Complementary Evidence Research Articles

Prospective associations of interleukin-6 and APOE allele with cognitive decline in biracial community-dwelling older adults: The Chicago Health and Aging Project (CHAP).

It is unclear whether inflammation, that is, high interleukin-6 (IL-6) levels, and genetic risk, that is, apolipoprotein E (APOE) ε4 allele, have a compounding effect on cognitive decline (CD). We analyzed a subset of participants from the longitudinal cohort study, Chicago Health and Aging Project, comprising 1120 biracial community-dwelling older adults (60% Black and 62% women), and mean follow-up=6.4 years. We ran adjusted mixed-effects models on2 longitudinal CD. In APOE ε4 carriers, higher serum IL-6 was not associated with the rate of CD (β=-0.0091 [standard deviation (SD)=0.0165, p=0.5800]). Conversely, in non-ε4 carriers, compared to the lower tertile, those with the upper tertile of serum IL-6 levels experienced significantly accelerated CD (β=-0.0257 [SD=0.0084, p=0.0023]). Even without the largest genetic risk factor for late-onset Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD), elevated serum IL-6 still accelerate the rate of CD in non-APOE ε4 carriers. Hence, interventions ameliorating inflammation may prevent AD/ADRD. Interleukin-6 (IL-6) and the apolipoprotein E (APOE) ε4 allele have been separately associated with an increased risk for cognitive decline, but their interaction remains unclear.In ε4 carriers, IL-6 was not associated with cognitive decline. However, even without the biggest genetic risk factor for Alzheimer's disease (AD), that is, APOE ε4, elevated serum IL-6 still could confer accelerated rate of cognitive decline, with a detrimental effect half of that imposed by APOE ε4 alone.We found no racial differences in these associations.These findings contribute complementary evidence on non-APOE ε4-dependent and non-AD biological pathways through which cognitive decline can still be accelerated in non-APOE ε4 carriers and highlight a specific subgroup of older adults who are at a higher risk of AD and thus may benefit from anti-inflammatory interventions.

New status of Bichromomyia subspecies (Diptera: Psychodidae: Phlebotominae) based on molecular taxonomy.

The sand fly of the genus Bichromomyia (Galati, 1995) includes 3 subspecies considered vectors of Leishmania, which share high morphological similarity. Through information from the Cytochrome Oxidase Subunit I (COI) gene, we provide complementary evidence to support that Bichromomyia olmeca olmeca, and Bichromomyia olmeca bicolor, should be raised to nominal species status. We recovered specimens of Bi. o. olmeca from Quintana Roo, Tabasco, and Oaxaca, Mexico, supply 17 new COI sequences, and also incorporate GenBank sequences for other Bichromomyia species. After a Maximum Likelihood (ML) analysis, all Bichromomyia species clustered with a bootstrap of 100%, although sequences of Bichromomyia flaviscutellata were divided into 2 clusters with an interspecific range distance of 11.16% between them, which confirm cryptic species in Brazil. The genetic distance of Bi. o. olmeca compared to related subspecies ranged between 12.59% and 14.64%. A total of 29 haplotypes (Hd = 0.987; π = 0.08783; S = 136) were recovered from the Bichromomyia sequences. Results of the TC network were consistent with the ML analysis, supporting that subspecies of Bichromomyia are genetically distinct and deserve being raised to valid species category: Bichromomyia olmeca (Vargas & Díaz-Nájera) and Bichromomyia bicolor (Fairchild & Theodor).

Financial Transparency of Private Firms: Evidence from a Randomized Field Experiment

ABSTRACTThis paper examines why private firms choose to be financially transparent or opaque by conducting a field experiment with more than 25,000 firms in Germany. We inform a randomly chosen set of firms about a disclosure option that allows eligible firms to restrict access to their otherwise publicly available financial statements. We also vary the messaging in subtle ways to induce experimental variation in the probability that firms take transacting (capital providers or customers and suppliers) versus non‐transacting stakeholders (competitors or general interest parties) into consideration when making their filing decision. Based on each firm's actual filing decision, we find that treated firms are 15% more likely to restrict access to their financial statements. This intention‐to‐treat effect is persistent and concentrated among firms that should derive lower net benefits from disclosure (smaller, more mature firms in less capital‐intensive industries). These findings indicate that informational constraints affect firms’ disclosure practice. Additionally, we show that the treatment effect is almost 40% larger for firms that have a higher, exogenously induced, probability of considering non‐transacting stakeholders when making their disclosure decision. By analyzing subsequent firm activity and complementary survey evidence, we also provide suggestive evidence that disclosure requirements put an undue burden on very small private firms.

Electromagnetic Enantiomer: Chiral Nanophotonic Cavities for Inducing Chemical Asymmetry.

Chiral molecules, a cornerstone of chemical sciences with applications ranging from pharmaceuticals to molecular electronics, come in mirror-image pairs called enantiomers. However, their synthesis often requires complex control of their molecular geometry. We propose a strategy called "electromagnetic enantiomers" for inducing chirality in molecules located within engineered nanocavities using light, eliminating the need for intricate molecular design. This approach works by exploiting the strong coupling between a nonchiral molecule and a chiral mode within a nanocavity. We provide evidence for this strong coupling through angular emission patterns verified by numerical simulations and with complementary evidence provided by luminescence lifetime measurements. In simpler terms, our hypothesis suggests that chiral properties can be conveyed on to a molecule with a suitable chromophore by placing it within a specially designed chiral nanocavity that is significantly larger (hundreds of nanometers) than the molecule itself. To demonstrate this concept, we showcase an application in display technology, achieving efficient emission of circularly polarized light from a nonchiral molecule. The electromagnetic enantiomer concept offers a simpler approach to chiral control, potentially opening doors for asymmetric synthesis.

Distinct Neural Plasticity Enhancing Visual Perception.

The developed human brain shows remarkable plasticity following perceptual learning, resulting in improved visual sensitivity. However, such improvements commonly require extensive stimuli exposure. Here we show that efficiently enhancing visual perception with minimal stimuli exposure recruits distinct neural mechanisms relative to standard repetition-based learning. Participants (n = 20, 12 women, 8 men) encoded a visual discrimination task, followed by brief memory reactivations of only five trials each performed on separate days, demonstrating improvements comparable with standard repetition-based learning (n = 20, 12 women, 8 men). Reactivation-induced learning engaged increased bilateral intraparietal sulcus (IPS) activity relative to repetition-based learning. Complementary evidence for differential learning processes was further provided by temporal-parietal resting functional connectivity changes, which correlated with behavioral improvements. The results suggest that efficiently enhancing visual perception with minimal stimuli exposure recruits distinct neural processes, engaging higher-order control and attentional resources while leading to similar perceptual gains. These unique brain mechanisms underlying improved perceptual learning efficiency may have important implications for daily life and in clinical conditions requiring relearning following brain damage.

Preclinical evaluation of [18F]FP-CIT, the radiotracer targeting dopamine transporter for diagnosing Parkinson’s disease: pharmacokinetic and efficacy analysis

BackgroundN-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson’s disease (PD). 123I- and 18F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [18F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [18F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [18F]FP-CIT and its efficacy for PD diagnosis using murine models.ResultsBiodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [18F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [18F]FP-CIT injection. [18F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [18F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [18F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011).ConclusionsThis study fills the gap regarding insufficient preclinical studies on [18F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [18F]FP-CIT excretion, provide complementary evidence that [18F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.

Association of dual task gait performance with cognitive outcomes among older adults: Piloting an inexpensive, portable assessment platform

Motor assessment has emerged as complementary evidence for the detection of late life cognitive disorders. Clinicians lack inexpensive, accurate, and portable tools for this purpose. To fill this void, the current study piloted measures from the Mizzou Point-of-care Assessment System a multimodal sensor platform. We examined the ability of these motor function measures to distinguish neurocognitive status and assessed their associations with cognitive performance. Data came from 42 older adults, including 16 with mild cognitive impairment (MCI). Participants performed dual task gait, pairing walking with serial subtraction by sevens, along with aa neuropsychological test battery. T-tests revealed that individuals with MCI demonstrated slower stride times (d = .55) and shorter stride lengths (d = .98) compared to healthy older adults. Results from hierarchical regression showed that stride time and stride length predicted cognitive performance across several domains, after controlling for cognitive status and demographics. Cognitive status moderated this relationship for global cognition and attention, wherein gait measures were significantly related to these outcomes for the cognitively normal group, but not the MCI group. Evidence from the current study provided preliminary support that MPASS measures demonstrate expected associations with cognitive performance and can distinguish amongst those with and without cognitive impairment.

Exploring the Pharmacognostical and Phytochemical Profiles of Aqueous Extracts of Kalanchoe.

The use of plants for medicinal purposes has a long history, however it is desirable a continuous evaluation seeking for complementary scientific evidences for their safe application. Species within the Kalanchoe genus are often referred to as "miracle leaf" due to their remarkable healing properties. Traditionally, these plants have been used to treat infections, inflammation, and cancer. Despite their widespread use, the identification of their active components remains incomplete. This study aimed to differentiate K. crenata (KC), K. marmorata (KM), and K. pinnata (KP) by conducting detailed histochemical and phytochemical analyses, and to assess their antioxidant capabilities. The investigation revealed significant differences between the species, highlighting the variability in phenolic (PC) and flavonoid contents (FC) and their distinct antioxidant effects. The KM demonstrated the greatest results (PC: 59.26±1.53 mgEqGA/g; FC: 12.63±0.91 mgEqCQ/g; DPPH⋅ (IC50): 110.66 ug/mL; ABTS⋅+ (IC50): 26.81 ug/mL; ORAC: 9.65±0.75 mmolTE) when compared to KC and KP. These findings underscore a new reference for research within the Kalanchoe genus.

Subarachnoid Hemorrhage Depletes Calcitonin Gene-Related Peptide Levels of Trigeminal Neurons in Rat Dura Mater.

Subarachnoid hemorrhage (SAH) remains a major cause of cerebrovascular morbidity, eliciting severe headaches and vasospasms that have been shown to inversely correlate with vasodilator calcitonin gene-related peptide (CGRP) levels. Although dura mater trigeminal afferents are an important source of intracranial CGRP, little is known about the effects of SAH on these neurons in preclinical models. The present study evaluated changes in CGRP levels and expression in trigeminal primary afferents innervating the dura mater 72 h after experimentally induced SAH in adult rats. SAH, eliciting marked damage revealed by neurological examination, significantly reduced the density of CGRP-immunoreactive nerve fibers both in the dura mater and the trigeminal caudal nucleus in the medulla but did not affect the total dural nerve fiber density. SAH attenuated ex vivo dural CGRP release by ~40% and in the trigeminal ganglion, reduced both CGRP mRNA levels and the number of highly CGRP-immunoreactive cell bodies. In summary, we provide novel complementary evidence that SAH negatively affects the integrity of the CGRP-expressing rat trigeminal neurons. Reduced CGRP levels suggest likely impaired meningeal neurovascular functions contributing to SAH complications. Further studies are to be performed to reveal the importance of impaired CGRP synthesis and its consequences in central sensory processing.

Music Exposure and Maternal Musicality Predict Vocabulary Development in Children with Cochlear Implants

Children with cochlear implants (CIs) exhibit large individual differences in vocabulary outcomes. We hypothesized that understudied sources of variance are amount of music engagement and exposure and maternal musicality. Additionally, we explored whether objective measures of music exposure captured from the CI data logs and parent reports about music engagement provide converging and/or complementary evidence, and whether these correlate with maternal musicality. Sixteen children with CIs (Mage = 16.7 months, SD = 7.7, range = 9.6–32.9) were tested before implantation and three, six, and 12 months post-CI activation. Music exposure throughout the first year post-activation was extracted from the CI data logs. Children’s vocabulary and home music engagement and maternal musicality were assessed using parent reports. Analyses revealed relatively low home music engagement and maternal musicality. Nonetheless, positive effects emerged for music exposure on children’s early receptive and expressive vocabulary and for maternal musicality on expressive vocabulary three months post-activation. Results underline the importance of combining automatic measures and parent reports to understand children’s acoustic environment and suggest that environmental music factors may affect early vocabulary acquisition in children with CIs. The presence of these effects despite poor music exposure and skills further motivates the involvement of children with CIs and their parents in music intervention programs.

Phosphate-mediated degradation of organic pollutants in water with peroxymonosulfate revisited: Radical or non-radical oxidation?

Whilst it is generally recognized that phosphate enables to promote the removal of some organic pollutants with peroxymonosulfate (PMS) oxidation, however, there is an ongoing debate as to whether free radicals are involved. By integrating different methodologies, here we provide new insights into the reaction mechanism of the binary mixture of phosphates (i.e., NaH2PO4, Na2HPO3, and NaH2PO2) with peroxymonosulfate (PMS) or hydrogen peroxide (H2O2). Enhanced degradation of organic pollutants and observation of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) adducts (i.e. DMPOOH and 5,5-dimethyl-2-oxopyrroline-1-oxyl (DMPOX)) with electron paramagnetic resonance (EPR) in most phosphates/PMS system seemly support a radical-dominant mechanism. However, fluorescence probe experiments confirm that no significant amount of hydroxyl radicals (•OH) are produced in such reaction systems. PMS in the phosphate solutions (without any organics) remains relatively stable, but is only consumed while organic substrates are present, which is distinct from a typical radical-dominant Co2+/PMS system where PMS is continuously decomposed. Through density functional theory (DFT) calculation, the energy barriers of the phosphates/PMS reaction processes are greatly decreased when non-radical mechanism dominates. Complementary evidence suggests that the reactive intermediates of PMS-phosphate complex, rather than the free radicals, are capable of oxidizing electron-rich substrates such as DMPO and organic pollutants. Taking the case of phosphate/PMS system as an example, this study demonstrates the necessity of acquisition of lines of evidence for resolving paradoxes in identifying EPR adducts.

Decoding bilingualism from resting-state oscillatory network organization.

Can lifelong bilingualism be robustly decoded from intrinsic brain connectivity? Can we determine, using a spectrally resolved approach, the oscillatory networks that better predict dual-language experience? We recorded resting-state magnetoencephalographic activity in highly proficient Spanish-Basque bilinguals and Spanish monolinguals, calculated functional connectivity at canonical frequency bands, and derived topological network properties using graph analysis. These features were fed into a machine learning classifier to establish how robustly they discriminated between the groups. The model showed excellent classification (AUC: 0.91 ± 0.12) between individuals in each group. The key drivers of classification were network strength in beta (15-30Hz) and delta (2-4Hz) rhythms. Further characterization of these networks revealed the involvement of temporal, cingulate, and fronto-parietal hubs likely underpinning the language and default-mode networks (DMNs). Complementary evidence from a correlation analysis showed that the top-ranked features that better discriminated individuals during rest also explained interindividual variability in second language (L2) proficiency within bilinguals, further supporting the robustness of the machine learning model in capturing trait-like markers of bilingualism. Overall, our results show that long-term experience with an L2 can be "brain-read" at a fine-grained level from resting-state oscillatory network organization, highlighting its pervasive impact, particularly within language and DMN networks.

Bankruptcy in the UK: Do Managers Talk the Talk Before Walking the Walk?

AbstractThis study examines whether managers employ annual report textual disclosures as a conduit to communicate the probability of future corporate bankruptcy or to intentionally mislead stakeholders owing to impression management incentives. We conduct various examinations around the information content of the tone conveyed by textual disclosures in unstructured UK annual reports and the probability of corporate bankruptcy. We document that firms that communicate a more net positive tone are associated with lower bankruptcy risk. Importantly, this association is found to be stronger for firms whose managers have a lower incentive to mislead investors owing to better board monitoring, stringent stock market regulation, and Big 4 audits. We also offer complementary evidence that firms conveying a more net positive tone exhibit higher future performance and earnings persistence, and lower future performance volatility. These firms are also less likely to exhibit extreme corporate policies and to receive a qualified auditor's opinion. Overall, this study sheds light on whether managers tend to inform or misinform (bury their heads in the sand) about corporate bankruptcy.

Experimental evidences of the direct influence of external magnetic fields on the mechanism of the electrocatalytic oxygen evolution reaction

The use of magnetic fields as external stimuli to improve the kinetics of electrochemical reactions is attracting substantial attention, given their potential to reduce energy losses. Despite recent reports showing a positive effect on catalytic performance upon applying a magnetic field to a working electrode, there are still many uncertainties and a lack of experimental evidence correlating the presence of the magnetic field to the electrocatalytic performance. Here, we present a combination of electrochemical and spectroscopic tools that demonstrate how the presence of an external magnetic field alters the reaction mechanism of the electrocatalytic oxygen evolution reaction (OER), accelerating the overall performance of a Ni4FeOx electrode. Complementary experimental evidence has been gathered supporting the participation of this microscopic magnetic field effect. Electrochemical impedance spectroscopy (EIS) points to a speed-up of the intrinsic reaction kinetics, independent of other indirect effects. In the same direction, the spectro-electrochemical fingerprint of the intermediate species that appear during the electrocatalytic cycle, as detected under operando conditions, indicates a change in the order of the reaction as a function of hole accumulation. All these experimental data confirm the direct influence of an external magnetic field on the reaction mechanism at the origin of the magnetically enhanced electrocatalytic OER.

Controversies in IPAA for Ulcerative Colitis: A Systematic Review of Different Anastomotic Techniques.

Available techniques for IPAA in ulcerative colitis include handsewn, double-stapled, and single-stapled anastomoses. There are controversies, indications, and different outcomes regarding these techniques. To describe technical details, indications, and outcomes of 3 specific types of anastomoses in restorative proctocolectomy. Systematic literature review for articles in the PubMed database according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Studies describing outcomes of the 3 different types of anastomoses, during pouch surgery, in patients undergoing restorative proctocolectomy for ulcerative colitis. IPAA technique. Postoperative outcomes (anastomotic leaks, overall complication rates, and pouch function). Twenty-one studies were initially included: 6 studies exclusively on single-stapled IPAA, 2 exclusively on double-stapled IPAA, 6 studies comparing single-stapled to double-stapled techniques, 6 comparing double-stapled to handsewn IPAA, and 1 comprising single-stapled to handsewn IPAA. Thirty-seven studies were added according to authors' discretion as complementary evidence. Between 1990 and 2015, most studies were related to double-stapled IPAA, either only analyzing the results of this technique or comparing it with the handsewn technique. Studies published after 2015 were mostly related to transanal approaches to proctectomy for IPAA, in which a single-stapled anastomosis was introduced instead of the double-stapled anastomosis, with some studies comparing both techniques. A low number of studies with handsewn IPAA technique and a large number of studies added at authors' discretion were the limitations of this strudy. Handsewn IPAA should be considered if a mucosectomy is performed for dysplasia or cancer in the low rectum or, possibly, for re-do surgery. Double-stapled IPAA has been more widely adopted for its simplicity and for the advantage of preserving the anal transition zone, having lower complications, and having adequate pouch function. The single-stapled IPAA offers a more natural design, is feasible, and is associated with reasonable outcomes compared to double-stapled anastomosis. See video from symposium.

Using a standalone ear-EEG device for focal-onset seizure detection

BackgroundSeizure detection is challenging outside the clinical environment due to the lack of comfortable, reliable, and practical long-term neurophysiological monitoring devices. We developed a novel, discreet, unobstructive in-ear sensing system that enables long-term electroencephalography (EEG) recording. This is the first study we are aware of that systematically compares the seizure detection utility of in-ear EEG with that of simultaneously recorded intracranial EEG. In addition, we present a similar comparison between simultaneously recorded in-ear EEG and scalp EEG.MethodsIn this foundational research, we conducted a clinical feasibility study and validated the ability of the ear-EEG system to capture focal-onset seizures against 1255 hrs of simultaneous ear-EEG data along with scalp or intracranial EEG in 20 patients with refractory focal epilepsy (11 with scalp EEG, 8 with intracranial EEG, and 1 with both).ResultsIn a blinded, independent review of the ear-EEG signals, two epileptologists were able to detect 86.4% of the seizures that were subsequently identified using the clinical gold standard EEG modalities, with a false detection rate of 0.1 per day, well below what has been reported for ambulatory monitoring. The few seizures not detected on the ear-EEG signals emanated from deep within the mesial temporal lobe or extra-temporally and remained very focal, without significant propagation. Following multiple sessions of recording for a median continuous wear time of 13 hrs, patients reported a high degree of tolerance for the device, with only minor adverse events reported by the scalp EEG cohort.ConclusionsThese preliminary results demonstrate the potential of using ear-EEG to enable routine collection of complementary, prolonged, and remote neurophysiological evidence, which may permit real-time detection of paroxysmal events such as seizures and epileptiform discharges. This study suggests that the ear-EEG device may assist clinicians in making an epilepsy diagnosis, assessing treatment efficacy, and optimizing medication titration.

Solid State Machinery of Multiple Dynamic Elements in a Metal–Organic Framework

AbstractEngineering coordinated rotational motion in porous architectures enables the fabrication of molecular machines in solids. A flexible two‐fold interpenetrated pillared Metal‐Organic Framework precisely organizes fast mobile elements such as bicyclopentane (BCP) (107 Hz regime at 85 K), two distinct pyridyl rotors and E‐azo group involved in pedal‐like motion. Reciprocal sliding of the two sub‐networks, switched by chemical stimuli, modulated the sizes of the channels and finally the overall dynamical machinery. Actually, iodine‐vapor adsorption drives a dramatic structural rearrangement, displacing the two distinct subnets in a concerted piston‐like motion. Unconventionally, BCP mobility increases, exploring ultra‐fast dynamics (107 Hz) at temperatures as low as 44 K, while the pyridyl rotors diverge into a faster and slower dynamical regime by symmetry lowering. Indeed, one pillar ring gained greater rotary freedom as carried by the azo‐group in a crank‐like motion. A peculiar behavior was stimulated by pressurized CO2, which regulates BCP dynamics upon incremental site occupation. The rotary dynamics is intrinsically coupled to the framework flexibility as demonstrated by complementary experimental evidence (multinuclear solid‐state NMR down to very low temperatures, synchrotron radiation XRD, gas sorption) and computational modelling, which helps elucidate the highly sophisticated rotor‐structure interplay.

Solid State Machinery of Multiple Dynamic Elements in a Metal-Organic Framework.

Engineering coordinated rotational motion in porous architectures enables the fabrication of molecular machines in solids. A flexible two-fold interpenetrated pillared Metal-Organic Framework precisely organizes fast mobile elements such as bicyclopentane (BCP) (107 Hz regime at 85 K), two distinct pyridyl rotors and E-azo group involved in pedal-like motion. Reciprocal sliding of the two sub-networks, switched by chemical stimuli, modulated the sizes of the channels and finally the overall dynamical machinery. Actually, iodine-vapor adsorption drives a dramatic structural rearrangement, displacing the two distinct subnets in a concerted piston-like motion. Unconventionally, BCP mobility increases, exploring ultra-fast dynamics (107 Hz) at temperatures as low as 44 K, while the pyridyl rotors diverge into a faster and slower dynamical regime by symmetry lowering. Indeed, one pillar ring gained greater rotary freedom as carried by the azo-group in a crank-like motion. A peculiar behavior was stimulated by pressurized CO2, which regulates BCP dynamics upon incremental site occupation. The rotary dynamics is intrinsically coupled to the framework flexibility as demonstrated by complementary experimental evidence (multinuclear solid-state NMR down to very low temperatures, synchrotron radiation XRD, gas sorption) and computational modelling, which helps elucidate the highly sophisticated rotor-structure interplay.

Structure-primed embedding on the transcription factor manifold enables transparent model architectures for gene regulatory network and latent activity inference

BackgroundModeling of gene regulatory networks (GRNs) is limited due to a lack of direct measurements of genome-wide transcription factor activity (TFA) making it difficult to separate covariance and regulatory interactions. Inference of regulatory interactions and TFA requires aggregation of complementary evidence. Estimating TFA explicitly is problematic as it disconnects GRN inference and TFA estimation and is unable to account for, for example, contextual transcription factor-transcription factor interactions, and other higher order features. Deep-learning offers a potential solution, as it can model complex interactions and higher-order latent features, although does not provide interpretable models and latent features.ResultsWe propose a novel autoencoder-based framework, StrUcture Primed Inference of Regulation using latent Factor ACTivity (SupirFactor) for modeling, and a metric, explained relative variance (ERV), for interpretation of GRNs. We evaluate SupirFactor with ERV in a wide set of contexts. Compared to current state-of-the-art GRN inference methods, SupirFactor performs favorably. We evaluate latent feature activity as an estimate of TFA and biological function in S. cerevisiae as well as in peripheral blood mononuclear cells (PBMC).ConclusionHere we present a framework for structure-primed inference and interpretation of GRNs, SupirFactor, demonstrating interpretability using ERV in multiple biological and experimental settings. SupirFactor enables TFA estimation and pathway analysis using latent factor activity, demonstrated here on two large-scale single-cell datasets, modeling S. cerevisiae and PBMC. We find that the SupirFactor model facilitates biological analysis acquiring novel functional and regulatory insight.

Modelling Alzheimer's disease in a dish: dissecting amyloid-β metabolism in human neurons.

This scientific commentary refers to 'Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-β deposition' by Rowland et al. (https://doi.org/10.1042/NS20230016). Insulin-degrading enzyme (IDE) and neprilysin (NEP) have been proposed as two Aβ-degrading enzymes supported by human genetics and in vivo data. Rowland et al. provide complementary evidence of a key role for IDE in Aβ metabolism in human-induced pluripotent stem cell (iPSC)-derived cortical neurons.