Common Pathway Research Articles

Boosting Effect of Sterically Protected Glucosyl Substituents in Formic Acid Dehydrogenation by Iridium(III) 2-Pyridineamidate Catalysts.

[Cp*Ir(R-pica)Cl] (Cp* = pentamethylcyclopentadienyl anion, pica = 2-picolineamide) complexes bearing carbohydrate substituents on the amide nitrogen atom (R = methyl-β-D-gluco-pyranosid-2-yl, 1; methyl-3,4,6-tri-O-acetyl-β-D-glucopyranosid-2-yl, 2) were tested as catalysts for formic acid dehydrogenation in water. TOFMAX values over 12000 h-1 and 50000 h-1 were achieved at 333 K for 1 and 2, respectively, with TON values over 35000 for both catalysts. Comparison with the simpler cyclohexyl-substituted analogue (3) indicated that glucosyl-based complexes are much better performing under the same experimental conditions (TOFMAX = 5144 h-1, TON = 5000 at pH 2.5 for 3) owing to a lower tendency to isomerize to the less active k2-N,O isomer upon protonation. The 5-fold increase in TOFMAX observed for 2 with respect to 1 is reasonably due to an optimal steric protection by the acetyl substituent, which may prevent unproductive inner-sphere reactivity. These results showcase a powerful strategy for the inhibition of the common deactivation pathways of [Cp*Ir(R-pica)X] catalysts for FA dehydrogenation, paving the way for the development of better performing hydrogen storage systems.

Novel homozygous frameshift insertion variant in the last exon of the EDARADD causing hypohidrotic ectodermal dysplasia in two siblings: case report and review of the literature

BackgroundHypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED.Case presentationFive-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature.ConclusionsIn this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.

Cough effectiveness during airway invasion in adults with oropharyngeal dysphagia: A systematic review of literature

BACKGROUND: Cough and swallowing share common neuroanatomic pathways, leading to an overlap between their mechanisms. Despite the widely recognised role of cough as an airway defence mechanism, empirical evidence supporting its effectiveness for airway clearance is lacking. OBJECTIVE: This review summarises and appraises available evidence regarding the effectiveness of cough in response to airway penetration and/or aspiration during videofluoroscopic swallow study (VFSS) or flexible endoscopic evaluation of swallowing (FEES) in adults with oropharyngeal dysphagia (OD) of any aetiology. METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines were followed. Literature search was conducted in March 2023 and updated in March 2024 across six databases without publication status, language, or date restrictions. Two independent reviewers performed screening, with disagreements resolved through consensus and majority vote. The principal investigator conducted data extraction and quality appraisal using the Downs and Black checklist. RESULTS: Of 6,049 studies retrieved, 25 met the eligibility criteria. Due to heterogeneous reporting, a summary of participant demographics could not be compiled. Absence of a standardised method for measuring cough effectiveness meant meta-analysis was impossible. Nonetheless, an effective cough response to penetration/aspiration was noted for some participants within 17 studies, ineffective cough responses for some within 17 studies, while one study reported a partially effective cough response for participants. CONCLUSIONS: Robust evidence on cough effectiveness is lacking due to study heterogeneity and inconsistent reporting. Developing a standardised tool to assess cough effectiveness would ensure consistency and comparability across studies, improving clinical reporting of VFSS and FEES outcomes.

Effect of carbon source on carbon and nitrogen metabolism of common heterotrophic nitrification-aerobic denitrification pathway

Pseudomonas sp. ZHL02, removing nitrogen via ammonia nitrogen (NH4+) → hydroxylamine (HN2OH) → nitrite (NO2−) → nitrate (NO3−) → NO2− → nitric oxide (NO) → nitrous oxide (N2O) pathway was employed for getting in-depth information on the heterotrophic nitrification-aerobic denitrification (HNAD) pathway from carbon oxidation, nitrogen conversion, electron transport process, enzyme activity, as well as gene expression while sodium succinate, sodium citrate, and sodium acetate were utilized as the carbon sources. The nitrogen balance analysis results demonstrated that ZHL02 mainly removed NH4+-N through assimilation. The carbon source metabolism resulted in the discrepancies in electron transport chain and nitrogen removal between different HNAD bacteria. Moreover, the prokaryotic strand-specific transcriptome method showed that, amo and hao were absent in ZHL02, and unknown genes may be involved in ZHL02 during the HNAD process. As a fascinating process for removing nitrogen, the HNAD process is still puzzling, and the relationship between carbon metabolism and nitrogen metabolism among different HNAD pathways should be studied further.

Peri-mortem arrhythmias in the non-cardiac intensive care unit.

Cardiovascular failure is recognized as a common final pathway at the end of life but there is a paucity of data describing terminal arrhythmias. We aimed to describe arrhythmias recorded peri-mortem in critically ill patients. We enrolled intensive care unit patients admitted to two tertiary Canadian medico-surgical centres. Participants wore a continuous electrocardiogram (ECG) monitor for 14 days, until discharge, removal or death. We recorded all significant occurrences of arrhythmias in the final hour of life. Among 39 patients wearing an ECG monitor at the time of death, 22 (56%) developed at least 1 terminal arrhythmia as adjudicated by an arrhythmia physician: 23% (n = 9) had ventricular fibrillation/polymorphic ventricular tachycardia, 18% (n = 7) had sinoatrial pauses, 15% (n = 6) had atrial fibrillation and 13% (n = 5) had high-degree atrioventricular block. Five participants (13%) developed multiple arrythmias. Arrhythmias are common in dying critically ill patients. There is a roughly even distribution between ventricular arrhythmias, atrial fibrillation, sinus node dysfunction and atrioventricular block. The results of this study may be most useful for critically ill patients who are organ donation candidates. The appearance of arrhythmias may serve as a marker of change in clinical status for organ donation teams to plan mobilization efforts. In participants who are sedated or intubated, arrhythmias could be a surrogate marker for respiratory or neurologic changes.

Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy.

Genomic studies of patient epithelioid sarcomas and rhabdoid tumors identify mutations converging on a common pathway for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell-cycle control. We identify an epigenetic combination strategy to overcome resistance and improve durability of response, supporting its investigation in clinical trials. See related commentary by Paolini and Souroullas, p. 903. This article is featured in Selected Articles from This Issue, p. 897.

Preliminary investigation and proposal of periodic orbits and their utilization for logistics in the cislunar regime

The world is in the midst of what is widely considered the second Space Age due to the vastly growing commercial space sector and progress with international initiatives such as the Artemis program, led by the National Aeronautics and Space Administration (NASA). Cislunar space is becoming a region of growing interest as nations, international organizations, and private corporations look to expand their presence and outreach. The planned development of space infrastructure, such as lunar habitats, mining operations, and other installations, is driving the need for studies regarding common orbital pathways to ensure logistical support for future cislunar missions. Along with common orbital pathways, comprehensive and internationally acknowledged space policy and doctrine is required to ensure the safety, stability, and peace of this new frontier of human endeavor. This study serves to address one of the mission sets that will come to shape the emerging economy of the wider Earth-Moon system, space logistics. Specifically, this study will discuss potential orbits for a cislunar space situational awareness network that would support a space traffic management service, along with three cislunar logistics missions: personnel and cargo transport, space tourism, and search and rescue. Characteristics considered for orbits include orbit stability, period, and the proximity to key nodes in cislunar space such as the Moon and Lagrange points. Using Circular Restricted Three-Body Problem (CR3BP) dynamics, fourteen sample cislunar periodic orbits are proposed to accomplish the cislunar missions discussed. This study adds to the limited work in the field of cislunar orbital design to generate novel orbits and apply them to logistical use cases. All missions, except tourism, feature a “touring” class of cislunar periodic orbits due to their unique geometries enabling them to traverse a wide range of cislunar space. Preliminary analysis indicates that all of the proposed orbits are classified as marginally unstable, and suggests that minimal propellant is required to maintain a space vehicle's intended cislunar trajectory. Finally, existing law, policy, and governance surrounding cislunar space logistics and operations is discussed specifically concerning space traffic management, transportation, and humans touring or being rescued from space. Special attention is given to both the ambiguity of the law and the limitations of current norms of behavior, patent and property concerns, and tense geopolitical situations that can further complicate peace. Overall, this study highlights the underdevelopment of current space law and policy with the ambiguity of present-day norms discussed.

Untargeted metabolomics revealed the mechanism of aucubin on glucocorticoid-induced osteoporosis in mice through modulating arachidonic acid metabolism

Glucocorticoid-induced osteoporosis (GIOP) represents the most prevalent form of secondary osteoporosis. Aucubin (AU), a principal active component found in traditional herbal medicines such as Eucommia ulmoides, has been demonstrated to enhance osteoblast differentiation. Nonetheless, the precise therapeutic effects of AU on GIOP and the complex underlying regulatory mechanisms warrant further investigation. We first established a GIOP model in female mice and then assessed the therapeutic effects of AU using micro-CT analysis, biomechanical testing, measurements of serum calcium (Ca) and phosphorus (P) levels, and histological analyses using Hematoxylin and Eosin (HE) and Masson staining. Subsequently, non-targeted metabolomics was employed in order to study the effects of AU on serum metabolites in GIOP mice. The levels of the factors related to these metabolites were quantified using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot analyses. Finally, the effects of AU on osteoblastic and osteoclastic differentiation were examined. We found that AU significantly ameliorated bone microarchitecture and strength in GIOP mice. It mitigated pathological damages such as impairment of trabecular bone structure and reduction in collagen fibers, while concurrently elevating serum levels of Ca and P. Non-targeted metabolomics revealed that Arachidonic acid (AA) metabolism serves as a common pathway between the control and GIOP groups, as well as between the high-dose AU (AUH) and GIOP groups. AU notably upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) and microsomal prostaglandin-E synthase 1 (PTGES) expression and downregulates prostaglandin-H2 D-isomerase (PTGDS) expression. Furthermore, AU treatment increased the expression of runt-related transcription factor 2 (Runx2) and transcription factor Sp7 (Osterix), enhanced serum alkaline phosphatase (ALP) activity, and reduced osteoclast expression. These results indicate that AU is a potential drug for treating GIOP, and its mechanism is related to regulating AA metabolism and promoting osteoblast differentiation. However, the key targets of AU in treating GIOP still need further exploration.

Unraveling the role of ubiquitin C-terminal hydrolase L1 in high grade serous ovarian cancer pathogenesis.

e15078 Background: High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies, due to the fact that the majority of patients are diagnosed at an advanced stage and eventually develop chemoresistant disease 12-18 months following completion of frontline therapy. Therefore, novel targeted therapies are urgently needed to combat chemoresistance and improve patient clinical outcomes. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that plays a vital role in protein homeostasis and is highly overexpressed in HGSOC. It was previously uncovered that targeting UCHL1 with small molecule inhibition reduced cell viability in a chemoresistant ovarian cancer cell line. Methods: Comparative-label free proteomic analysis was used to uncover significant changes in HGSOC cell line OVCAR8WT following treatment with UCHL1 small molecule inhibitor, LDN-5744 or corresponding DMSO control. Significant pathway changes were determined by KEGG analysis. Matched chemosensitive and resistant HGSOC cells PEA1 and PEA2 were treated in combination with LDN-5744 and carboplatin, with cell viability was determined by an MTS assay. Furthermore, western blot analysis was employed to compare common cell growth pathway changes as a result of UCHL1 inhibition in HGSOC cells. Results: Proteomic analysis revealed a significant (p<0.05) upregulation in methyl phosphate capping enzyme (MEPCE) (4.9-fold), asparagine synthetase (ASNS) (2.5-fold), Phosphoserine aminotransferase 1 (PSAT1) (1.7-fold), and downregulation in centrosomal protein 55 (CEP55) (-7.2-fold), These identified proteomic changes were confirmed by western blot. KEGG pathways analysis using all significantly (p<0.05) differentially expressed proteins showcased significant (p<0.05) enrichment in amino acid biosynthesis, and metabolism, and chemical carcinogenesis-reactive oxygen species. Chemoresistant PEA2 cells treated in combination with LDN-5744 and carboplatin demonstrated a 59% reduction in cell viability, significantly (p<0.001) lower than the 13% and 22%, that was observed from UCHL1 and carboplatin treatment alone, respectively. Conversely, PEA1, the chemosensitive counterpart to PEA2 demonstrated a significant (p<0.001) 37% increase in cell viability upon combinatorial treatment compared with carboplatin alone, indicating that UCHL1 inhibition rescues the cells from chemotherapy induced cell death. Finally, LDN-5744 treatment in PEA2 led to a reduction in levels of phospho-(p-)AKT, p-STAT3, and p-ERK, while conversely in PEA1 cells levels of these proteins were increase or unchanged. Conclusions: Our findings demonstrate that targeting UCHL1 results in prominent metabolic changes in HGSOC cells and that the efficacy of UCHL1 inhibition is heavily dependent upon platinum status. Overall, this study highlights UCHL1’s novel therapeutic role in the recurrent HGSOC.

Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

Disruption of common ocular developmental pathways in patient-derived optic vesicle models of microphthalmia

Genetic perturbations influencing early eye development can result in microphthalmia, anophthalmia, and coloboma (MAC). Over 100 genes are associated with MAC, but little is known about common disease mechanisms. In this study, we generated induced pluripotent stem cell (iPSC)-derived optic vesicles (OVs) from two unrelated microphthalmia patients and healthy controls. At day 20, 35, and 50, microphthalmia patient OV diameters were significantly smaller, recapitulating the "small eye" phenotype. RNA sequencing (RNA-seq) analysis revealed upregulation of apoptosis-initiating and extracellular matrix (ECM) genes at day 20 and 35. Western blot and immunohistochemistry revealed increased expression of lumican, nidogen, and collagen type IV, suggesting ECM overproduction. Increased apoptosis was observed in microphthalmia OVs with reduced phospho-histone 3 (pH3+) cells confirming decreased cell proliferation at day 35. Pharmacological inhibition of caspase-8 activity with Z-IETD-FMK decreased apoptosis in one patient model, highlighting a potential therapeutic approach. These data reveal shared pathophysiological mechanisms contributing to a microphthalmia phenotype.

Formation of long-period post-common envelope binaries

Context. It has been claimed for more than a decade that energies other than orbital and thermodynamic internal are required to explain post-common envelope (CE) binaries with sufficiently long orbital periods (≳1 d) hosting AFGK-type main-sequence stars (∼0.5 − 2.0 M⊙) paired with oxygen-neon white dwarfs (≳1.1 M⊙). This would imply a completely different energy budget during CE evolution for these post-CE binaries in comparison to the remaining systems hosting M dwarfs and/or less massive white dwarfs. Aims. In this first in a series of papers related to long-period post-CE binaries, we investigated whether extra energy is required to explain the currently known post-CE binaries with sufficiently long orbital periods consisting of oxygen-neon white dwarfs with AFGK-type main-sequence star companions. Methods. We carried out binary population simulations with the BSE code adopting empirically derived inter-correlated main-sequence binary distributions for the initial binary population and assuming that the only energy, in addition to orbital, that help to unbind the CE is thermal energy. We also searched for the formation pathways of the currently known systems from the zero-age main-sequence binary to their present-day observed properties. Results. Unlike what has been claimed for a long time, we show that all such post-CE binaries can be explained by assuming inefficient CE evolution, which is consistent with results achieved for the remaining post-CE binaries. There is therefore no need for an extra energy source. We also found that for CE efficiency close to 100%, post-CE binaries hosting oxygen-neon white dwarfs with orbital periods as long as one thousand days can be explained. For all known systems we found formation pathways consisting of CE evolution triggered when a highly evolved (i.e. when the envelope mass is comparable to the core mass), thermally pulsing, asymptotic giant branch star fills its Roche lobe at an orbital period of several thousand days. Due to the sufficiently low envelope mass and sufficiently long orbital period, the resulting post-CE orbital period can easily be several tens of days. Conclusions. We conclude that the known post-CE binaries with oxygen-neon white dwarfs and AFGK-type main-sequence stars can be explained without invoking any energy source other than orbital and thermal energy. Our results strengthen the idea that the most common formation pathway of the overall population of post-CE binaries hosting white dwarfs is through inefficient CE evolution.

New Insights on Mechanisms and Therapeutic Targets of Cerebral Edema.

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to bloodbrain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

Self-Reported Sleep Duration Is a Useful Tool to Predict Sarcopenia in Chilean Older Adults: Evidence from the ALEXANDROS Longitudinal Study.

Age-related sleep disorders share common pathways with sarcopenia. Prospective data from Latin American populations are scarce, and the association between sleep disorders and sarcopenia in Chileans remains unknown. Thus, we aimed to study the longitudinal association between sleep disorders and sarcopenia in a cohort study of 1116 community-dwelling Chilean older people ≥60 years old from the ALEXANDROS cohorts. After the exclusion criteria, 318 subjects were followed. Sociodemographic data, self-reported chronic diseases, sedentarism, sleep characteristics, anthropometric measurements, handgrip strength, and muscle performance were assessed. Results indicated that at baseline, the prevalence of sarcopenia was 24.10% without gender differences, and the prevalence of self-reported sleep problems was 23.3%, higher in women (26.46% versus 17.15% in men). The adjusted Cox regression models for sarcopenia showed an association between sarcopenia, sleep disorders (HR = 2.08, 95% IC 1.14-3.80), and long sleep duration (HR = 2.42, 95% IC 1.20-4.91). After 8.24 years of follow-up, there were 2.2 cases of sarcopenia per 100 person-years. This study demonstrates that sleep disorders are an independent risk factor for sarcopenia in Chilean older people. The identification of sleep disorders through self-reported data provides an opportunity for early identification of risk and cost-effective sarcopenia prevention.

Network pharmacology and transcriptomics analysis reveal the mechanism of BushenHuoxue formula attenuates premature ovarian failure via modulation PI3K/AKT pathway.

This study aims to analyze the active components and mechanism of Bushen Huoxue (BSHX) formula on the autoimmune premature ovarian insufficiency (POI) by combining network pharmacology and Transcriptomics. The active components and targets of BSHXF were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). POI-related targets were identified through Therapeutic Targets Database (TTD), DisGeNET and drugbank database. The Veen diagram was performed to obtain the action targets. The active compound-target network and Protein-Protein Interaction (PPI) network were built by using STRING database and Cytoscape software. Key targets and active compounds were further identified by topological analysis. Molecular docking shows that Kaempferol, Isorhamnetin and Anhydroicaritin have strong binding to AKT. Finally, a zp3-induced autoimmune ovarian function deficiency mouse model was used to explore the potential mechanism of POI. The potential pathways of BSHXF for the treatment of POI were identified by Transcriptomic analysis. PI3K-AKT and NF-kb pathways were the common pathways between network pharmacology and transcriptomics. Our results revealed that BSHXF could reduce the FSH expression levels and raise the E2, and AMH levels in the serum. Western bloting demonstrates that BSHXF could upregulate the expression of p-PI3K and p-AKT.

Tryptophan Promotes the Production of Xanthophyll Compounds in Yellow Abdominal Fat through HAAO.

Abdominal fat, which in the past was often regarded as waste and discarded, has in recent years been used as a fat source to produce meat by-products. Yellow abdominal fat has higher economic value. Therefore, improving the color of abdominal fat plays an important role in improving the appearance of meat products. This study aimed to identify the contributors and the regulatory network involved in the formation of yellow and white color in abdominal fat. We found that four xanthophyll compounds were significantly different in yellow and white abdominal fat chicken, including zeaxanthin, lutein, canthaxanthin, and β-cryptoxanthin. There were 551 different and 8 common metabolites significantly correlated with these 4 xanthophyll compounds. Similarly, a total of 54 common genes were identified in 4 common related pathways (Complement and coagulation cascades, Metabolic pathways, PPAR signaling pathway, Carbon metabolism) of the 8 common metabolites. The high expression of HAAO in the yellow abdominal fat group leads to the degradation of tryptophan and its intermediate 5-hydroxyindole, and subsequently to the formation of the four xanthophyll compounds. This process is also regulated by tyrosine, kynurenine 3-monooxygenase (KMO), homogentisate 1, 2-dioxygenase (HGD), etc. Together, these findings show the effect of tryptophan on abdominal fat color, as well as a negative regulatory effect of HAAO and 5-hydroxyindole on the production of xanthophyll compounds involved in abdominal fat coloration.

Adaptation in the spinal cord after stroke: Implications for restoring cortical control over the final common pathway.

Control of voluntary movement is predicated on integration between circuits in the brain and spinal cord. Although damage is often restricted to supraspinal or spinal circuits in cases of neurological injury, both spinal motor neurons and axons linking these cells to the cortical origins of descending motor commands begin showing changes soon after the brain is injured by stroke. The concept of 'transneuronal degeneration' is not new and has been documented in histological, imaging and electrophysiological studies dating back over a century. Taken together, evidence from these studies agrees more with a system attempting to survive rather than one passively surrendering to degeneration. There tends to be at least some preservation of fibres at the brainstem origin and along the spinal course of the descending white matter tracts, even in severe cases. Myelin-associated proteins are observed in the spinal cord years after stroke onset. Spinal motor neurons remain morphometrically unaltered. Skeletal muscle fibres once innervated by neurons that lose their source of trophic input receive collaterals from adjacent neurons, causing spinal motor units to consolidate and increase in size. Although some level of excitability within the distributed brain network mediating voluntary movement is needed to facilitate recovery, minimal structural connectivity between cortical and spinal motor neurons can support meaningful distal limb function. Restoring access to the final common pathway via the descending input that remains in the spinal cord therefore represents a viable target for directed plasticity, particularly in light of recent advances in rehabilitation medicine.

Emicizumab as a Promising Form of Therapy for Type A Hemophilia - A Review of Current Knowledge from Clinical Trials.

Hemophilia is a plasma bleeding disorder characterized by a deficiency of certain blood clotting factors. The most common forms of this disease, i.e., type A and type B, affect approximately 400,000 people worldwide. Without appropriate treatment ensuring the proper coagulation cascade, this disease may lead to serious disability. Minimizing patient discomfort is possible via replacement therapy, consisting of the substitution of a missing coagulation factor via intravenous administration. Frequent medication and the risk related to factor inhibitors are significant disadvantages, necessitating the improvement of current therapies or the development of novel ones. This review examines the humanized bispecific antibody Emicizumab which ensures hemostasis by mimicking the action of the coagulation factor VIII, a deficiency of which causes type A hemophilia. The paper outlines the topic and then summarizes available clinical trials on Emicizumab in type A hemophilia. Several interventional clinical trials have found Emicizumab to be effective in decreasing bleeding episodes and raising patient satisfaction among various hemophilia A populations. Current Emicizumab-related trials are forecast to be completed between 2024 and 2030, and in addition to congenital hemophilia A, the trials cover acquired hemophilia A and patients playing sports. Providing a more comprehensive understanding of Emicizumab may revolutionize the management of hemophilia type A and improve quality of life. Conclusively, Emicizumab is a gentler therapy owing to subcutaneous delivery and fewer injections, which reduces injection-site reactions and makes therapy less burdensome, ultimately decreasing hospital visits and indirect costs.

#1581 Anoctamin 3 inhibits gluconeogenesis and contributes to renal interstitial fibrosis through EZH2

Abstract Background and Aims Renal fibrosis is the common pathological pathway of various chronic kidney diseases progressing to the end stage of renal failure. Anoctamin 3 (ANO3) has been identified as a K-channel regulator and been extensively studied in the field of neurobiology. The role of ANO3 in kidney diseases is currently unknown. Method Mouse models of renal fibrosis were established by unilateral ureteral obstruction (UUO) operation or aristolochic acid I (AAI) injection. Human proximal tubular cell line (HK2) was used as an in vitro model. ANO3 was deleted in vitro by siRNA. Western blotting analysis was performed. Glucogenic metabolites were measured. Results We found that ANO3 is upregulated in mouse kidneys with unilateral ureteral obstruction (UUO) or aristolochic acid nephropathy (AAN), and tightly correlated with the progression of renal fibrosis and negatively correlated with expression of several rate-limiting enzymes of renal gluconeogenesis. Knockdown of ANO3 with siRNA increased the concentration of glucose and reduced the concentration of lactate in the supernatant of TGF-β stimulated renal proximal tubular (HK2) cells. In parallel, transfection of ANO3 siRNA significantly reduced the expression of epithelial-to-mesenchymal transition (EMT) and fibrotic markers in TGF-β stimulated HK2 cells. We further showed that ANO3 expression is positively correlated with the expression of a methyltransferase enhancer of zeste homologue 2 (EZH2) in UUO and AAN mouse kidneys by time. Transfection of ANO3 siRNA significantly reduced the expression of EZH2 in TGF-β stimulated HK2 cells. Overexpression of EZH2 by adenovirus reversed the pro-gluconeogenic and anti-fibrotic effect of ANO3 siRNA in TGF-β stimulated HK2 cells by measuring the concentration of glucose and lactate in supernatant and analyzing the expression of EMT or fibrotic markers. Conclusion In conclusion, ANO3 inhibits renal gluconeogenesis through EZH2 and contributes to renal fibrosis. ANO3 could be promising therapeutic target to inhibit renal fibrosis in chronic kidney disease patients.

Heavy metal exposure and metabolomics analysis: an emerging frontier in environmental health.

Exposure to heavy metals in various populations can lead to extensive damage to different organs, as these metals infiltrate and bioaccumulate in the human body, causing metabolic disruptions in various organs. To comprehensively understand the metal homeostasis, inter-organ "traffic," and extensive metabolic alterations resulting from heavy metal exposure, employing complementary analytical methods is crucial. Metabolomics is pivotal in unraveling the intricacies of disease vulnerability by furnishing thorough understandings of metabolic changes linked to different metabolic diseases. This field offers exciting prospects for enhancing the disease prevention, early detection, and tailoring treatment approaches to individual needs. This article consolidates the existing knowledge on disease-linked metabolic pathways affected by the exposure of diverse heavy metals providing concise overview of the underlying impact mechanisms. The main aim is to investigate the connection between the altered metabolic pathways and long-term complex health conditions induced by heavy metals such as diabetes mellitus, cardiovascular diseases, renal disorders, inflammation, neurodegenerative diseases, reproductive risks, and organ damage. Further exploration of common pathways may unveil the shared targets for treating associated pathological conditions. In this article, the role of metabolomics in disease susceptibility is emphasized that metabolomics is expected to be routinely utilized for the diagnosis and monitoring of diseases and practical value of biomarkers derived from metabolomics, as well as determining their appropriate integration into extensive clinical settings.