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The Retriever complex recycles a wide range of transmembrane proteins from endosomes to the plasma membrane. The cargo adapter protein SNX17 has been implicated in recruiting the Retriever complex to endosomal membranes, yet the details of this interaction have remained elusive. Through biophysical and structural model-guided mutagenesis studies with recombinant proteins and liposomes, we have gained a deeper understanding of this process. Here, we demonstrate a direct interaction between SNX17 and Retriever, specifically between the C-terminal region of SNX17 and the interface of the Retriever subunits VPS35L and VPS26C. This interaction is enhanced upon the binding of SNX17 to its cargo in solution, due to the disruption of an intramolecular autoinhibitory interaction between the C-terminal region of SNX17 and the cargo binding pocket. In addition, SNX17 binding to membranes containing phosphatidylinositol-3-phosphate also promotes Retriever recruitment in a cargo-independent manner. Therefore, this work provides evidence of the dual activation mechanisms by which SNX17 modulates Retriever recruitment to the proximity of cargo and membranes, offering significant insights into the regulatory mechanisms of protein recycling at endosomes., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

The Grover algorithm is a crucial solution for addressing unstructured search problems and has emerged as an essential quantum subroutine in various complex algorithms. By using a different approach with previous studies, this research extensively investigates Grover's search methodology within non-uniformly distributed databases, a scenario frequently encountered in practical applications. Our analysis reveals that the behavior of the Grover evolution differs significantly when applied to non-uniform databases compared to uniform or 'unstructured databases'. Based on the property of differential equation, it is observed that the search process facilitated by this evolution does not consistently result in a speed-up, and we have identified specific criteria for such situations. Furthermore, we have extended this investigation to databases characterized by coherent states, confirming the speed-up achieved through Grover evolution via rigorous numerical verification. In conclusion, our study provides an enhancement to the original Grover algorithm, offering insights to optimize implementation strategies and broaden its range of applications., (© 2024. The Author(s).)

The anti-polyelectrolyte effect, a characteristic unique to polymer chains containing zwitterions, was investigated for its impact on colloidal stabilization during emulsion polymerization and on the resulting polymer characteristics. The zwitterionic monomer (ZM) 3-[(3-Acrylamidopropyl)dimethylammonio]propane-1-sulfonate (A3361) was selected for the synthesis of 30 wt% emulsifier-free methyl methacrylate/n-butyl acrylate (MMA/n-BA) polymer latex. Three pH conditions were examined: neutral, where the zwitterionic chains are in a collapsed state, and acidic and basic, where these chains adopt an extended conformation, leading to the anti-polyelectrolyte effect. The study of the anti-polyelectrolyte phenomenon on colloidal stability was challenging due to the increased ionic strength in the dispersions. Nevertheless, films cast from the acidic latex demonstrated enhanced mechanical properties, water resistance, and humidity barrier compared to films produced at neutral pH. This improvement is attributed to the anti-polyelectrolyte phenomenon, where the extended polymer chains rich in zwitterions offer enhanced ionic complexation, resulting in a denser and thicker ionic complexed network within the MMA/n-BA matrix. Under basic pH conditions, these improvements were modest, indicating that the anti-polyelectrolyte mechanism is influenced by pH. Furthermore, the high incorporation of A3361 facilitated, for the first time, the synthesis of 50% solids content emulsifier-free latexes, highlighting practical importance of this technology., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The unusual properties of superconductivity in magic-angle twisted bilayer graphene (MATBG) have sparked considerable research interest 1-13 . However, despite the dedication of intensive experimental efforts and the proposal of several possible pairing mechanisms 14-24 , the origin of its superconductivity remains elusive. Here, by utilizing angle-resolved photoemission spectroscopy with micrometre spatial resolution, we reveal flat-band replicas in superconducting MATBG, where MATBG is unaligned with its hexagonal boron nitride substrate 11 . These replicas show uniform energy spacing, approximately 150 ± 15 meV apart, indicative of strong electron-boson coupling. Strikingly, these replicas are absent in non-superconducting twisted bilayer graphene (TBG) systems, either when MATBG is aligned to hexagonal boron nitride or when TBG deviates from the magic angle. Calculations suggest that the formation of these flat-band replicas in superconducting MATBG are attributed to the strong coupling between flat-band electrons and an optical phonon mode at the graphene K point, facilitated by intervalley scattering. These findings, although they do not necessarily put electron-phonon coupling as the main driving force for the superconductivity in MATBG, unravel the electronic structure inherent in superconducting MATBG, thereby providing crucial information for understanding the unusual electronic landscape from which its superconductivity is derived., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

To simplify fast-growth broiler welfare assessments and use them as a benchmarking tool, decision trees were used to identify iceberg indicators discriminating flocks passing/failing welfare assessments as with the complete AWIN protocol. A dataset was constructed with data from 57 flocks and 3 previous projects. A final flock assessment score, previously not included in the dataset, was calculated and used as the benchmarking assessment classifier (pass/fail). A decision tree to classify flocks was built using the Chi-square Automatic Interaction Detection (CHAID) criterion. Cost-complexity pruning, and tenfold cross-validation were used. The final decision tree included cumulative mortality (%), immobile, lame birds (%), and birds with back wounds (%). Values were (mean ± se) 2.77 ± 0.14%, 0.16 ± 0.02%, 0.25 ± 0.02%, and 0.003 ± 0.001% for flocks passing the assessment; and 4.39 ± 0.49%, 0.24 ± 0.05%, 0.49 ± 0.09%, and 0.015 ± 0.006% for flocks failing. Cumulative mortality had the highest relative importance. The validated model correctly predicted 80.70% of benchmarking assessment outcomes. Model specificity was 0.8696; sensitivity was 0.5455. Decision trees can be useful to simplify welfare assessments. Model improvements will be possible as more information becomes available, and predictions are based on more samples., (© 2024. The Author(s).)

Conservation, restoration and land management are increasingly implemented at landscape scales 1,2 . However, because species interaction data are typically habitat- and/or guild-specific, exactly how those interactions connect habitats and affect the stability and function of communities at landscape scales remains poorly understood. We combine multi-guild species interaction data (plant-pollinator and three plant-herbivore-parasitoid communities, collected from landscapes with one, two or three habitats), a field experiment and a modelling approach to show that multi-habitat landscapes support higher species and interaction evenness, more complementary species interactions and more consistent robustness to species loss. These emergent network properties drive improved pollination success in landscapes with more habitats and are not explained by simply summing component habitat webs. Linking landscape composition, through community structure, to ecosystem function, highlights mechanisms by which several contiguous habitats can support landscape-scale ecosystem services., (© 2024. The Author(s).)

The druggable proteome refers to proteins that can bind to small molecules with appropriate chemical affinity, inducing a favorable clinical response. Predicting druggable proteins through screening and in silico modeling is imperative for drug design. To contribute to this field, we developed an accurate predictive classifier for druggable cancer-driving proteins using amino acid composition descriptors of protein sequences and 13 machine learning linear and non-linear classifiers. The optimal classifier was achieved with the support vector machine method, utilizing 200 tri-amino acid composition descriptors. The high performance of the model is evident from an area under the receiver operating characteristics (AUROC) of 0.975 ± 0.003 and an accuracy of 0.929 ± 0.006 (threefold cross-validation). The machine learning prediction model was enhanced with multi-omics approaches, including the target-disease evidence score, the shortest pathways to cancer hallmarks, structure-based ligandability assessment, unfavorable prognostic protein analysis, and the oncogenic variome. Additionally, we performed a drug repurposing analysis to identify drugs with the highest affinity capable of targeting the best predicted proteins. As a result, we identified 79 key druggable cancer-driving proteins with the highest ligandability, and 23 of them demonstrated unfavorable prognostic significance across 16 TCGA PanCancer types: CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, and SMARCA4. Moreover, we prioritized 11 clinically relevant drugs targeting these proteins. This strategy effectively predicts and prioritizes biomarkers, therapeutic targets, and drugs for in-depth studies in clinical trials. Scripts are available at https://github.com/muntisa/machine-learning-for-druggable-proteins ., (© 2024. The Author(s).)

Seminal plasma (SP) is rich in extracellular vesicles (EVs), which are still poorly studied, especially in livestock species. To better understand their functional role in both spermatozoa and endometrial epithelial cells, proper characterization of EVs is an essential step. The objective was to phenotypically characterize porcine seminal EVs (sEVs) using cryogenic electron microscopy (cryo-EM), which allows visualization of EVs in their native state. Porcine ejaculates are released in fractions, each containing SP from different source. This allows characterization sEVs released from various male reproductive tissues. Two experiments were performed, the first with SP from the entire ejaculate (n:6) and the second with SP from three ejaculate fractions (n:15): the first 10 mL of the sperm-rich ejaculate fraction (SRF-P1) with SP mainly from the epididymis, the remainder of the SRF (SRF-P2) with SP mainly from the prostate, and the post-SRF with SP mainly from the seminal vesicles. The sEVs were isolated by size exclusion chromatography and 1840 cryo-EM sEV images were acquired using a Jeol-JEM-2200FS/CR-EM. The size, electron density, complexity, and peripheral corona layer were measured in each sEV using the ImageJ software. The first experiment showed that sEVs were structurally and morphologically heterogeneous, although most (83.1%) were small (less than 200 nm), rounded, and poorly electrodense, and some have a peripheral coronal layer. There were also larger sEVs (16.9%) that were irregularly shaped, more electrodense, and few with a peripheral coronal layer. The second experiment showed that small sEVs were more common in SRF-P1 and SRF-P2, indicating that they originated mainly from the epididymis and prostate. Large sEVs were more abundant in post-SRF, indicating that they originated mainly from seminal vesicles. Porcine sEVs are structurally and morphologically heterogeneous. This would be explained by the diversity of reproductive organs of origin., (© 2024. The Author(s).)

Adeno-associated viruses (AAVs) are promising gene therapy vectors, but challenges arise when treating patients with preexisting neutralizing antibodies. Worldwide seroprevalence studies provide snapshots of existing immunity in diverse populations. Owing to the uniqueness of the Basque socio-geographical landscape, we investigated the seroprevalence of eight AAV serotypes in residents of the Basque Country. We found the highest seroprevalence of AAV3, and the lowest seroprevalence of AAV9. Additionally, less than 50% of the Basque population has neutralizing antibodies against AAV4, AAV6, and AAV9. Our findings provide insight into AAV infections in the Basque region, public health, and the development of AAV-based therapeutics., (© 2024. The Author(s).)

The magnetization value and electric resistivity of the single-crystalline sample of Ni 50 Fe 19 Co 4 Ga 27 shape memory alloy were measured. The elastic modulus was determined by the Dynamic Mechanical Analysis (DMA). The characteristic temperatures of martensitic transformation (MT) of the alloy were estimated from the temperature dependences of magnetization, electric resistivity and elastic modulus. A significant disparity between MT temperatures resulting from DMA and those estimated from magnetic and resistivity measurements was discovered. It was argued that the discrepancy is caused by the non-uniform mechanical stressing of twinned single crystal by the DMA analyzer. Moreover, the DMA measurements revealed a significant decrease of the elastic modulus of twinned martensite under the applied magnetic field of 1.5 kOe. To explain this effect, the temperature-dependent Young's modulus of twinned crystal lattice was computed. The computations showed that the experimentally observed field-induced change of the elastic modulus is caused by the stress-assisted detwinning of the crystal lattice by the applied magnetic field., (© 2024. The Author(s).)

Cancer cells employ adaptive mechanisms to survive various stressors, including genotoxic drugs. Understanding the factors promoting survival is crucial for developing effective treatments. In this study, we unveil a previously unexplored long non-coding RNA, JUNI (JUN-DT, LINC01135), which is upregulated by genotoxic drugs through the activation of stress-activated MAPKs, JNK, and p38 and consequently exerts positive control over the expression of its adjacent gene product c-Jun, a well-known oncoprotein, which transduces signals to multiple transcriptional outputs. JUNI regulates cellular migration and has a crucial role in conferring cellular resistance to chemotherapeutic drugs or UV radiation. Depletion of JUNI markedly increases the sensitivity of cultured cells and spheroids to chemotherapeutic agents. We identified 57 proteins interacting with JUNI. The activity of one of them the MAPK phosphatase and inhibitor, DUSP14, is counteracted by JUNI, thereby, facilitating efficient JNK phosphorylation and c-Jun induction when cells are exposed to UV radiation. The antagonistic interplay with DUSP14 contributes not only to c-Jun induction but also augments the survival of UV-exposed cells. In summary, we introduce JUNI as a novel stress-inducible regulator of c-Jun, positioning it as a potential target for enhancing the sensitivity of cancer cells to chemotherapy., (© 2024. The Author(s).)

Although the 16S rRNA gene is frequently used as a phylogenetic marker in analysis of environmental DNA, this marker often fails to distinguish closely related species, including those in the genus Vibrio. Here, we investigate whether inclusion and analysis of 23S rRNA sequence can help overcome the intrinsic weaknesses of 16S rRNA analyses for the differentiation of Vibrio species. We construct a maximum likelihood 16S rRNA gene tree to assess the use of this gene to identify clades of Vibrio species. Within the 16S rRNA tree, we identify the putative informative bases responsible for polyphyly, and demonstrate the association of these positions with tree topology. We demonstrate that concatenation of 16S and 23S rRNA genes increases the number of informative nucleotide positions, thereby overcoming ambiguities in 16S rRNA-based phylogenetic reconstructions. Finally, we experimentally demonstrate that this approach considerably improves the differentiation and identification of Vibrio species in environmental samples., (© 2024. The Author(s).)

The emergence of infectious diseases with pandemic potential is a major public health threat worldwide. The World Health Organization reports that about 60% of emerging infectious diseases are zoonoses, originating from spillover events. Although the mechanisms behind spillover events remain unclear, mathematical modeling offers a way to understand the intricate interactions among pathogens, wildlife, humans, and their shared environment. Aiming at gaining insights into the dynamics of spillover events and the outcome of an eventual disease outbreak in a population, we propose a continuous time stochastic modeling framework. This framework links the dynamics of animal reservoirs and human hosts to simulate cross-species disease transmission. We conduct a thorough analysis of the model followed by numerical experiments that explore various spillover scenarios. The results suggest that although most epidemic outbreaks caused by novel zoonotic pathogens do not persist in the human population, the rising number of spillover events can avoid long-lasting extinction and lead to unexpected large outbreaks. Hence, global efforts to reduce the impacts of emerging diseases should not only address post-emergence outbreak control but also need to prevent pandemics before they are established., (© 2024. The Author(s).)

In this work we endeavor to further understand the genetic architecture of the cerebellum by examining the genetic underpinnings of the different cerebellar lob(ul)es, identifying their genetic relation to cortical and subcortical regions, as well as to psychiatric disorders, as well as traces of their evolutionary trajectories. We confirm the moderate heritability of cerebellar volumes, and reveal genetic clustering and variability across their different substructures, which warranted a detailed analysis using this higher structural resolution. We replicated known genetic correlations with several subcortical volumes, and report new cortico-cerebellar genetic correlations, including negative genetic correlations between anterior cerebellar lobules and cingulate, and positive ones between lateral Crus I and lobule VI with cortical measures in the fusiform region. Heritability partitioning for evolutionary annotations highlighted that the vermis of Crus II has depleted heritability in genomic regions of "archaic introgression deserts", but no enrichment/depletion of heritability in any other cerebellar regions. Taken together, these findings reveal novel insights into the genetic underpinnings of the different cerebellar lobules., (© 2024. The Author(s).)

Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro. Replacement of wild-type iPSC-derived dopamine neurons (iPSC-DaNs) in the striatal microcircuit with those carrying the PD-related GBA-N370S mutation led to a depolarisation of resting membrane potential and an increase in rheobase in iPSC-MSNs, as well as a reduction in both voltage-gated sodium and potassium currents. Such deficits were resolved in late microcircuit cultures, and could be reversed in younger cultures with antagonism of protein kinase A activity in iPSC-MSNs. Taken together, our results highlight the unique utility of modelling striatal neurons in a modular physiological circuit to reveal mechanistic insights into GBA1 mutations in PD., (© 2024. The Author(s).)

Solution-based memristors deposited by inkjet printing technique have a strong technological potential based on their scalability, low cost, environmentally friendlier processing by being an efficient technique with minimal material waste. Indium-gallium-zinc oxide (IGZO), an oxide semiconductor material, shows promising resistive switching properties. In this work, a printed Ag/IGZO/ITO memristor has been fabricated. The IGZO thickness influences both memory window and switching voltage of the devices. The devices show both volatile counter8wise (c8w) and non-volatile 8wise (8w) switching at low operating voltage. The 8w switching has a SET and RESET voltage lower than 2 V and - 5 V, respectively, a retention up to 10 5  s and a memory window up to 100, whereas the c8w switching shows volatile characteristics with a low threshold voltage (Vth < - 0.65 V) and a characteristic time (τ) of 0.75 ± 0.12 ms when a single pulse of - 0.65 V with width of 0.1 ms is applied. The characteristic time alters depending on the number of pulses. These volatile characteristics allowed them to be tested on different 4-bit pulse sequences, as an initial proof of concept for temporal signal processing applications., (© 2024. The Author(s).)

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2-3 h) and more potently (IC 50 : 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance., (© 2024. The Author(s).)

The human brain is an extremely complex network of structural and functional connections that operate at multiple spatial and temporal scales. Investigating the relationship between these multi-scale connections is critical to advancing our comprehension of brain function and disorders. However, accurately predicting structural connectivity from its functional counterpart remains a challenging pursuit. One of the major impediments is the lack of public repositories that integrate structural and functional networks at diverse resolutions, in conjunction with modular transcriptomic profiles, which are essential for comprehensive biological interpretation. To mitigate this limitation, our contribution encompasses the provision of an open-access dataset consisting of derivative matrices of functional and structural connectivity across multiple scales, accompanied by code that facilitates the investigation of their interrelations. We also provide additional resources focused on neuro-genetic associations of module-level network metrics, which present promising opportunities to further advance research in the field of network neuroscience, particularly concerning brain disorders., (© 2024. The Author(s).)

We propose detecting the moment an atom emits a photon by means of a nearly classical macroscopic clock and discuss its viability. It is shown that what happens in such a measurement depends on the relation between the clock's accuracy and the width of the energy range available to the photon. Implications of the analysis for the long standing Schrödinger's cat problem are reported., (© 2024. The Author(s).)

We hypothesised that resource choice during early life contributes to both current and longer-term beneficial effects on animal welfare. We investigated this hypothesis in a longitudinal cross-over experiment with laying hen pullets (Gallus gallus domesticus) reared in pens with one or four litter and perch types, respectively (n = 8 pens/treatment, all providing ample and identical litter and perch space). After 4 weeks (chick period), half the pens were modified to provide the opposite treatment (juvenile period). After 11 more weeks, all groups were moved to novel, identical laying pens (adult period; Week 16-27). In support of our hypothesis, the opportunity to choose between multiple litter and perch variants was associated with higher levels of positively-valenced behaviours, including play as chicks and dustbathing as juveniles and adults, and lower levels of negatively-valenced behaviours, including feather pecking as chicks and juveniles and aggressive pecking as adults. Resource choice in the juvenile period also led to better juvenile and adult plumage condition, and greater growth as adults. We conclude that the opportunity to choose among different litter and perch types, instead of having only one type of each, had both short- and longer-term positive effects on the birds' affective states and physical condition., (© 2024. The Author(s).)

Retinal thickness may serve as a biomarker in Parkinson's disease (PD). In this prospective longitudinal study, we aimed to determine if PD patients present accelerated thinning rate in the parafoveal ganglion cell-inner plexiform layer (pfGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) compared to controls. Additionally, we evaluated the relationship between retinal neurodegeneration and clinical progression in PD. A cohort of 156 PD patients and 72 controls underwent retinal optical coherence tomography, visual, and cognitive assessments between February 2015 and December 2021 in two Spanish tertiary hospitals. The pfGCIPL thinning rate was twice as high in PD (β [SE] = -0.58 [0.06]) than in controls (β [SE] = -0.29 [0.06], p < 0.001). In PD, the progression pattern of pfGCIPL atrophy depended on baseline thickness, with slower thinning rates observed in PD patients with pfGCIPL below 89.8 µm. This result was validated with an external dataset from Moorfields Eye Hospital NHS Foundation Trust (AlzEye study). Slow pfGCIPL progressors, characterized by older at baseline, longer disease duration, and worse cognitive and disease stage scores, showed a threefold increase in the rate of cognitive decline (β [SE] = -0.45 [0.19] points/year, p = 0.021) compared to faster progressors. Furthermore, temporal sector pRNFL thinning was accelerated in PD (β time x group [SE] = -0.67 [0.26] μm/year, p = 0.009), demonstrating a close association with cognitive score changes (β [SE] = 0.11 [0.05], p = 0.052). This study suggests that a slower pattern of pfGCIPL tissue loss in PD is linked to more rapid cognitive decline, whereas changes in temporal pRNFL could track cognitive deterioration., (© 2024. The Author(s).)

This study assessed whether Non-native Directed Speech (NNDS) facilitates second language (L2) learning, specifically L2 word learning and production. Spanish participants (N = 50) learned novel English words, presented either in NNDS or Native-Directed Speech (NDS), in two tasks: Recognition and Production. Recognition involved matching novel objects to their labels produced in NNDS or NDS. Production required participants to pronounce these objects' labels. The novel words contained English vowel contrasts, which approximated Spanish vowel categories more (/i-ɪ/) or less (/ʌ-æ/). Participants in the NNDS group exhibited faster recognition of novel words, improved learning, and produced the /i-ɪ/ contrast with greater distinctiveness in comparison to the NDS group. Participants' ability to discriminate the target vowel contrasts was also assessed before and after the tasks, with no improvement detected in the two groups. These findings support the didactic assumption of NNDS, indicating the relevance of the phonetic adaptations in this register for successful L2 acquisition., (© 2023. The Author(s).)

The study of mild cognitive impairment (MCI) is critical to understand the underlying processes of cognitive decline in Parkinson's disease (PD). Functional connectivity (FC) disruptions in PD-MCI patients have been observed in several networks. However, the functional and cognitive changes associated with the disruptions observed in these networks are still unclear. Using a data-driven methodology based on independent component analysis, we examined differences in FC RSNs among PD-MCI, PD cognitively normal patients (PD-CN) and healthy controls (HC) and studied their associations with cognitive and motor variables. A significant difference was found between PD-MCI vs PD-CN and HC in a FC-trait comprising sensorimotor (SMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. This FC-trait was associated with working memory, memory and the UPDRS motor scale. SMN involvement in verbal memory recall may be related with the FC-trait correlation with memory deficits. Meanwhile, working memory impairment may be reflected in the DAN, VAN and FPN interconnectivity disruptions with the SMN. Furthermore, interactions between the SMN and the DAN, VAN and FPN network reflect the intertwined decline of motor and cognitive abilities in PD-MCI. Our findings suggest that the memory impairments observed in PD-MCI are associated with reduced FC within the SMN and between SMN and attention networks., (© 2023. The Author(s).)

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies., (© 2023. West China Hospital, Sichuan University.)

Processing efficiency differs between high- and low-frequency words, with less frequent words resulting in longer response latencies in several linguistic behavioral tasks. Nevertheless, studies using functional MRI to investigate the word frequency effect have employed diverse methodologies and produced heterogeneous results. In this study, we examine the effect of word frequency through complementary analytical approaches and functional connectivity analyses. Furthermore, we examine whether reading demands, which have been shown to influence reading-related activation, modulate the effects of word frequency. We conducted MRI scanning on 54 healthy participants who performed two versions of a single-word reading task involving high- and low-frequency words: a low-level perceptual reading task and a high-level semantic reading task. The results indicate that word frequency influenced the activation of the pars orbitalis and pars triangularis of the inferior frontal gyrus, but only in the semantic reading task. Additionally, the ventral occipitotemporal cortex exhibited stronger regional activation during the semantic reading task compared to the perceptual reading task, with no effects of word frequency. Functional connectivity analyses demonstrated significant coupling among regions within both the dorsal and ventral reading networks, without any observable effects of word frequency or task. These findings were consistent across group- and individual-level analytical approaches. Overall, our results provide further support for the involvement of the inferior frontal gyrus in semantic processing during reading, as indicated by the effect of word frequency and the influence of reading demands, highlighting the role of the ventral reading network. These findings are discussed in line with their implications for lexical and pre-lexical reading processing., (© 2023. Springer Nature Limited.)

Recent evidence demonstrates potential links between mitochondrial dysfunction and inflammatory bowel diseases (IBD). In addition, bidirectional interactions between the intestinal microbiota and host mitochondria may modulate intestinal inflammation. We observed previously that mice deficient in the mitochondrial protein MCJ (Methylation-controlled J protein) exhibit increased susceptibility to DSS colitis. However, it is unclear whether this phenotype is primarily driven by MCJ -/- associated gut microbiota dysbiosis or by direct effects of MCJ-deficiency. Here, we demonstrate that fecal microbiota transplantation (FMT) from MCJ-deficient into germ-free mice was sufficient to confer increased susceptibility to colitis. Therefore, an FMT experiment by cohousing was designed to alter MCJ-deficient microbiota. The phenotype resulting from complex I deficiency was reverted by FMT. In addition, we determined the protein expression pathways impacted by MCJ deficiency, providing insight into the pathophysiology of IBD. Further, we used magnetic activated cell sorting (MACS) and 16S rRNA gene sequencing to characterize taxa-specific coating of the intestinal microbiota with Immunoglobulin A (IgA-SEQ) in MCJ-deficient mice. We show that high IgA coating of fecal bacteria observed in MCJ-deficient mice play a potential role in disease progression. This study allowed us to identify potential microbial signatures in feces associated with complex I deficiency and disease progression. This research highlights the importance of finding microbial biomarkers, which might serve as predictors, permitting the stratification of ulcerative colitis (UC) patients into distinct clinical entities of the UC spectrum., (© 2023. Springer Nature Limited.)

Coffee extraction involves many complex physical and transport processes extremely difficult to model. Among the many factors that will affect the final quality of coffee, the microstructure of the coffee matrix is one of the most critical ones. In this article, we use X-ray micro-computed (microCT) technique to capture the microscopic details of coffee matrices at particle-level and perform fluid dynamics simulation based on the smoothed particle hydrodynamics method (SPH) with the 3D reconstructured data. Information like flow permeability and tortuosity of the matrices can be therefore obtained from our simulation. We found that inertial effects can be quite significant at the normal pressure gradient conditions typical for espresso brewing, and can provide an explanation for the inconsistency of permeability measurements seen in the literature. Several types of coffee powder are further examined, revealing their distinct microscopic details and resulting flow features. By comparing the microCT images of pre- and post-extraction coffee matrices, it is found that a decreasing porosity profile (from the bottom-outlet to the top-inlet) always develops after extraction. This counterintuitive phenomenon can be explained using a pressure-dependent erosion model proposed in our prior work. Our results reveal not only some important hydrodynamic mechanisms of coffee extraction, but also show that microCT scan can provide useful microscopic details for coffee extraction modelling. MicroCT scan establishes the basis for a data-driven numerical framework to explore the link between coffee powder microstructure and extraction dynamics, which is the prerequisite to study the time evolution of both volatile and non-volatile organic compounds and then the flavour profile of coffee brews., (© 2023. Springer Nature Limited.)

Mutual diffusion of six hydrocarbons (methane, ethane, isobutane, benzene, toluene or naphthalene) diluted in supercritical carbon dioxide ([Formula: see text]) is studied by molecular dynamics simulation near the Widom line, i.e., in the temperature range from 290 to 345 K along the isobar 9 MPa. The [Formula: see text] + aromatics mixtures are additionally sampled at 10 and 12 MPa and an experimental database with Fick diffusion coefficient data for those systems is provided. Taylor dispersion experiments of [Formula: see text] with benzene, toluene, n-dodecane and 1,2,3,4-tetrahydronaphthalene are conducted along the [Formula: see text] 10 MPa isobar. Maxwell-Stefan and Fick diffusion coefficients are analyzed, together with the thermodynamic factor that relates them. It is found that the peculiar behavior of the Fick diffusion coefficient of some [Formula: see text] mixtures in the extended critical region is a consequence of the thermodynamic factor minimum due to pronounced clustering on the molecular scale. Further, the strong dependence of the Fick diffusion coefficient on the molecular mass of the solute as well as the breakdown of the Stokes-Einstein relation near the Widom line are confirmed. Eleven correlations for the prediction of the Fick diffusion coefficient of [Formula: see text] mixtures are assessed. An alternative two-step approach for the prediction of the infinite dilution Fick diffusion coefficient of supercritical [Formula: see text] mixtures is proposed. It requires only the state point in terms of temperature and pressure (or density) as well as the molecular solute mass as input parameters. First, entropy scaling is applied to estimate the self-diffusion coefficient of [Formula: see text]. Subsequently, this coefficient is used to determine the infinite dilution Fick diffusion coefficient of the mixture, based on the finding that these two diffusion coefficients exhibit a linear relationship, where the slope depends only on the molecular solute mass., (© 2023. Springer Nature Limited.)

Ideal drug carriers feature a high loading capacity to minimize the exposure of patients with excessive, inactive carrier materials. The highest imaginable loading capacity could be achieved by nanocarriers, which are assembled from the therapeutic cargo molecules themselves. Here, we describe peptide nucleic acid (PNA)-based zirconium (Zr) coordination nanoparticles which exhibit very high PNA loading of [Formula: see text] w/w. This metal-organic hybrid nanomaterial class extends the enormous compound space of coordination polymers towards bioactive oligonucleotide linkers. The architecture of single- or double-stranded PNAs was systematically varied to identify design criteria for the coordination driven self-assembly with Zr(IV) nodes at room temperature. Aromatic carboxylic acid functions, serving as Lewis bases, and a two-step synthesis process with preformation of [Formula: see text] turned out to be decisive for successful nanoparticle assembly. Confocal laser scanning microscopy confirmed that the PNA-Zr nanoparticles are readily internalized by cells. PNA-Zr nanoparticles, coated with a cationic lipopeptide, successfully delivered an antisense PNA sequence for splicing correction of the [Formula: see text]-globin intron mutation IVS2-705 into a functional reporter cell line and mediated splice-switching via interaction with the endogenous mRNA splicing machinery. The presented PNA-Zr nanoparticles represent a bioactive platform with high design flexibility and extraordinary PNA loading capacity, where the nucleic acid constitutes an integral part of the material, instead of being loaded into passive delivery systems., (© 2023. Springer Nature Limited.)

Interactions among electrons create novel many-body quantum phases of matter with wavefunctions that reflect electronic correlation effects, broken symmetries and collective excitations. Many quantum phases have been discovered in magic-angle twisted bilayer graphene (MATBG), including correlated insulating 1 , unconventional superconducting 2-5 and magnetic topological 6-9 phases. The lack of microscopic information 10,11 of possible broken symmetries has hampered our understanding of these phases 12-17 . Here we use high-resolution scanning tunnelling microscopy to study the wavefunctions of the correlated phases in MATBG. The squares of the wavefunctions of gapped phases, including those of the correlated insulating, pseudogap and superconducting phases, show distinct broken-symmetry patterns with a √3 × √3 super-periodicity on the graphene atomic lattice that has a complex spatial dependence on the moiré scale. We introduce a symmetry-based analysis using a set of complex-valued local order parameters, which show intricate textures that distinguish the various correlated phases. We compare the observed quantum textures of the correlated insulators at fillings of ±2 electrons per moiré unit cell to those expected for proposed theoretical ground states. In typical MATBG devices, these textures closely match those of the proposed incommensurate Kekulé spiral order 15 , whereas in ultralow-strain samples, our data have local symmetries like those of a time-reversal symmetric intervalley coherent phase 12 . Moreover, the superconducting state of MATBG shows strong signatures of intervalley coherence, only distinguishable from those of the insulator with our phase-sensitive measurements., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Twenty-five years since foundational publications on valuing ecosystem services for human well-being 1,2 , addressing the global biodiversity crisis 3 still implies confronting barriers to incorporating nature's diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever 4 . Notwithstanding agreements to incorporate nature's values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF) 5 and the UN Sustainable Development Goals 6 , predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature 7 . Arguably, a 'values crisis' underpins the intertwined crises of biodiversity loss and climate change 8 , pandemic emergence 9 and socio-environmental injustices 10 . On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature's diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions 7,11 . Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures., (© 2023. The Author(s).)

Numbers and letters are the fundamental building blocks of our everyday social interactions. Previous studies have focused on determining the cortical pathways shaped by numeracy and literacy in the human brain, partially supporting the hypothesis of distinct perceptual neural circuits involved in the visual processing of the two categories. In this study, we aim to investigate the temporal dynamics for number and letter processing. We present magnetoencephalography (MEG) data from two experiments (N = 25 each). In the first experiment, single numbers, letters, and their respective false fonts (false numbers and false letters) were presented, whereas, in the second experiment, numbers, letters, and their respective false fonts were presented as a string of characters. We used multivariate pattern analysis techniques (time-resolved decoding and temporal generalization), testing the strong hypothesis that the neural correlates supporting letter and number processing can be logistically classified as categorically separate. Our results show a very early dissociation (~ 100 ms) between numbers, and letters when compared to false fonts. Number processing can be dissociated with similar accuracy when presented as isolated items or strings of characters, while letter processing shows dissociable classification accuracy for single items compared to strings. These findings reinforce the evidence indicating that early visual processing can be differently shaped by the experience with numbers and letters; this dissociation is stronger for strings compared to single items, thus showing that combinatorial mechanisms for numbers and letters could be categorically distinguished and influence early visual processing., (© 2023. The Author(s).)

The prevalent one-dimensional alignment of genomic signals to a reference landmark is a cornerstone of current methods to study transcription and its DNA-dependent processes but it is prone to mask potential relations among multiple DNA elements. We developed a systematic approach to align genomic signals to multiple locations simultaneously by expanding the dimensionality of the genomic-coordinate space. We analyzed transcription in human and uncovered a complex dependence on the relative position of neighboring transcription start sites (TSSs) that is consistently conserved among cell types. The dependence ranges from enhancement to suppression of transcription depending on the relative distances to the TSSs, their intragenic position, and the transcriptional activity of the gene. Our results reveal a conserved hierarchy of alternative TSS usage within a previously unrecognized level of genomic organization and provide a general methodology to analyze complex functional relationships among multiple types of DNA elements., (© 2023. The Author(s).)

We propose quantum neural networks that include multi-qubit interactions in the neural potential leading to a reduction of the network depth without losing approximative power. We show that the presence of multi-qubit potentials in the quantum perceptrons enables more efficient information processing tasks such as XOR gate implementation and prime numbers search, while it also provides a depth reduction to construct distinct entangling quantum gates like CNOT, Toffoli, and Fredkin. This simplification in the network architecture paves the way to address the connectivity challenge to scale up a quantum neural network while facilitating its training., (© 2023. The Author(s).)

In the first billion years after the Big Bang, sources of ultraviolet (UV) photons are believed to have ionized intergalactic hydrogen, rendering the Universe transparent to UV radiation. Galaxies brighter than the characteristic luminosity L* (refs.  1,2 ) do not provide enough ionizing photons to drive this cosmic reionization. Fainter galaxies are thought to dominate the photon budget; however, they are surrounded by neutral gas that prevents the escape of the Lyman-α photons, which has been the dominant way to identify them so far. JD1 was previously identified as a triply-imaged galaxy with a magnification factor of 13 provided by the foreground cluster Abell 2744 (ref. 3 ), and a photometric redshift of z ≈ 10. Here we report the spectroscopic confirmation of this very low luminosity (≈0.05 L*) galaxy at z = 9.79, observed 480 Myr after the Big Bang, by means of the identification of the Lyman break and redward continuum, as well as multiple ≳4σ emission lines, with the Near-InfraRed Spectrograph (NIRSpec) and Near-InfraRed Camera (NIRCam) instruments. The combination of the James Webb Space Telescope (JWST) and gravitational lensing shows that this ultra-faint galaxy (M UV  = -17.35)-with a luminosity typical of the sources responsible for cosmic reionization-has a compact (≈150 pc) and complex morphology, low stellar mass (10 7.19  M ⊙ ) and subsolar (≈0.6 Z ⊙ ) gas-phase metallicity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production 1,2 . This adaptation is triggered in part by post-partum environmental changes 3 , but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors 4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Transport processes of many structures inside living cells display anomalous diffusion, such as endosomes in eukaryotic cells. They are also heterogeneous in space and time. Large ensembles of single particle trajectories allow the heterogeneities to be quantified in detail and provide insights for mathematical modelling. The development of accurate mathematical models for heterogeneous dynamics has the potential to enable the design and optimization of various technological applications, for example, the design of effective drug delivery systems. Central questions in the analysis of anomalous dynamics are ergodicity and statistical ageing which allow for selecting the proper model for the description. It is believed that non-ergodicity and ageing occur concurrently. However, we found that the anomalous dynamics of endosomes is paradoxical since it is ergodic but shows ageing. We show that this behaviour is caused by ensemble heterogeneity that, in addition to space-time heterogeneity within a single trajectory, is an inherent property of endosomal motion. Our work introduces novel approaches for the analysis and modelling of heterogeneous dynamics., (© 2023. The Author(s).)