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This study introduces an overhead heat-integrated distillation column (OHIDiC), a novel approach that maximizes heat recovery by multiple heat exchanges and product circulation. By utilizing the overhead vapor as a direct heat source, low-temperature feed and product water were used as cooling agents, thereby significantly reducing the condenser duty and reliance on cooling utilities. Additionally, the heated feed transfers heat to the column, leading to a substantial reduction of reboiler heat duty. Some of the heated product water is recycled back to the decanter for product cycling, while the rest is released as the final product. This circulation process ensures a continuous coolant supply, which contributes the reduction of condenser duty. Two processes were considered in this study, utilizing the water product from a non-reactive, and from a reactive separation within the system. When applied to the separation of a water-dodecanol mixture, OHIDiC reduced the condenser duty by 69.21% compared to a traditional distillation column, with a 31.46% reduction in the total utility consumption. When reactive distillation was incorporated into the OHIDiC, the higher overhead vapor temperature facilitated high heat transfer in the multiple heat exchange sections, thereby significantly reducing the total thermal load. This resulted in a reduction of up to 46.96% in total heat duty and a 36.06% decrease in CO2 emissions. These findings confirm that the OHIDiC achieves significant energy savings through the utilization of process-derived substances, with pronounced benefits when the temperature of the overhead vapor becomes higher.

Heterozygous mutations in the FOXG1 gene manifest as FOXG1 syndrome, a severe neurodevelopmental disorder characterized by structural brain anomalies, including agenesis of the corpus callosum, hippocampal reduction, and myelination delays. Despite the well-defined genetic basis of FOXG1 syndrome, therapeutic interventions targeting the underlying cause of the disorder are nonexistent. In this study, we explore the therapeutic potential of adeno-associated virus 9 (AAV9)-mediated delivery of the FOXG1 gene. Remarkably, intracerebroventricular injection of AAV9-FOXG1 to Foxg1 heterozygous mouse model at the postnatal stage rescues a wide range of brain pathologies. This includes the amelioration of corpus callosum deficiencies, the restoration of dentate gyrus morphology in the hippocampus, the normalization of oligodendrocyte lineage cell numbers, and the rectification of myelination anomalies. Our findings highlight the efficacy of AAV9-based gene therapy as a viable treatment strategy for FOXG1 syndrome and potentially other neurodevelopmental disorders with similar brain malformations, asserting its therapeutic relevance in postnatal stages.

Abstract Individuals with incomplete spinal-cord injury/disease are at an increased risk of falling due to their impaired ability to maintain balance. Our research group has developed a closed-loop visual-feedback balance training (VFBT) system coupled with functional electrical stimulation (FES) for rehabilitation of standing balance (FES + VFBT system); however, clinical usage of this system is limited by the use of force plates, which are expensive and not easily accessible. This study aimed to investigate the feasibility of a more affordable and accessible sensor such as a depth camera or pressure mat in place of the force plate. Ten able-bodied participants (7 males, 3 females) performed three sets of four different standing balance exercises using the FES + VFBT system with the force plate. A depth camera and pressure mat collected centre of mass and centre of pressure data passively, respectively. The depth camera showed higher Pearson's correlation (r > 98) and lower root mean squared error (RMSE 0.82; RMSE

As an eco-friendly alternative to the conventional anthraquinone process, electrochemical production of hydrogen peroxide (H2O2) through the oxygen reduction reaction has been attracting attention. The goal of this work is to derive a carbon-based material from carbon dioxide (CO2) to achieve high performance in electrochemical H2O2 production. Doping heterogeneous element such as oxygen on a carbon catalyst has been mainly explored to increase the selectivity and activity, but little research has been conducted on enhancing catalytic activity with oxidized boron insertion. This study proposes porous carbon materials synthesized from CO2 as electrocatalysts. Polyethylene oxide (PEO) was thermally treated together to increase the boron-oxygen bonding sites. As a result, the synthesized carbon materials having oxidized boron functional groups of BC2O and BCO2 showed high activity (1.25 mA cm−2) and selectivity (∼90 %) over a wide voltage range in two-electron ORR (Oxygen Reduction Reaction) at alkaline media. Furthermore, in an H-cell where 0.4 V vs. RHE was applied, the average H2O2 production rate was maintained at 452.96 mmol g−1 h−1 for four hours with a high faraday efficiency of 90 %.

Abstract Background Most individuals living with spinal cord injuries/diseases (SCI/D) or stroke experience at least one fall each year; hence, the development of interventions and technologies that target balance control is needed. The purpose of this study was to identify and explore the priorities for balance-focused interventions and technologies from the perspectives of end-users to assist with the design of an intervention that combines functional electrical stimulation (FES) with visual feedback training for standing balance. Methods Two individuals with SCI/D, one individual with stroke, two physical therapists (PT) and one hospital administrator were recruited. Participants attended three focus group meetings that followed a participatory co-design approach. A semi-structured interview guide, developed from the FAME (Feasibility, Appropriateness, Meaningfulness, Effectiveness, Economic Evidence) framework, was used to lead the discussion, querying participants’ experiences with balance deficits and interventions, and FES. Meetings were audio-recorded and transcribed verbatim. An iterative and reflexive inductive thematic analysis was applied to the transcripts by three researchers. Results Four themes were identified: (1) Balance is meaningful for daily life and rehabilitation. Participants acknowledged various factors influencing balance control and how balance deficits interfered with participation in activities. End-users stressed the importance of continuing to work on one’s balance after discharge from hospital-based rehabilitation. (2) Desired characteristics of balance interventions. Participants explained that balance interventions should be tailored to an individual’s unique needs and goals, relevant to their lives, balance their safety and risk, and be engaging. (3) Prior experiences with FES to inform future therapeutic use. Participants with stroke or SCI/D described initial apprehension with FES, but experienced numerous benefits that motivated them to continue with FES. Challenges with FES were mentioned, including wires, cost, and time of set up. (4) Potential role of FES in balance interventions. Participants felt that FES would complement balance interventions; however, they had not experienced this combination of therapies previously. Conclusions End-users described how their experiences with balance deficits, rehabilitation, and FES informed their priorities for balance interventions. The findings inform the design and implementation of future balance interventions for individuals with SCI/D or stroke, including an intervention involving FES and visual feedback training.

Abstract Lung endothelial permeability is a key pathological feature of acute respiratory distress syndrome. Hyaluronic acid (HA), a major component of the glycocalyx layer on the endothelium, is generated by HA synthase (HAS) during inflammation and injury and is critical for repair. We hypothesized that administration of exogenous high molecular weight (HMW) HA would restore protein permeability across human lung microvascular endothelial cells (HLMVEC) injured by an inflammatory insult via upregulation of HAS by binding to CD44. A transwell coculture system was used to study the effects of HA on protein permeability across HLMVEC injured by cytomix, a mixture of IL‐1β, TNFα, and IFNγ, with or without HMW or low molecular weight (LMW) HA. Coincubation with HMW HA, but not LMW HA, improved protein permeability following injury at 24 h. Fluorescence microscopy demonstrated that exogenous HMW HA partially prevented the increase in “actin stress fiber” formation. HMW HA also increased the synthesis of HAS2 mRNA expression and intracellular HMW HA levels in HLMVEC following injury. Pretreatment with an anti‐CD44 antibody or 4‐methylumbelliferone, a HAS inhibitor, blocked the therapeutic effects. In conclusion, exogenous HMW HA restored protein permeability across HLMVEC injured by an inflammatory insult in part through upregulation of HAS2.

Neural cell type diversification during development is a complex and highly regulated process. Here, the authors show that the histone H3-lysine 27 demethylase Kdm6b promotes and inhibits the generation of specific motor neuron subtypes during the development of the mouse spinal cord.

Abstract Previous findings indicate that co-contractions of plantarflexors and dorsiflexors during quiet standing increase the ankle mechanical joint stiffness, resulting in increased postural sway. Balance impairments in individuals with incomplete spinal cord injury (iSCI) may be due to co-contractions like in other individuals with reduced balance ability. Here we investigated the effect of co-contraction between plantar- and dorsiflexors on postural balance in individuals with iSCI (iSCI-group) and able-bodied individuals (AB-group). Thirteen able-bodied individuals and 13 individuals with iSCI were asked to perform quiet standing with their eyes open (EO) and eyes closed (EC). Kinetics and electromyograms from the tibialis anterior (TA), soleus and medial gastrocnemius were collected bilaterally. The iSCI-group exhibited more co-contractions than the AB-group (EO: 0.208% vs. 75.163%, p = 0.004; EC: 1.767% vs. 92.373%, p = 0.016). Furthermore, postural sway was larger during co-contractions than during no co-contraction in the iSCI-group (EO: 1.405 cm/s2 vs. 0.867 cm/s2, p = 0.023; EC: 1.831 cm/s2 vs. 1.179 cm/s2, p = 0.030), but no differences were found for the AB-group (EO: 0.393 cm/s2 vs. 0.499 cm/s2, p = 1.00; EC: 0.686 cm/s2 vs. 0.654 cm/s2, p = 1.00). To investigate the mechanism, we performed a computational simulation study using an inverted pendulum model and linear controllers. An increase of mechanical stiffness in the simulated iSCI-group resulted in increased postural sway (EO: 2.520 cm/s2 vs. 1.174 cm/s2, p

Abstract Background Ovarian sex cord‐stromal tumors (OSCTs) are rare ovarian tumors that can develop from sex cord, stromal cells, or both. OSCTs can be benign or malignant. Bilateral and/or unilateral ovarian fibromas, a type of OSCT of the stromal cells, have been reported in individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Calcified ovarian fibromas have been reported in 15–25% of individuals diagnosed with NBCCS while 75% of those cases occur bilaterally. The average age at diagnosis of OSCT/ovarian fibromas in patients with NBCSS is in the second to third decade compared with age 50 in the general population. Ovarian tumors are rare in pediatric populations. Methods The patient is a 5‐year‐old female diagnosed with bilateral ovarian fibromas at age 4. Multigene panel for the patient and subsequent targeted molecular evaluation of parents were completed. Histological evaluations on the surgically resected ovaries were performed for microscopic characterization of fibromas. Results Germline testing identified de novo heterozygous novel likely pathogenic variants in PTCH1 gene, exon 12 deletion, and an SMARCA4 splicing variant c.2002‐1G > A. Microscopic examination of bilateral tumors was consistent with an ovarian fibroma. Conclusions To our knowledge, this is the first report of bilateral benign ovarian fibroma in a child with a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) with a potential predisposition to Rhabdoid Tumor Predisposition Syndrome (RTPS).

Abstract Background Individuals with an incomplete spinal cord injury (iSCI) are highly susceptible to falls during periods of walking or standing. We recently reported the findings of a novel intervention combining functional electrical stimulation with visual feedback balance training (FES + VFBT) on standing balance abilities among five individuals with motor iSCI. However, the previous publication did not report the perceived impact of the intervention on the participants’ lives. In this report, the experiences of these five individuals with incomplete spinal cord injury (iSCI) who had recently completed the four-week balance training program are described. Methods Five individuals with a motor iSCI took part in this study. Each individual was at least 12 months post-injury, capable of unassisted standing for 60 s and had a Berg Balance Scale Score

Background: Limited evidence exists on the association between dietary fat intake and lipid profiles in Southeast Asian populations. Objectives: We aimed to examine the cross-sectional associations of dietary intake of total and specific types of fat with dyslipidemia in Filipino immigrant women in Korea. Methods: We included 406 Filipino women married to Korean in the Filipino Women’s Diet and Health Study (FiLWHEL). Dietary fat intake was assessed using 24-hour recalls. Impaired blood lipid profiles were defined as high total cholesterol (TC) (≥200 mg/dL), high triglyceride (TG) (≥150 mg/dL), high LDL Cholesterol (LDL-C) (≥ 130 mg/dL), or low HDL cholesterol (HDL-C) (

An 8-bit switched-capacitor multiply-and-accumulator (MAC) in 65nm CMOS is presented. Based on a cascaded low-power ring-amplifier-based switched-capacitor DACs, the MAC circuit features a programmable accumulation length in MAC computation. Fabricated in 65nm CMOS, the prototype MAC circuit achieves a precision-scaled energy efficiency of 1.32fJ per MAC operation, which is comparable to other state-of-the-art MAC circuits, along with best-in-class linearity. The noise performance has been verified using four real-world convolutional neural networks (CNNs) and 10,000-image data sets with up to 1,000 classes with an accuracy drop of less than 2% compared to the baseline 32-bit floating-point MAC.

Mutations in the MLL4 gene can cause Kabuki syndrome, whose underlying molecular mechanisms are unclear. Here, the authors show that Mll4 epigenetically regulates the transcriptional program leading to the formation of GHRH-neurons in the developing mouse hypothalamus.

FOXG1 syndrome (FS, aka a congenital variant of Rett syndrome) is a recently defined rare and devastating neurodevelopmental disorder characterized by various symptoms, including severe intellectual disability, autistic features, involuntary, and continuous jerky movements, feeding problems, sleep disturbances, seizures, irritability, and excessive crying. FS results from mutations in a single allele of the FOXG1 gene, leading to impaired FOXG1 function. Therefore, in establishing mouse models for FS, it is important to test if heterozygous (HET) mutation in the Foxg1 gene, mimicking genotypes of the human FS individuals, also manifests phenotypes similar to their symptoms. We analyzed HET mice with a null mutation allele in a single copy of Foxg1, and found that they show various phenotypes resembling the symptoms of the human FS individuals. These include increased anxiety in the open field as well as impairment in object recognition, motor coordination, and fear learning and contextual and cued fear memory. Our results suggest that Foxg1 HET mice recapitulate at least some symptoms of the human FS individuals.

Abstract TiO2–carbon nanosheets (TiO2‐C NS) with high electrical conductivity are synthesized by CO2 oxidation of Ti3C2 MXene. Importantly, the synthesized TiO2‐C NS (high TiO2 content of 98.45%) can be used without adding a conductive material to impart electrical conductivity. The electrochemical properties show good capacity reversibility at a current density of 2 A g−1 in coin‐type half‐cells. In particular, a prototype pouch cell of TiO2‐C NS//NCM523 also demonstrates that TiO2‐C NS as an anode material is a good match with commercial cathode materials for lithium‐ion batteries. The good electrochemical performance of TiO2‐C NS is attributed to the following factors: 1) the high surface area has abundant exposed active sites offering more Li+ insertion channels and short pathways of the Li+ and electrons; 2) TiO2‐C NS has structural stability and low volume expansion (

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Despite the crucial physiological processes governed by neurons in the hypothalamic arcuate nucleus (ARC), the developmental pathways and regulators for ARC neurons remain understudied. In this study the authors use single cell RNA-seq analyses of mouse embryonic ARC to identify cell type-specific markers for developing ARC neurons and give key insight into the underlying developmental pathways and regulators.

Low oxygen: Protein signalling in human disease A protein family that plays diverse roles in acute and chronic hypoxia (low oxygen) may prove valuable in developing novel therapies for different diseases. Hypoxia, the short- or long-term depletion of oxygen in cells, tissues and organs, is involved in many disease conditions. Holger Eltzschig at the McGovern Medical School in Houston, USA, and co-workers reviewed research into the roles of a key hypoxia regulator, the hypoxia-inducible factor (HIF) protein group, in diseases affecting the heart, lung, liver and kidneys. HIF protein activity is often beneficial in acute conditions such as myocardial ischemia, sending signals to protect cells and increasing tissue tolerance to hypoxia. However, during chronic hypoxia, HIF signaling may contribute to the progression of disease, for example in pulmonary fibrosis. HIF stabilizers and HIF-induced targets as drugs could prove valuable in future treatments.

Introduction: Impaired balance leads to falls in individuals with motor incomplete spinal cord injury or disease (iSCI/D). Reactive stepping is a strategy used to prevent falls and Perturbation-based Balance Training (PBT) can improve this ability.Objective: The objective of this study was to determine if PBT results in greater improvements in reactive stepping ability than frequency-matched Conventional Intensive Balance Training (CIBT) in adults with iSCI/D.Design: Randomized clinical trial.Setting: Tertiary SCI/D rehabilitation center.Participants: Twenty-one adults with chronic (>1 year) iSCI/D were randomized. Due to one drop out 20 participants completed the study.Methods: Participants were randomly allocated to complete either PBT or CIBT three times per week for 8 weeks. Both programs included challenging static and dynamic balance tasks, but the PBT group also experienced manual external balance perturbations.Main Outcome Measures: Assessments of reactive stepping ability using the Lean-and-Release test were completed at baseline, and after 4 and 8 weeks of training, and 3 and 6 months after training completion. A blinded assessor evaluated secondary outcomes.Results: Twenty-five participants were screened and 21 consented; one withdrew. Ten PBT and 10 CIBT participants were included in analyses. Across all participants there were improvements in reactive stepping ability (p = 0.049), with retention of improvements at follow up assessments. There were no differences in reactive stepping ability between groups [median (interquartile range): PBT 0.08 (0.68); CIBT 0.00 (0.22)]. One participant in the PBT group experienced a non-injurious fall during training.Conclusions: Balance training is beneficial for individuals with iSCI/D, but the addition of manual perturbations (i.e., PBT) did not prove advantageous for performance on a measure of reactive stepping ability.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02960178.

Individuals with an incomplete spinal cord injury (iSCI) are highly susceptible to falls during walking or standing. Our objective was to evaluate a therapeutic tool for standing balance that combined functional electrical stimulation, applied bilaterally to the plantarflexors and dorsiflexors, with visual feedback balance training (FES+VFBT). Five adults with iSCI completed 12 FES+VFBT sessions over 4 weeks. During the training sessions, participants completed each of the four balance exercises twice. Visual feedback of the center-of-pressure (COP) location was provided as participants completed the balance exercises and received FES to assist with performance of the exercises. A closed-loop FES system was used in which the COP was continually monitored and the level of electrical current administered was automatically adjusted. Balance abilities were assessed pre- and post- training using clinical balance scales (i.e., Berg Balance Scale, Mini-Balance Evaluation Systems Test, and Activities-specific Balance Confidence Scale) and biomechanical assessments (i.e., postural sway measures and limits of stability test during standing). User acceptability was explored through semi-structured interviews. Improvements were seen for four of the five participants on at least one of the clinical scales following completion of the training intervention. All participants showed greater maximal COP excursion area during the limits of stability test after the training intervention, whereas only one participant demonstrated a reduction in postural sway. Specific components of FES+VFBT, including the ability to safely practice challenging balance exercises, were deemed important by the participants. These results suggest that FES+VFBT has potential as an intervention for standing balance after iSCI.

In the hypothalamus, the arcuate nucleus (ARC) contains AgRP-neurons that regulate energy balance as well as GHRH-neurons that regulate linear growth. Here, the authors looked at how the transcription factors Dlx1/2 and Otp link development of AgRP- and GHRH-neurons.

Myocardial ischemia–reperfusion injury stabilizes the hypoxia-inducible factor HIF2-alpha. Here, the authors show that HIF2-alpha protects the heart from injury via induction of the epidermal growth factor amphiregulin, and that amphiregulin administration is cardioprotective in mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The liver is the most common organ site of cancer metastasis. Molecular determinants of this organotropism, though, are poorly understood. We recently showed that hepatocytes regulate the formation of a “pro-metastatic” niche in the liver via their release of serum amyloid proteins.

The pathophysiologic continuum of non-alcoholic fatty liver disease begins with steatosis. Despite recent advances in our understanding of the gene regulatory program directing steatosis, how it is orchestrated at the chromatin level is unclear. PPARγ2 is a hepatic steatotic transcription factor induced by overnutrition. Here, we report that the histone H3 lysine 4 methyltransferase MLL4/KMT2D directs overnutrition-induced murine steatosis via its coactivator function for PPARγ2. We demonstrate that overnutrition facilitates the recruitment of MLL4 to steatotic target genes of PPARγ2 and their transactivation via H3 lysine 4 methylation because PPARγ2 phosphorylated by overnutrition-activated ABL1 kinase shows enhanced interaction with MLL4. We further show that Pparg2 (encoding PPARγ2) is also a hepatic target gene of ABL1-PPARγ2-MLL4. Consistently, inhibition of ABL1 improves the fatty liver condition of mice with overnutrition by suppressing the pro-steatotic action of MLL4. Our results uncover a murine hepatic steatosis regulatory axis consisting of ABL1-PPARγ2-MLL4, which may serve as a target of anti-steatosis drug development.

During development, two cell types born from closely related progenitor pools often express identical transcriptional regulators despite their completely distinct characteristics. This phenomenon implies the need for a mechanism that operates to segregate the identities of the two cell types throughout differentiation after initial fate commitment. To understand this mechanism, we investigated the fate specification of spinal V2a interneurons, which share important developmental genes with motor neurons (MNs). We demonstrate that the paired homeodomain factor Chx10 functions as a critical determinant for V2a fate and is required to consolidate V2a identity in postmitotic neurons. Chx10 actively promotes V2a fate, downstream of the LIM-homeodomain factor Lhx3, while concomitantly suppressing the MN developmental program by preventing the MN-specific transcription complex from binding and activating MN genes. This dual activity enables Chx10 to effectively separate the V2a and MN pathways. Our study uncovers a widely applicable gene regulatory principle for segregating related cell fates.

Reverse water–gas shift chemical looping (RWGS-CL) offers a promising means of converting the greenhouse gas of CO2 to CO because of its relatively low operating temperatures and high CO selectivity without any side product. This paper introduces a core–shell structured oxygen carrier for RWGS-CL. The prepared oxygen carrier consists of a metal oxide core and perovskite shell, which was confirmed by inductively coupled plasma mass spectroscopy (ICP-MS), XPS, and high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) measurements. The perovskite-structured shell of the prepared oxygen carrier facilitates the formation and consumption of oxygen defects in the metal oxide core during H2-CO2 redox looping cycles. As a result, amounts of CO produced per unit weight of the core–shell structured oxygen carriers were higher than that of a simple perovskite oxygen carrier. Of the metal oxide cores tested, CeO2, NiO, Co3O4, and Co3O4-NiO, La0.75Sr0.25FeO3-encapsulated Co3O4-NiO was found to be the most promising oxygen carrier for RWGS-CL, because it was most productive in terms of CO production and exhibited long-term stability.

Abstract Hydrogen peroxide has been used in many industrial sectors including applications such as water purification, bleaching, oxidizing agents, and rocket fuels. As the conventional anthraquinone route of hydrogen peroxide production consumes significant energy and generates a substantial amount of chemical waste, an alternative method, the electrochemical production through the two‐electron oxygen reduction reaction (ORR), has garnered attention on the basis of eco‐friendly in situ synthesis with low energy input. For practical viability, the use of non‐precious metal‐based catalysts is necessary, such as a transition metal (Fe, Co, Ni)‐heteroatom (N, B, O, P, S) moiety or mesoporous structures with efficient mass transfer of the reactants and products from metal‐organic frameworks (MOFs). The ORR reaction pathway and the adsorption energy of the reaction intermediate of *OOH are affected by the combination of transition metals and heteroatoms. For the MOF, the interaction between metal and ligands, types of transition metals, and the synergistic effect between the two metal species of metal alloys can alter the ORR activity. This review discusses recently reported non‐precious metal catalysts for the two‐electron ORR focusing on modification of the atomic configuration for increasing the electrocatalytic activity towards the two‐electron ORR.

The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). Conditional inactivation of Isl1, a LIM homeodomain factor expressed in both differentiating MNs and FCNs, led to a drastic loss of cholinergic neurons in the developing spinal cord and forebrain. We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Consistently, the Isl1-Lhx3-hexamer directly coordinated upregulation of cholinergic pathways genes in embryonic spinal cord. Similarly, in the developing forebrain, the Isl1-Lhx8-hexamer was recruited to the cholinergic gene battery and promoted cholinergic gene expression. Furthermore, the expression of the Isl1-Lhx8-complex enabled the acquisition of cholinergic fate in embryonic stem cell-derived neurons. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover an important gene regulatory mechanism that directs a specific neurotransmitter identity in vertebrate CNS development.

Biomarkers prognostic for colorectal cancer (CRC) would be highly desirable in clinical practice. Proteins that regulate bile acid (BA) homeostasis, by linking metabolic sensors and metabolic enzymes, also called bridge proteins, may be reliable prognostic biomarkers for CRC. Based on a devised metric, "bridgeness," we identified bridge proteins involved in the regulation of BA homeostasis and identified their prognostic potentials. The expression patterns of these bridge proteins could distinguish between normal and diseased tissues, suggesting that these proteins are associated with CRC pathogenesis. Using a supervised classification system, we found that these bridge proteins were reproducibly prognostic, with high prognostic ability compared to other known markers.