluctuations in cognition and alertness being among the most common clinical features. Disruptions in functional connectivity are thought to underlie these fluctuations, but it remains unclear whether such patterns are already present at prodromal stages. We investigated the presence of static and dynamic functional connectivity alterations and their contribution to the clinical phenotype of prodromal DLB, and explored their association with declining locus coeruleus integrity, while considering premorbid intelligence (a proxy for cognitive reserve) as a moderating factor. Three groups of participants on the prodromal spectrum were analyzed: 29 healthy controls, 58 cognitively normal subjects with core clinical features of prodromal DLB (CN-CCF), and 39 subjects with mild cognitive impairment due to Lewy body dementia (MCI-LB). Dynamic and static functional connectivity features were derived from resting-state source-reconstructed high-density EEG, and integrity of the right caudal locus coeruleus was quantified using neuromelanin-sensitive MRI. Robust analyses, such as PERMANOVA, Spearman correlations and general linear models were conducted to study the relationships. We observed a nonlinear trajectory of two functional connectivity metrics-temporal variability (fluidity) and connectedness (average node strength)-across symptom severity, especially in the delta frequency band. Both measures (F(2,123) = 1.86, p =.037; F(2,123) = 1.51, p =.023, respectively) were elevated in the intermediate severity groups-that is, in CN-CCF and possible MCI-LB (i.e., one core clinical feature)-and this was associated with better executive functioning after controlling for age and premorbid intelligence (rho = 0.26, p =.004; rho = 0.28, p =.002, respectively). Additionally, elevated fluidity (rho = - 0.34, p =.034) and average node strength (rho = - 0.37, p =.022) were also correlated with fewer fluctuations in alertness in subjects with MCI-LB. Fluidity was further associated with right caudal locus coeruleus integrity, particularly among individuals with lower premorbid intelligence (F(5,97) = 3.56, p =.005). Our findings indicate that increased dynamic reconfiguration and enhanced connectivity may serve compensatory functions in early DLB, helping temporarily preserve cognition. As DLB progresses, these mechanisms wane, with noradrenergic contributions more evident in individuals with lower cognitive reserve. Clinical trial number Not applicable.

• Keywords
• Cognitive reserve, Dementia with lewy bodies, Dynamic functional connectivity, Fluidity, Locus coeruleus, Node strength, Prodromal dementia with lewy bodies,
• MeSH
• Lewy Body Disease * physiopathology   diagnostic imaging   psychology   MeSH
• Electroencephalography MeSH
• Cognitive Dysfunction * physiopathology   diagnostic imaging   MeSH
• Middle Aged MeSH
• Humans MeSH
• Locus Coeruleus * physiopathology   diagnostic imaging   MeSH
• Magnetic Resonance Imaging MeSH
• Prodromal Symptoms MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are associated with alterations in the functional connectome, specifically in canonical resting state networks including the default mode (DMN), central executive (CEN), and salience networks (SN). Comorbid PTSD+mTBI is linked to worse functional outcomes, but little is known about effects on the functional connectome. METHODS: We investigated brain phenotypes from resting-state fMRI associated with PTSD (n=326), mTBI (n=448), and comorbid PTSD+mTBI (n=289) in military veterans and civilians (n=1526) from ENIGMA-TBI and -PTSD. We examined static functional connectivity (SFC) and dynamic functional connectivity (DFC), quantified both as variability in FC (VFC) over time and as dwell time in recurring FC states identified through clustering. ANCOVA was followed by post-hoc linear regression to test main and interaction effects of diagnosis on FC metrics. RESULTS: We found a significant (pFDR<0.05) interaction of diagnosis by age on VFC. Older comorbid subjects had greater VFC within SN, between SN-to-CEN and SN-to-DMN than older controls. Comorbid relative to control subjects had significantly greater dwell time in an externally focused state. Comorbid and mTBI groups, relative to control subjects, had greater dwell time in a moderate connectivity transition state. CONCLUSIONS: DFC related to the SN revealed distinct brain network patterns across diagnostic groups, with comorbid PTSD+mTBI showing age- and anxiety-related effects. Older comorbid subjects had heightened hypervigilance and reduced network segregation. PTSD and anxiety may synergistically worsen network instability, while mTBI reflects more rigid, disconnected states, highlighting DFC as a sensitive marker of neuropsychiatric comorbidity.

• Keywords
• Canonical Networks, Comorbid PTSD and mTBI, Dynamic Functional Connectivity, Military Veterans, PTSD, Resting-state fMRI, Static Functional Connectivity, mTBI,
• Publication type
• Journal Article MeSH

UNLABELLED: Flagellar motility is crucial for the swim-and-stick lifestyle and plays an important role in bacterial-algal interactions of Rhodobacterales. This alphaproteobacterial order contains three distinct types of flagellar gene clusters (FGCs) for the formation of a functional flagellum. Our phylogenetically broad taxon sampling of more than 300 genomes revealed that the most common FGC, the fla1-type, was probably already present in the common ancestor of Rhodobacterales and was strictly vertically inherited, while the other two FGC types, fla2 and fla3, were spread via horizontal operon transfers. Swimming of the marine model organism Phaeobacter inhibens DSM 17395 (Roseobacteraceae) is mediated by the archetypal fla1-type flagellum. Screening of 13,000 transposon mutants of P. inhibens on soft agar plates revealed that 40 genes, including four genes encoding conserved but not yet characterized proteins (CP1-4) within the FGC, are essential for motility. Exoproteome analyses indicated that CP1-4 are required at different stages of flagellar assembly. Only eight genes outside the FGC were identified as essential for swimming motility, including all three genes of the CtrA phosphorelay. Using comparative transcriptomics of ΔcckA, ΔchpT, and ΔctrA mutants of the distantly related model organisms P. inhibens and Dinoroseobacter shibae DSM 16493, we identified genes for the flagellum and cyclic di-GMP turnover as core targets of the CtrA phosphorelay and a conserved connection with quorum sensing across members of the Rhodobacterales. IMPORTANCE: The bacterial flagellum is a sophisticated nanomachine for swimming motility and rapid chemotactic response to gradients of attractants or repellents in the environment. It is structurally highly conserved and has been intensively studied in gammaproteobacterial model bacteria such as Escherichia coli and Salmonella enterica. However, the flagellar gene clusters of different alphaproteobacterial orders have distinct structures and compositions, as demonstrated by the three flagellar systems of Rhodobacterales investigated in the current study. The archetypal fla1-type flagellum originated in its common ancestor and evolved synchronously with the host. The universal presence of four as yet uncharacterized essential genes in fla1-type FGCs (CP1-4) reflects the order-specific adaptation of the flagellar system during bacterial evolution. Comparative transcriptome analyses of ΔcckA, ΔchpT, and ΔctrA mutants showed that the core function of the CtrA phosphorelay in Rhodobacterales is the transcriptional control of flagellar genes.

• Keywords
• CtrA phosphorelay, Rhodobacterales, evolution, flagellar gene regulation, flagellar motility,
• Publication type
• Journal Article MeSH

Covalent organic frameworks (COFs) have shown promise as photocatalysts for chemical transformations. However, their dense micropores and poor pore connectivity hinder mass transport and charge separation/transfer, limiting their efficiency. Herein, we develop a one-step self-sacrificing template strategy to synthesize three-dimensional ordered macroporous COFs (3DOM-COFs). This approach uniquely integrates in situ Tp-Tta COF crystallization with synchronized degradation of polystyrene templates under solvothermal conditions. This method introduces unreported kinetic match between template decomposition and framework growth. Such a confined growth mechanism leads to structurally robust and highly ordered macroporosity without post-processing. 3DOM architecture enables uniform dispersion of fine ZnCdS nanoparticles for the generation a 3DOM-COF based S-scheme heterojunction, which exhibits remarkable performance in the oxidation of benzylamine (BA) for simultaneous N-benzylbenzaldimine production with 99% selectivity at a rate of 15.1 mmol g-1 h-1 and H2 generation with a rate of 17.8 mmol g-1 h-1. The 3DOM architecture confers 50-fold faster mass transport than bulk COFs, while the heterojunction facilitates directional charge separation and interface charge transfer. Density functional theory calculations confirm that the heterojunction optimizes reaction thermodynamics by lowering the potential energy barriers of BA activation. The work pioneers a template-concurrent synthesis paradigm, resolving COFs' critical pore engineering challenges.

• Keywords
• COFs, Charge separation, H2 evolution, Imine synthesis, Mass transfer,
• Publication type
• Journal Article MeSH

Many freshwater ecosystems rely on the decomposition of organic matter as a key process for nutrient cycling and energy flow. Small lentic freshwater ecosystems, such as ponds, often derive a large amount of energy from allochthonous detritus due to their close connection with the terrestrial environment. However, the process of leaf litter decomposition in ponds remains poorly understood. We conducted a microcosm experiment in a pond environment to investigate intra- and inter-specific variation in organic matter processing by three shredders (Tipula sp., Sericostoma sp. and Gammarus fossarum) and to assess the effects of shredder community characteristics on the mass loss of black alder (Alnus glutinosa) leaf litter. We developed a novel approach to quantify functional traits directly related to litter processing. Detailed gut content analysis revealed significant inter- and intra-specific variation in the organic matter particles ingested by individual shredder taxa. Our results showed that neither taxonomic nor functional diversity reliably predicts leaf litter decomposition rates in ponds. Instead, the keystone shredder Sericostoma showed a pronounced effect on decomposition rates driven by their unique feeding behaviour and density-dependent shifts in particle size preferences. These findings highlight the importance of a detailed understanding of species-specific functional traits and behaviour in shaping ecosystem processes, as the role of keystone species can outweigh the contributions of overall diversity measures in driving ecosystem processes.

• Publication type
• Journal Article MeSH

Although rapid eye movement (REM) sleep is often thought of as a singular state, it consists of two substates, phasic and tonic REM, defined by the presence (respectively absence) of bursts of rapid eye movements. These two substates have distinct EEG signatures and functional properties. However, whether they exhibit regional specificities remains unknown. Using intracranial EEG recordings from 31 patients, we analyzed expert-labeled segments from tonic and phasic REM and contrasted them with wakefulness segments. We assessed the spectral and connectivity content of these segments using Welch's method to estimate power spectral density and the phase locking value to assess functional connectivity. Overall, we found a widespread power gradient between low and high frequencies (p < 0.05, Cohen's d = 0.17 ± 0.20), with tonic REM being dominated by lower frequencies (p < 0.01, d = 0.18 ± 0.08), and phasic REM by higher frequencies (p < 0.01, d = 0.18 ± 0.19). However, some regions, such as the occipito-temporal areas as well as medial frontal regions, exhibit opposite trends. Connectivity was overall higher in all bands except in the low and high ripple frequency bands in most networks during tonic REM (p < 0.01, d = 0.08 ± 0.09) compared to phasic REM. Yet, functional connections involving the visual network were always stronger during phasic REM when compared to tonic REM. These findings highlight the spatiotemporal heterogeneity of REM sleep which is consistent with the concept of focal sleep in humans.

• Keywords
• REM, connectivity, microstate, phasic REM, spectrum, tonic REM,
• Publication type
• Journal Article MeSH

Despite our ongoing fascination with love's pleasures and pain, psychologists and neurobiologists have only recently begun to explore the neurobiological connections shared by feelings of romantic love and the experience of drug addiction. Functional imaging studies have revealed that feelings resulting from romantic love and those resulting from active drug use both activate the central reward system, which is a series of forebrain and midbrain structures that transmit signals primarily via dopamine release. Similarly, the relaxation response, which is a series of behaviors designed to alleviate stress-related physiologic sequelae, may also be helpful as an adjunct therapy for drug withdrawal. The benefits of the relaxation response and related mind-body practices may stem directly from its impact on mitochondria, organelles that are central to balanced energy production. Nitric oxide (NO) is a central neurotransmitter and also a key regulatory molecule that modulates mitochondrial respiration and oxygen utilization. Thus, we propose that observed behaviorally mediated changes that emerge from engaging the relaxation response may be the result of NO-mediated improvements in mitochondrial bioenergetics. Future research might focus on elucidating the important links between cellular bioenergetics, the relaxation response, and the central reward system and might explore NO modulation as a potentially effective target for drug development.

• Keywords
• Bioenergetics, Brain, Broken heart, Dopamine, Drug addiction, Nitric oxide, Relaxation response, Reward pathway, Romantic love, Stress,
• Publication type
• Journal Article MeSH
• Review MeSH

Climate change is predicted to drive geographical range shifts that will result in changes in species diversity and functional composition and have potential repercussions for ecosystem functioning. However, the effect of these changes on species composition and functional diversity (FD) remains unclear, especially for mammals, specifically bats. We used species distribution models and a comprehensive ecological and morphometrical trait database to estimate how projected future climate and land-use changes could influence the distribution, composition, and FD of the European bat community. Future bat assemblages were predicted to undergo substantial shifts in geographic range and trait structure. Range suitability decreased substantially in southern Europe and increased in northern latitudes. Our findings highlight the potential for climate change to drive shifts in bat FD, which has implications for ecosystem function and resilience at a continental scale. It is important to incorporate FD in conservation strategies. These efforts should target species with key functional traits predicted to be lost and areas expected to experience losses in FD. Conservation strategies should include habitat and roost protection, enhancing landscape connectivity, and international monitoring to preserve bat populations and their ecosystem services.

Cambios en la composición de la comunidad y la diversidad funcional de murciélagos europeos bajo el cambio climático Resumen Se prevé que el cambio climático provocará desplazamientos geográficos que alterarán la diversidad de las especies y su composición funcional, con posibles repercusiones en el funcionamiento de los ecosistemas. Sin embargo, el efecto de estos cambios sobre la composición de las especies y la diversidad funcional aun no es claro, especialmente en el caso de los mamíferos, en concreto los murciélagos. Utilizamos modelos de distribución de especies y una base de datos integral de rasgos ecológicos y morfométricos para estimar cómo los futuros cambios previstos en el clima y el uso del suelo podrían influir en la distribución, composición y diversidad funcional de la comunidad europea de murciélagos. Se predijo que los futuros conjuntos de murciélagos sufrirían cambios sustanciales en su distribución geográfica y en la estructura de sus atributos. La idoneidad del área de distribución disminuyó sustancialmente en el sur de Europa y aumentó en las latitudes septentrionales. Nuestros resultados ponen de relieve la posibilidad de que el cambio climático provoque cambios en la diversidad funcional de los murciélagos, lo que tiene implicaciones para la función y la resiliencia de los ecosistemas a escala continental. Es importante incorporar la diversidad funcional a las estrategias de conservación. Estos esfuerzos deberían centrarse en las especies con rasgos funcionales clave que se prevé que se pierdan y en las zonas en las que se espera que se produzcan pérdidas de diversidad funcional. Las estrategias de conservación deberían incluir la protección del hábitat y de los dormideros, la mejora de la conectividad del paisaje y el seguimiento internacional para preservar las poblaciones de murciélagos y sus servicios ecosistémicos.

• Keywords
• Cambio global, bats, community composition, composición de la comunidad, composición funcional, functional composition, global change, modelización de la distribución de especies, murciélagos, species distribution modeling,
• MeSH
• Biodiversity * MeSH
• Chiroptera * physiology   MeSH
• Ecosystem MeSH
• Climate Change * MeSH
• Animal Distribution * MeSH
• Conservation of Natural Resources * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH