The slow code is a complex and ethically sensitive phenomenon in cardiopulmonary resuscitation (CPR), referring to a deliberately partial or delayed resuscitation attempt in patients with poor prognosis or terminal conditions. Although it is recognized in clinical practice, the concept remains ambiguous and ethically controversial. Clarifying its defining attributes, antecedents, and consequences is essential for ensuring ethical and responsible end-of-life decision-making in healthcare. This study applied Walker and Avant's (2019) concept analysis method to clarify the concept of slow code in CPR. A comprehensive literature review was performed using PubMed, Scopus, Web of Science, CINAHL, ProQuest, and SID databases. The search covered studies published up to 2025 in both English and Persian. The following keywords and their combinations were used with Boolean operators AND and OR: slow code, symbolic resuscitation, code status, do not resuscitate, end-of-life decision-making, nursing ethics, and CPR ethics. Relevant literature was screened and analyzed to identify defining attributes, antecedents, and consequences of the concept. The analysis revealed that the slow code represents a symbolic and ethically complex clinical act, performed when resuscitation is deemed clinically futile but ethical, cultural, or familial expectations pressure healthcare teams to act. Defining attributes include partial or intentionally delayed resuscitation, symbolic compliance with clinical or institutional norms, and an underlying intent to reconcile professional ethics with contextual constraints. Antecedents include patient-related factors (terminal illness, poor prognosis, low probability of return of spontaneous circulation), team-related factors (moral distress, perception of futility, prior ethical conflict), and organizational factors (absence of DNR policies, ambiguous end-of-life care guidelines, hierarchical team culture, and time pressure). Consequences include prolonged patient suffering, family misunderstanding or loss of trust, moral distress and emotional burden among healthcare providers, and organizational ethical dilemmas. However, transparent management guided by ethical frameworks can facilitate constructive discussions about end-of-life care, improve communication with families, and inform institutional policy development. This concept analysis clarifies slow code as a distinct yet ethically controversial phenomenon characterized by intentionally limited or symbolic resuscitation despite perceived medical futility. Clarifying this concept does not endorse its clinical use; rather, it provides a clearer conceptual framework for distinguishing slow code from related end-of-life practices, supporting ethical education, informing institutional policies, and guiding future empirical research. The findings further highlight the importance of advance care planning, transparent communication, and documented do-not-resuscitate (DNR) decisions as ethically appropriate alternatives to slow code in end-of-life care.
Cultivated peatlands are a major CO2 emission source, but the processes that regulate the decomposition of drained peat are debated, especially as drained peat becomes increasingly shallow. Many cultivated peatlands are underlain by a mineral soil layer. Surface subsidence, oxidation and tillage reduce the peat thickness, which intermixes peat with minerals as peat is lost. A key question is whether this mixing can reduce emissions by making soil organic carbon (SOC) more stable by transforming particulate organic carbon (POC)-which dominates the carbon stock in deep drained peatlands and is readily accessible to microbial decomposers-into mineral-associated organic carbon (MAOC), which is less accessible to decomposers. To explore this question, we surveyed ten sites across the East Anglian Fens in England, a once extensive (~3900 km2) peatland landscape that has been drained for cultivation since the mid-seventeenth century. We used variation in cultivation to establish a peat loss gradient to evaluate how topsoil SOC (0-40 cm) and its forms change as peat is lost. As the peat was lost, the soils became rich in minerals (rising from 46% to 88% silt+clay content), resulting in an initial 11-fold rise in newly-formed MAOC, but a monotonic decline and near-total loss of POC. POC turnover times were 3158 ± 62 years, indicative of peat, and POC was always older than MAOC; consequently, microbially-processed peat along with gradual contributions of recently fixed carbon were sources of MAOC. A four-month laboratory incubation showed that the MAOC:POC ratio was negatively correlated with respiration. We conclude that long-term carbon retention via MAOC formation has the potential to reduce carbon loss from degraded, mineral-mixed peatlands. However, because this MAOC pool is itself vulnerable to loss under continued agricultural drainage, this mechanism is expected to slow rather than halt long-term soil carbon loss from drained peatlands.
We describe a novel slow oscillation in intracellular recordings from cortical association areas 5 and 7, motor areas 4 and 6, and visual areas 17 and 18 of cats under various anesthetics. The recorded neurons (n = 254) were antidromically and orthodromically identified as corticothalamic or callosal elements receiving projections from appropriate thalamic nuclei as well as from homotopic foci in the contralateral cortex. Two major types of cells were recorded: regular-spiking (mainly slow-adapting, but also fast-adapting) neurons and intrinsically bursting cells. A group of slowly oscillating neurons (n = 21) were intracellularly stained and found to be pyramidal-shaped cells in layers III-VI, with luxuriant basal dendritic arbors. The slow rhythm appeared in 88% of recorded neurons. It consisted of slow depolarizing envelopes (lasting for 0.8-1.5 sec) with superimposed full action potentials or presumed dendritic spikes, followed by long-lasting hyperpolarizations. Such sequences recurred rhythmically at less than 1 Hz, with a prevailing oscillation between 0.3 and 0.4 Hz in 67% of urethane-anesthetized animals. While in most neurons (approximately 70%) the repetitive spikes superimposed on the slow depolarization were completely blocked by slight DC hyperpolarization, 30% of cells were found to display relatively small (3-12 mV), rapid, all-or-none potentials after obliteration of full action potentials. These fast spikes were suppressed in an all-or-none fashion at Vm more negative than -90 mV. The depolarizing envelope of the slow rhythm was reduced or suppressed at a Vm of -90 to -100 mV and its duration was greatly reduced by administration of the NMDA blocker ketamine. In keeping with this action, most (56%) neurons recorded in animals under ketamine and nitrous oxide or ketamine and xylazine anesthesia displayed the slow oscillation at higher frequencies (0.6-1 Hz) than under urethane anesthesia (0.3-0.4 Hz). In 18% of the oscillating cells, the slow rhythm mainly consisted of repetitive (15-30 Hz), relatively short-lasting (15-25 msec) IPSPs that could be revealed by bringing the Vm at more positive values than -70 mV. The long-lasting (approximately 1 sec) hyperpolarizing phase of the slow oscillation was best observed at the resting Vm and was reduced at about -100 mV. Simultaneous recording of another cell across the membrane demonstrated synchronous inhibitory periods in both neurons. Intracellular diffusion of Cl- or Cs+ reduced the amplitude and/or duration of cyclic long-lasting hyperpolaryzations.(ABSTRACT TRUNCATED AT 400 WORDS)
Proton gradients power diverse biological processes, yet how interfacial proton migration is regulated remains unclear. Here we quantify how membrane composition controls interfacial proton migration using an approach that releases protons directly at the surface of a membrane patch via an embedded ionophore. Fluorometrically monitoring proton arrival at a distant patch across neutral, negatively charged, and positively charged membranes, we confirm that both the lateral surface diffusion coefficient and the activation barrier for proton release into the bulk vary rather modestly. In contrast to membrane electrostatics, membrane incorporation of glycolipids typical of thylakoid membranes-digalactosyldiacylglycerol and sulfoquinovosyldiacylglycerol-leads to a more pronounced reduction of the lateral proton diffusion coefficient, with comparatively small effects on the surface-to-bulk release barrier. Thus, interfacial proton migration is governed primarily by hydration-layer properties rather than membrane charge. These results establish membrane-anchored sugars as potent modulators of long-range proton conduction and provide a mechanistic framework for localized proton coupling in glycolipid-rich biological membranes.
Present concepts around the neurophysiology of delirium suggest impairments in excitatory/inhibitory balance, leading to EEG slowing, altered synaptic activity and integration of information. We aim to clarify the mechanisms involved, hypothesising that, in postoperative delirium, the EEG peak alpha frequency (PAF; decreased peak frequency indicating slowing in alpha frequency) would slow and the spectral exponent (SE; a higher slope indicating an increased neural inhibitory tone) would be steeper compared with a baseline collected before surgery. The primary aim was to determine the association of PAF and SE with postoperative delirium. The secondary aim was to determine the association of perioperative changes in inflammation and executive function with PAF and SE. High-density 256-channel EEG data were collected perioperatively (i.e. obtained pre-, post-, after 1-yr post-surgery) in a cohort study of 202 patients aged >65 yr undergoing major surgery conducted from 2015 to 2025 at a major quaternary care hospital. Thirty-three participants experienced postoperative delirium, 169 participants did not, with 113 participants followed up at the 1-yr interval. Linear mixed-effects modelling was conducted for PAF and SE estimates. Further analyses tested associations of PAF and SE with the Delirium Rating Scale, Trail Making Test-B (TMT-B) and plasma cytokine levels. After surgery, mean PAF was significantly slower and mean SE was significantly steeper compared with preoperative and 1-yr postoperative values (P<0.0001). These changes were larger in the delirium compared with the non-delirium group (P<0.05 to P<0.001). After surgery, PAF and SE estimates were significantly associated with delirium severity scores. Decreases in PAF or SE estimates (pre to post) were significantly associated with increases in TMT-B time and cytokine levels (reflecting worsening cognitive performance and increases in inflammation levels, respectively). Lower mean PAF and steeper SE are consistent with slower neuronal repolarisation and increased inhibition in delirium. PAF and SE estimates provide new information about delirium pathophysiology and could be further explored as noninvasive EEG biomarkers of detection and monitoring of delirium state.
To investigate the key genes and inflammatory signaling pathways involved in the pathogenesis of ventilator-induced diaphragmatic dysfunction (VIDD) in rats, with the aim of identifying potential therapeutic targets. Adult male Wistar rats were randomly assigned to a control (0 h) group, a 6-hour controlled mechanical ventilation (CMV 6 h) group, and a 12-hour controlled mechanical ventilation (CMV 12 h) group, with 3 rats in each group. After model establishment, diaphragmatic tissues were collected for hematoxylin-eosin (HE) staining, immunohistochemical staining, and RNA extraction. HE staining was used to assess pathological changes and quantify myofiber cross-sectional area (CSA); immunohistochemistry was employed to detect the expression of slow (MHCslow) and fast (MHCfast) myosin heavy chain isoforms and quantify the percentage of positive area per field of view; and transcriptome sequencing (RNA-Seq) was utilized to analyze mRNA expression changes across groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to determine the biological functions and pathways associated with significant differentially expressed genes (DEGs). HE staining revealed diaphragmatic muscle fiber atrophy in both the CMV 6 h and 12 h groups, accompanied by varying degrees of inflammatory cell infiltration. Quantitative analysis showed that myofiber CSA was significantly reduced in the CMV 6 h group (P < 0.05) and further reduced in the CMV 12 h group (P < 0.01) compared with the control group.Immunohistochemical analysis showed no statistically significant difference in MHCslow and MHCfast expression in the CMV 6 h group compared to the control group (P > 0.05), whereas the percentage of positive area for both MHCslow and MHCfast was significantly reduced in the CMV 12 h group (P < 0.05). RNA-Seq identified 2,048 DEGs in the CMV 6 h group (321 upregulated and 1,727 downregulated) (P < 0.05) and 1,495 DEGs in the CMV 12 h group (534 upregulated and 961 downregulated) (P < 0.05). GO analysis revealed that the CMV 6 h group comprised 1,310 DEGs related to molecular functions (n = 262), cellular components (n = 179), and biological processes (n = 869) (P < 0.05). The CMV 12 h group comprised 1,017 DEGs related to molecular functions (n = 185), cellular components (n = 149), and biological processes (n = 683) (P < 0.05). KEGG pathway analysis showed that the top 20 significantly enriched pathways in the CMV 6 h and 12 h groups included inflammatory responses, aldosterone synthesis and secretion, oxytocin signaling pathways, ECM-receptor interaction, and insulin signaling pathways (P < 0.05). The most significantly enriched pathways known to play important roles in inflammatory responses included MAPK, PI3K-Akt, and Calcium signaling pathways, with key genes in these pathways screened and validated using RT-qPCR. MAPK, PI3K-Akt, and Calcium signaling pathways, along with their associated genes, are associated with diaphragmatic structural damage and inflammatory responses in VIDD in rats, warranting further investigation into their potential roles in dysfunction.
Alzheimer's disease (AD) is a leading cause of death worldwide, with growing prevalence as life expectancy increases. An important neurological hallmark of AD is the deposition of extracellular neuritic amyloid-β (Aβ) plaques that can disrupt synaptic transmission and cause neuronal death. More recent studies suggest that targeting Aβ species can slow the progression of cognitive decline in AD. This narrative review examines the efficacy of monoclonal antibodies targeting the amyloid-β (Aβ) protein in the treatment of AD. It discusses the mechanisms by which these antibodies aim to mitigate amyloid pathology and explores their clinical outcomes in various trials. The review highlights the importance of amyloid plaque reduction to less than 25 Centiloids observed through amyloid positron emission tomography (PET) scans as a predictor of slowing cognitive decline. The findings suggest that targeting insoluble amyloid plaques is crucial for achieving clinical benefits in AD treatment. This review also discusses the phenomenon of amyloid-related imaging abnormalities (ARIA) that may be associated with monoclonal antibody therapy. Monoclonal antibodies that target Aβ monomers, soluble oligomers and protofibrils, and insoluble fibrils/plaques were developed, and not all have provided clinical benefit. Emerging evidence suggests that it is important to reduce amyloid plaque burden to less than 25 Centiloids, consistent with a visually negative amyloid PET scan, in order to slow cognitive decline in early symptomatic AD.
Wheat is a major global food crop, and the content of essential minerals and toxic elements in the grains is crucial for human nutrition and health. However, their accumulation dynamics across developmental stages and their allocation mechanisms during grain filling remain poorly understood. Here, we systematically investigated the accumulation of essential minerals and toxic elements in field-grown wheat throughout its growth cycle and integrated source contribution analysis with temporal grain transcriptomics during grain filling. Shoot accumulation of Fe, Mn, Cu, Zn, and Cd followed a characteristic slow-fast-slow pattern, peaking at the jointing stage. Element allocation strategies were strongly influenced by phloem mobility: Cu and Zn were primarily remobilized from vegetative organs (>55% contribution), whereas Fe, Mn, and Cd were mainly derived from direct root uptake (>70%). During grain filling, ten elements exhibited three distinct temporal patterns: early accumulation (Ca), mid-phase accumulation (Mg, S, P, K, Mn, Cu, Zn, Cd) synchronized with dry matter, and continuous accumulation (Fe). Organ-level analysis further indicated that the flag leaf and node I acted primarily as transfer and regulatory hubs rather than major direct sources for grain loading. Temporal transcriptomic analysis of developing grains identified early and sustained gene expression patterns corresponding to these phased accumulation dynamics, suggesting stage-specific regulation of element import, redistribution, buffering, and deposition. Together, these results support a two-level interpretation of wheat grain mineral accumulation under the field conditions examined, in which whole-plant source dynamics interact with grain-associated handling processes. This study provides a mechanistically informed insights that may guide future efforts to improve grain mineral nutrition and reduce Cd accumulation through integrated breeding and agronomic strategies.
The United States Environmental Protection Agency (USEPA) established regulatory frameworks (Pre-Tier 2, Tier 2, and Tier 3) to address vehicle emissions. Simultaneously, a technological shift from port fuel injection (PFI) to gasoline direct injection (GDI) engines (began in 2007), has been underway. GDI has greater fuel efficiency, but potentially produces more secondary organic aerosol (SOA) under Tier 2 emissions than Tier 3. This study examined light-duty vehicle fleet transitions in New York State from 2013-2025, specifically the shift between engine technology and fleet turnover across emission tiers. Registration data from the New York State Department of Motor Vehicles were analyzed and vehicles classified into Pre-Tier 2, Tier 2, and Tier 3 based on Model Year, Vehicle Identification Number (VIN), and regulatory phase-in schedules. Manufacturer-reported statistics and VIN were used to categorize vehicles. New vehicles sold after 2007 had to meet Tier 2 standards, but only 53% of the total fleet were Tier 2 vehicles in 2013 suggesting lag time in fleet-wide penetration. Similarly, penetration of Tier 3 vehicles (introduced in 2017) was slower than expected. By 2025 only 36% of the fleet consisted of Tier 3 vehicles, and ~6% were plug-in electric or hybrid vehicles. Meanwhile, GDI technology adoption increased rapidly and grew from 5% in 2013 to 36% in 2025. The slow fleet turnover highlights substantial lag between regulatory implementation and fleet composition changes. This lag resulted in continuing higher emissions and SOA formation indicating that air quality benefits from Tier 3 implementation will take longer to be realized.
We propose a Multiscale Deep Reservoir Computing (MSDRC) framework for predicting complex nonlinear dynamical systems. The framework incorporates a k-hop information propagation mechanism into deep reservoir architectures, aligning multi-hop state interactions with the hierarchical organization of sub-reservoirs to represent system dynamics across multiple temporal scales. Based on this principle, four MSDRC-based reservoir computer variants-deepMSFESN, deepMSBESN, groupedMSESN, and deepMSESN-are developed to achieve hierarchical multiscale feature fusion. Experiments on the Hindmarsh-Rose and Lorenz-63 systems demonstrate that MSDRC achieves higher predictive accuracy, robustness, and generalization under different initial conditions than standard and deep reservoir computing models. Parameter analyses further indicate that sparse reservoirs can still generate rich dynamics, while increasing reservoir size yields diminishing but consistent improvements in prediction performance. DeepESNs and MSDRC also outperform standard ESN and simple cycle reservoir models under varying slow timescale parameters, with MSDRC maintaining lower prediction errors and modest improvements by more effectively capturing the coupling between fast and slow dynamics. The sampling interval plays a critical role: smaller intervals improve predictive accuracy but require more steps to reach the same prediction time, thereby amplifying error accumulation in closed-loop operation. In contrast, larger intervals reduce temporal resolution and fail to capture system dynamics, revealing an inherent trade-off. Overall, MSDRC provides an effective and structurally interpretable multiscale framework for chaotic time series prediction and offers new insights into multiscale information fusion in reservoir computing.
Breastfeeding is recommended as the ideal nutrient source for infants, with the benefit of reducing future metabolic risk. Rapid catch-up growth in infancy has been associated with increased later adiposity and cardiometabolic risk. Few studies have evaluated growth and feeding patterns in Japanese infants. This study aimed to clarify growth and feeding patterns in Japanese infants. Participants were children enrolled in the Japan Environment and Children's Study cohort. Height, weight, and body mass index (BMI) at 3-4 and 8-12 mo, and 1, 1.5, 2, 2.5, and 3 yr were compared between three feeding patterns at 6 mo: breast-, formula-, and combination-feeding. The breast-, combination-, and formula-feeding groups comprised 19,987, 8,804, and 5,071 infants, respectively. In the combination-feeding group, measured indices at 3-4 mo were lower than in the breastfeeding group (p < 0.0001), although combination-fed infants showed catch-up growth from 8-12 mo to 1 yr (p < 0.05). Breastfed infants showed rapid growth and high BMI from birth to 3-4 mo, and slow growth and low BMI after 8-12 mo. Combination- and formula-fed infants showed slow growth in early infancy then rapid growth. Catch-up pattern observed in combination- and formula-fed infants warrants growth monitoring and access to individualized feeding support.
Bead-spring systems in spatially periodic potentials, such as the Frenkel-Kontorova model, exhibit complex behavior due to the interplay of elastic spring energies and external potentials. Here, we study the one-dimensional diffusion of a trimer, three beads connected by springs. In our system, all beads feel a sinusoidal external potential, but with different amplitudes. Using Langevin dynamics simulations and analytical expressions in limiting cases, we show that the diffusion constant of this system exhibits non-monotonic behavior, depending on the spring stiffness. The elastic coupling of the springs can slow down diffusion by anchoring faster beads to slower ones or accelerate it by annihilating potential barriers of different signs.
The aging population presents both opportunities and challenges. Both global and Malaysian statistics have shown that an increase in longevity is also marked by an increase in the time spent in poor health. A key measure of healthy aging is the ability to lead an independent life. This has implications not only for the individual's quality of life but also for society as a whole; loss of independence with age is associated with increased economic burden and reduced workforce productivity. Understanding and subsequently addressing these age-related declines (slowing or reversing them) is critical in improving the health and societal challenges faced by older adults. However, most studies are focused on Western populations. The scarcity of interventions tailored to multiethnic Asian populations is compounded by the fact that existing measurements rely heavily on Western-designed psychometric instruments, which frequently fail in capturing true cognitive health because of large cultural and educational gaps. We aim to examine whether our long-term intervention packages can, over 4 years, significantly slow down the normal rate of aging-related decline in cognitive function and brain structure and function, as well as assess changes in aging-related salivary biomarkers. We will also measure the economic impact of such interventions in a cost-benefit analysis. We propose 3 ecologically valid intervention packages (cognitive stimulation, physical activity, or both combined) and aim to assess them against a control group. We will target a sample of 400 participants as representative of the population of community-dwelling aging citizens in Malaysia (aged 60 years and older). The 5 projects of this study examined (1) psychology (social interaction and emotional well-being); (2) neuroscience, looking at neural markers of cognition (magnetic resonance imaging and electroencephalogram); (3) decision-making (risk and challenges in decision making); (4) economics (cost-benefits and effectiveness of the study interventions); and (5) biological markers of aging, using salivary samples. The Sunway University Institutional Review Board has reviewed and approved the study (SUREC2020/039). Briefly, primary outcomes will include changes in cognitive scores (Montreal Cognitive Assessment), changes in cognitive behavioral measurements, changes in electroencephalogram and structural magnetic resonance imaging, changes in everyday problem-solving and Iowa gambling task scores, changes in salivary biomarkers (lactoferrin, C-reactive protein, and telomere length), and cost-benefit analysis of the intervention. The study grant was awarded in August 2019, with recruitment starting in May 2022 and concluding in July 2023. In 2023, the intervention phase began and is currently ongoing, with the first publications of outcomes expected in 2026. The effectiveness of these interventions will be examined from the perspective of multiple disciplines, including psychology, neuroscience, biology, and economics. We anticipate that the results of our study will be of interest to both the academic and general community and will hopefully influence policymaking. We hope that this study will provide robust and impactful, evidence-based insights on healthy aging and, thus, contribute to improving the overall quality of life associated with aging. ClinicalTrials.gov NCT06376656; https://clinicaltrials.gov/study/NCT06376656. DERR1-10.2196/88268.
A stepwise "LEGO®-brick" strategy has been employed for the targeted assembly of rare low-nuclearity MnIII/LnIII clusters from preformed molecular building units. The mononuclear MnIII metalloligand (Pr2NH2)[MnIII(sacb)2] (1; sacbH2 = N-salicylidene-2-amino-5-chlorobenzoic acid) was combined with newly isolated dinuclear lanthanide complexes [Ln2(sacb)(sacbH)3L(MeOH)] [LnIII = Dy (2), Gd (3); L- = 2-amino-5-chlorobenzoate], affording the trinuclear heterometallic compounds [MnIIILn2(sacb)3(sacbH)2L] [LnIII = Dy (4), Gd (5)]. Single-crystal X-ray diffraction studies revealed that 4 and 5 possess triangular {MnIIILn2(μ-O2CR)3}6+ cores, representing the first structurally characterized triangular {MnIIILn2} complexes and rare examples of triangular {MLn2} (M = any 3d-metal ion) clusters. Magnetic studies have demonstrated that the MnIII-free {Dy2} precursor 2 displays weak field-induced slow relaxation of magnetization, whereas incorporation of the Jahn-Teller active MnIII ion leads to ferromagnetically coupled {MnIIILn2} species. In particular, the {MnIIIGd2} analogue 5 exhibits a high-spin ground state of S = 9, with weak ferromagnetic MnIII⋯GdIII and GdIII⋯GdIII exchange interactions. Although no slow magnetic relaxation was observed for the trinuclear complexes, the results demonstrate that controlled integration of a MnIII metalloligand can promote ferromagnetic exchange in preassembled {Ln2} units and provide a direct route to structurally defined high-spin 3d/4f triangles.
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.
This review examines the key pathways of bidirectional communication between the gut and brain along the microbiota-gut-brain axis, with particular emphasis on the effects of metabolites of lactic acid bacteria (metLABs) on neurons of the enteric and central nervous systems. Special attention is given to the role of metLABs in intracellular signaling. The review further explores the direct effects of metLABs on mitochondrial function in nervous tissue, neuronal plasticity, and neuritogenesis. Potential mechanisms for the release of neurotrophic factors in both cells and host organism following exposure to metLABs or probiotic products are analyzed. Although clinical evidence remains limited, existing studies suggest that regular consumption of metLAB-containing fermented foods may positively influence brain functions through modulation of the microbiota-gut-brain axis. At least two ongoing clinical trials currently investigate whether normalization of the gut microbiota through probiotic interventions can slow the progression of Alzheimer's disease. As this field continues to advance rapidly, further studies are expected to provide important insights into the therapeutic potential of microbiota-targeted strategies for neurological health.
Giant condyloma of Buschke-Loewenstein is a rare benign tumor characterized by viral etiology, slow growth, the ability to cause disfigurement of the affected areas and a certain potential for malignancy. The main treatment option for this disease is surgery. Our clinical case is dedicated to the successful surgical treatment of a 57-year-old patient, in whom giant condyloma of Buschke-Loewenstein of the penis developed over 10 years without malignant transformation.
Asteroid impact monitoring systems search for potential collisions of near-Earth objects (NEOs) with the Earth over 100 years. A necessary condition for an impact is the intersection between the orbit of the asteroid and the orbit of the Earth. This condition is measured by the Minimum Orbit Intersection Distance (MOID), which can be computed reliably for longer periods of time to identify when an Earth impact is possible. As the orbit is propagated into the future, the uncertainty in position grows faster than the uncertainty in the MOID. If the MOID is low but the position along the orbit is unknown, we compute an analytical approximation of the frequency of close encounters for a given distance. The NEO population spreads widely in orbital uncertainty, which we consider by propagating multiple samples from the initial orbital uncertainty distribution. We demonstrate and validate the methodology for 99942 Apophis, whose MOID is secularly increasing at a slow rate that still allows for future deep encounters. We apply this methodology to the NEO population, and for a large fraction we rule out the crossing of Earth's orbit in the next 1000 years. Otherwise, we rank NEOs in terms of how long their MOID will be low, long-term frequency of close encounters, and frequency relative to the background close encounter frequency for objects of similar size. These rankings identify NEOs that should be prioritized for future tracking and orbit refinement.
Understanding the mechanism of isotope exchange between biomolecules and solvent molecules has very important implications in two areas of life sciences, namely, the studies of biomolecular dynamics using the exchange of labile atoms as a structural probe and the investigation of metabolic pathways using stable isotope-labeled (SIL) compounds. While the former has benefited greatly from the fast exchange of heteroatom-bound hydrogens with water molecules, several other elements have been shown to exhibit fast-to-moderate exchange kinetics with the solvent molecules, raising the hopes that they can also be used as structural probes in isotope exchange reactions. Conversely, significant isotope exchange between SIL compounds and the solvent molecules in metabolic studies would be highly detrimental vis-à-vis the reliability of quantitative (and in extreme cases also qualitative) aspects of such investigations. We use phosphatidylserine 16:0/16:0 (PS) as a model compound to probe catalyst-free oxygen exchange (16O/18O) with water in a site-specific fashion using tandem mass spectrometry (MS/MS) as a readout. All three oxygen-containing functionalities are targeted: the carboxylate end-group, the phosphate linker, and the fatty acids' acyl ester groups (nonbridging oxygen atoms). Oxygen exchange within both the carboxylic moiety and the acyl ester groups is slow under the physiologically relevant conditions but is dramatically accelerated in acidic media at elevated temperatures. In contrast, exchange of the oxygen atoms within the phosphate linker remains below the limit of detection under all conditions tested in this work. While these results may be viewed as disappointing vis-à-vis the prospects of using oxygen exchange to study phospholipid dynamics (e.g., to quantify PS localization on the outer membrane leaflet upon cell activation or apoptosis), they are both reassuring and helpful in the context of studies relying on stable isotopes as tracers of metabolic processes. Indeed, the uneven distribution of oxygen lability across three different functionalities, as well as the identification of conditions that result in oxygen exchange acceleration, will be invaluable for both designing the SIL compounds and selecting the sample-handling conditions that eliminate the possibility of "isotope leaching" in the studies of metabolic pathways.
Biomedical research is increasingly constrained by repetitive, fragmented workflows that slow discovery. We introduce Biomni, a general-purpose biomedical artificial intelligence agent that autonomously executes diverse research tasks. To map the biomedical action space, Biomni's action-discovery agent mines tools, databases, and protocols from thousands of publications across 25 domains, building a unified agentic environment. Its general-purpose architecture integrates large language model reasoning with retrieval-augmented planning and code-based execution, dynamically composing workflows without predefined templates. Systematic benchmarking shows strong generalization across heterogeneous tasks-causal gene prioritization, drug repurposing, rare-disease diagnosis, microbiome analysis, and molecular cloning-without task-specific tuning. Real-world case studies demonstrate Biomni interpreting multi-modal datasets, optimizing protein stability, orchestrating wet-lab instruments, and generating experimentally testable protocols. Biomni envisions artificial intelligence augmenting human scientists and accelerating discovery.