Since the school's inception in 1979, students in the Morningside Graduate School of Biomedical Sciences at UMass Chan Medical School have contributed thousands of research publications to the field of biomedical sciences. This collection makes this body of work accessible to our students, faculty, potential recruits, the citizens of Massachusetts, and the world.


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Recently Published

  • Co-transmission of neuropeptides and monoamines choreograph the C. elegans escape response

    Florman, Jeremy T.; Alkema, Mark J. (2022-03-03)
    Co-localization and co-transmission of neurotransmitters and neuropeptides is a core property of neural signaling across species. While co-transmission can increase the flexibility of cellular communication, understanding the functional impact on neural dynamics and behavior remains a major challenge. Here we examine the role of neuropeptide/monoamine co-transmission in the orchestration of the C. elegans escape response. The tyraminergic RIM neurons, which coordinate distinct motor programs of the escape response, also co-express the neuropeptide encoding gene flp-18. We find that in response to a mechanical stimulus, flp-18 mutants have defects in locomotory arousal and head bending that facilitate the omega turn. We show that the induction of the escape response leads to the release of FLP-18 neuropeptides. FLP-18 modulates the escape response through the activation of the G-protein coupled receptor NPR-5. FLP-18 increases intracellular calcium levels in neck and body wall muscles to promote body bending. Our results show that FLP-18 and tyramine act in different tissues in both a complementary and antagonistic manner to control distinct motor programs during different phases of the C. elegans flight response. Our study reveals basic principles by which co-transmission of monoamines and neuropeptides orchestrate in arousal and behavior in response to stress.
  • Cell-Type-Specific Circadian Bioluminescence Rhythms in Dbp Reporter Mice

    Smith, Ciearra B.; van der Vinne, Vincent; McCartney, Eleanor; Stowie, Adam C.; Leise, Tanya L.; Martin-Burgos, Blanca; Molyneux, Penny C.; Garbutt, Lauren A.; Brodsky, Michael H.; Davidson, Alec J.; et al. (Sage Publishers, 2022-02-01)
    Circadian rhythms are endogenously generated physiological and molecular rhythms with a cycle length of about 24 h. Bioluminescent reporters have been exceptionally useful for studying circadian rhythms in numerous species. Here, we report development of a reporter mouse generated by modification of a widely expressed and highly rhythmic gene encoding D-site albumin promoter binding protein (Dbp). In this line of mice, firefly luciferase is expressed from the Dbp locus in a Cre recombinase-dependent manner, allowing assessment of bioluminescence rhythms in specific cellular populations. A mouse line in which luciferase expression was Cre-independent was also generated. The Dbp reporter alleles do not alter Dbp gene expression rhythms in liver or circadian locomotor activity rhythms. In vivo and ex vivo studies show the utility of the reporter alleles for monitoring rhythmicity. Our studies reveal cell-type-specific characteristics of rhythms among neuronal populations within the suprachiasmatic nuclei ex vivo. In vivo studies show Dbp-driven bioluminescence rhythms in the liver of Albumin-Cre;DbpKI/+ "liver reporter" mice. After a shift of the lighting schedule, locomotor activity achieved the proper phase relationship with the new lighting cycle more rapidly than hepatic bioluminescence did. As previously shown, restricting food access to the daytime altered the phase of hepatic rhythmicity. Our model allowed assessment of the rate of recovery from misalignment once animals were provided with food ad libitum. These studies confirm the previously demonstrated circadian misalignment following environmental perturbations and reveal the utility of this model for minimally invasive, longitudinal monitoring of rhythmicity from specific mouse tissues.
  • A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior

    Ramachandran, Shankar; Banerjee, Navonil; Bhattacharya, Raja; Lemons, Michele L.; Florman, Jeremy; Lambert, Christopher M.; Touroutine, Denis; Alexander, Kellianne; Schoofs, Liliane; Alkema, Mark J.; et al. (2021-11-12)
    Neuromodulators promote adaptive behaviors that are often complex and involve concerted activity changes across circuits that are often not physically connected. It is not well understood how neuromodulatory systems accomplish these tasks. Here, we show that the Caenorhabditis elegans NLP-12 neuropeptide system shapes responses to food availability by modulating the activity of head and body wall motor neurons through alternate G-protein coupled receptor (GPCR) targets, CKR-1 and CKR-2. We show ckr-2 deletion reduces body bend depth during movement under basal conditions. We demonstrate CKR-1 is a functional NLP-12 receptor and define its expression in the nervous system. In contrast to basal locomotion, biased CKR-1 GPCR stimulation of head motor neurons promotes turning during local searching. Deletion of ckr-1 reduces head neuron activity and diminishes turning while specific ckr-1 overexpression or head neuron activation promote turning. Thus, our studies suggest locomotor responses to changing food availability are regulated through conditional NLP-12 stimulation of head or body wall motor circuits.
  • A phase transition enhances the catalytic activity of SARM1, an NAD(+) glycohydrolase involved in neurodegeneration

    Loring, Heather S.; Czech, Victoria L.; Icso, Janneke D.; O'Connor, Lauren C.; Parelkar, Sangram; Byrne, Alexandra B.; Thompson, Paul R. (2021-06-29)
    Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is a neuronally expressed NAD(+) glycohydrolase whose activity is increased in response to stress. NAD(+) depletion triggers axonal degeneration, which is a characteristic feature of neurological diseases. Notably, loss of SARM1 is protective in murine models of peripheral neuropathy and traumatic brain injury. Herein, we report that citrate induces a phase transition that enhances SARM1 activity by ~2000-fold. This phase transition can be disrupted by mutating a residue involved in multimerization, G601P. This mutation also disrupts puncta formation in cells. We further show that citrate induces axonal degeneration in C. elegans that is dependent on the C. elegans orthologue of SARM1 (TIR-1). Notably, citrate induces the formation of larger puncta indicating that TIR-1/SARM1 multimerization is essential for degeneration in vivo. These findings provide critical insights into SARM1 biology with important implications for the discovery of novel SARM1-targeted therapeutics.
  • Flexible motor sequence generation during stereotyped escape responses

    Wang, Yuan; Zhang, Xiaoqian; Xin, Qi; Hung, Wesley; Florman, Jeremy; Huo, Jing; Xu, Tianqi; Xie, Yu; Alkema, Mark J.; Zhen, Mei; et al. (2020-06-05)
    Complex animal behaviors arise from a flexible combination of stereotyped motor primitives. Here we use the escape responses of the nematode Caenorhabditis elegans to study how a nervous system dynamically explores the action space. The initiation of the escape responses is predictable: the animal moves away from a potential threat, a mechanical or thermal stimulus. But the motor sequence and the timing that follow are variable. We report that a feedforward excitation between neurons encoding distinct motor states underlies robust motor sequence generation, while mutual inhibition between these neurons controls the flexibility of timing in a motor sequence. Electrical synapses contribute to feedforward coupling whereas glutamatergic synapses contribute to inhibition. We conclude that C. elegans generates robust and flexible motor sequences by combining an excitatory coupling and a winner-take-all operation via mutual inhibition between motor modules.
  • The 'Take a Break' game: Randomized trial protocol for a technology-assisted brief abstinence experience designed to engage lower-motivated smokers.

    Amante, Daniel J.; Blok, Amanda C.; Nagawa, Catherine S.; Wijesundara, Jessica G.; Allison, Jeroan J.; Person, Sharina D.; Morley, Jeanne; Conigliaro, Joseph; Mattocks, Kristin M.; Garber, Lawrence D.; et al. (2020-06-01)
    BACKGROUND: While smoking continues to be the most preventable cause of mortality in the United States, most current smokers remain not ready to quit at any given time. Engaging these 'motivation phase' smokers with brief experiences to build confidence and practice skills related to cessation could lead to sooner and more successful quit attempts. Increasingly available mobile technology and gamification can be used to provide smokers with accessible and engaging support. METHODS: We describe our protocol for conducting a randomized controlled trial evaluating Take a Break, an mHealth-based smoking pre-cessation challenge designed for smokers not ready to quit. Participants in the intervention receive 1) Motivational Messages, 2) text message Challenge Quizzes, 3) Goal-setting with tobacco treatment specialist, 4) Coping Mini-Games apps, and 5) Recognition and Rewards for participation during a 3-week challenge. Access to coping mini-games and motivational messaging continues for 6-months. Both intervention and comparison group participants receive brief Nicotine Replacement Therapy (NRT) sampling and daily smoking assessment text messages for three weeks. Primary outcomes include number of days abstinent during the challenge, change in patient-reported self-efficacy after the challenge, time to first quit attempt following the challenge, and 7-day point prevalent smoking cessation at six months. CONCLUSION: Take a Break is an innovative approach to engage those not prepared for a quit attempt. Take a Break provides motivation phase smokers with tools and a brief experience to prepare them for a quit attempt, filling a gap in tobacco cessation support and current research.
  • A highly efficient method for single-cell electroporation in mouse organotypic hippocampal slice culture

    Keener, David G.; Cheung, Amy; Futai, Kensuke (2020-05-01)
    BACKGROUND: Exogenous gene introduction by transfection is one of the most important approaches for understanding the function of specific genes at the cellular level. Electroporation has a long-standing history as a versatile gene delivery technique in vitro and in vivo. However, it has been underutilized in vitro because of technical difficulty and insufficient transfection efficiency. NEW METHOD: We have developed an electroporation technique that combines the use of large glass electrodes, tetrodotoxin-containing artificial cerebrospinal fluid and mild electrical pulses. Here, we describe the technique and compare it with existing methods. RESULTS: Our method achieves a high transfection efficiency ( approximately 80 %) in both excitatory and inhibitory neurons with no detectable side effects on their function. We demonstrate this method is capable of transferring at least three different genes into a single neuron. In addition, we demonstrate the ability to transfect different genes into neighboring cells. COMPARISON WITH EXISTING METHODS: The majority of existing methods use fine-tipped glass electrodes (i.e. > 10MOmega) and apply high voltage (10V) pulses with high frequency (100Hz) for 1s. These parameters contribute to practical difficulties thus lowering the transfection efficiency. Our unique method minimizes electrode clogging and therefore procedure duration, increasing transfection efficiency and cellular viability. CONCLUSIONS: Our modifications, relative to current methods, optimize electroporation efficiency and cell survival. Our approach offers distinct research strategies not only in elucidating cell-autonomous functions of genes but also for assessing genes contributing to intercellular functions, such as trans-synaptic interactions.
  • In Situ Regulated Dopamine Transporter Trafficking: There's No Place Like Home

    Fagan, Rita R.; Kearney, Patrick J.; Melikian, Haley E. (2020-03-07)
    Dopamine (DA) is critical for motivation, reward, movement initiation, and learning. Mechanisms that control DA signaling have a profound impact on these important behaviors, and additionally play a role in DA-related neuropathologies. The presynaptic SLC6 DA transporter (DAT) limits extracellular DA levels by clearing released DA, and is potently inhibited by addictive and therapeutic psychostimulants. Decades of evidence support that the DAT is subject to acute regulation by a number of signaling pathways, and that endocytic trafficking strongly regulates DAT availability and function. DAT trafficking studies have been performed in a variety of model systems, including both in vitro and ex vivo preparations. In this review, we focus on the breadth of DAT trafficking studies, with specific attention to, and comparison of, how context may influence DAT's response to different stimuli. In particular, this overview highlights that stimulated DAT trafficking not only differs between in vitro and ex vivo environments, but also is influenced by both sex and anatomical subregions.
  • Drosophila Cryptochrome: Variations in Blue

    Foley, Lauren E.; Emery, Patrick (2020-02-01)
    CRYPTOCHROMES (CRYs) are structurally related to ultraviolet (UV)/blue-sensitive DNA repair enzymes called photolyases but lack the ability to repair pyrimidine dimers generated by UV exposure. First identified in plants, CRYs have proven to be involved in light detection and various light-dependent processes in a broad range of organisms. In Drosophila, CRY's best understood role is the cell-autonomous synchronization of circadian clocks. However, CRY also contributes to the amplitude of circadian oscillations in a light-independent manner, controls arousal and UV avoidance, influences visual photoreception, and plays a key role in magnetic field detection. Here, we review our current understanding of the mechanisms underlying CRY's various circadian and noncircadian functions in fruit flies.
  • Polymodal Nociception in Drosophila Requires Alternative Splicing of TrpA1

    Gu, Pengyu; Gong, Jiaxin; Shang, Ye; Wang, Fei; Takle, Kendra; Ma, Zhiguo; Sheehan, Amy E.; Freeman, Marc R.; Xiang, Yang (2019-12-02)
    Transcripts of noxious stimulus-detecting TrpA1 channels are alternatively spliced. Despite the importance of nociception for survival, the in vivo significance of expressing different TrpA1 isoforms is largely unknown. Here, we develop a novel genetic approach to generate Drosophila knockin strains expressing single TrpA1 isoforms. Drosophila TrpA1 mediates heat and UVC-triggered nociception. We show that TrpA1-C and TrpA1-D, two alternative isoforms, are co-expressed in nociceptors. When examined in heterologous cells, both TrpA1-C and TrpA1-D are activated by heat and UVC. By contrast, analysis of knockin flies reveals the striking functional specificity; TrpA1-C mediates UVC-nociception, whereas TrpA1-D mediates heat-nociception. Therefore, in vivo functions of TrpA1-C and TrpA1-D are different from each other and are different from their in vitro properties. Our results indicate that a given sensory stimulus preferentially activates a single TrpA1 isoform in vivo and that polymodal nociception requires co-expression of TrpA1 isoforms, providing novel insights of how alternative splicing regulates nociception.
  • Two sides of the same coin – compensatory proliferation in regeneration and cancer

    Diwanji, Neha; Bergmann, Andreas (2019-09-14)
    Apoptosis has long been regarded as a tumor suppressor mechanism and evasion from apoptosis is considered to be one hallmark of cancer. However, this principle is not always consistent with clinical data which often illustrate a correlation between apoptosis and poor prognosis. Work in the last 15 years has provided an explanation for this apparent paradox. Apoptotic cells communicate with their environment and can produce signals which promote compensatory proliferation of surviving cells. This behavior of apoptotic cells is important for tissue regeneration in several model organisms, ranging from hydra to mammals. However, it may also play an important feature for tumorigenesis and tumor relapse. Several distinct forms of apoptosis-induced compensatory proliferation (AiP) have been identified, many of which involve reactive oxygen species (ROS) and immune cells. One type of AiP, "undead" AiP, in which apoptotic cells are kept in an immortalized state and continuously divide, may have particular relevance for tumorigenesis. Furthermore, given that chemo- and radiotherapy often aim to kill tumor cells, an improved understanding of the effects of apoptotic cells on the tumor and the tumor environment is of critical importance for the well-being of the patient. In this review, we summarize the current knowledge of AiP and focus our attention on recent findings obtained in Drosophila and other model organisms, and relate them to tumorigenesis.
  • Are we “missing the big picture” in transitions of care? Perspectives of healthcare providers managing patients with unplanned hospitalization

    Abu, Hawa Ozien; Anatchkova, Milena D.; Erskine, Nathaniel A. K.; Lewis, Joanne; McManus, David D.; Kiefe, Catarina I.; Santry, Heena P. (2018-12-01)
    Background Healthcare providers play a critical role in the care transitions. Therefore, efforts to improve this process should be informed by their perspectives. Aim The study objective was to explore the factors that negatively/positively influence care transitions following an unplanned hospitalization from the perspective of healthcare providers. Methods A qualitative study using semi-structured interviews conducted between February and September of 2016 at a single academic medical center. We enrolled fifteen healthcare providers from multiple disciplines involved in the management of patients experiencing an unplanned hospitalization. Respondents shared their experiences with care transitions and identified factors within and outside of the discharging health facility that impede or facilitate this process. Transcribed interviews were analyzed using emerging themes from the interviews. Results We identified six themes and associated subthemes from the interviews on factors that influence care transitions. Three themes focused on factors within the discharging healthcare facility: untailored and overloaded patient discharge information, timing of the post-discharge care conversation, provider-to-patient and provider-to-provider miscommunication. The other three themes were related to external factors including caregiver involvement, having a safe and stable housing environment, and access to healthcare and community resources. Providers discussed how these factors positively/negatively influence the hospital-to-home transition. Conclusions Our study identifies factors within and outside the discharging healthcare facility that influence care transitions, ultimately affect patient-centered outcomes and provider satisfaction with delivered care. Strategies aimed at improving the quality of care transitions should address these barriers and actively engage healthcare providers who are pivotal in care transitions.
  • Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration

    Farley, Jonathan E.; Burdett, Thomas C.; Barria, Romina; Neukomm, Lukas J.; Kenna, Kevin P.; Landers, John E.; Freeman, Marc R. (National Academy of Sciences, 2018-01-02)
    Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the Drosophila C2H2 zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling.
  • Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development and craniofacial morphogenesis.

    Milstone, Zachary J.; Lawson, Grace; Trivedi, Chinmay M. (Wiley-Liss, 2017-08-09)
    BACKGROUND: Craniofacial anomalies involve defective pharyngeal arch development and neural crest function. Copy number variation at 1p35, containing histone deacetylase 1 (Hdac1), or 6q21-22, containing Hdac2, are implicated in patients with craniofacial defects, suggesting an important role in guiding neural crest development. However, the roles of Hdac1 and Hdac2 within neural crest cells remain unknown. RESULTS: The neural crest and its derivatives express both Hdac1 and Hdac2 during early murine development. Ablation of Hdac1 and Hdac2 within murine neural crest progenitor cells cause severe hemorrhage, atrophic pharyngeal arches, defective head morphogenesis, and complete embryonic lethality. Embryos lacking Hdac1 and Hdac2 in the neural crest exhibit decreased proliferation and increased apoptosis in both the neural tube and the first pharyngeal arch. Mechanistically, loss of Hdac1 and Hdac2 upregulates cyclin-dependent kinase inhibitors Cdkn1a, Cdkn1b, Cdkn1c, Cdkn2b, Cdkn2c, and Tp53 within the first pharyngeal arch. CONCLUSIONS: Our results show that Hdac1 and Hdac2 function redundantly within the neural crest to regulate proliferation and the development of the pharyngeal arches via repression of cyclin-dependent kinase inhibitors. This article is protected by copyright. All rights reserved.
  • Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function

    McFleder, Rhonda L.; Mansur, Fernanda; Richter, Joel D. (2017-07-18)
    Translation of mRNAs in dendrites mediates synaptic plasticity, the probable cellular basis of learning and memory. Coordination of translational inhibitory and stimulatory mechanisms, as well as dendritic transport of mRNA, is necessary to ensure proper control of this local translation. Here, we find that the deadenylase CNOT7 dynamically regulates dendritic mRNA translation and transport, as well as synaptic plasticity and higher cognitive function. In cultured hippocampal neurons, synaptic stimulation induces a rapid decrease in CNOT7, which, in the short-term, results in poly(A) tail lengthening of target mRNAs. However, at later times following stimulation, decreased poly(A) and dendritic localization of mRNA take place, similar to what is observed when CNOT7 is depleted over several days. In mice, CNOT7 is essential for hippocampal-dependent learning and memory. This study identifies CNOT7 as an important regulator of RNA transport and translation in dendrites, as well as higher cognitive function.
  • Methods to investigate the structure and connectivity of the nervous system

    Lee, Donghyung; Huang, Ting-Hao; De La Cruz, Aubrie; Callejas, Antuca; Lois, Carlos (2017-02-16)
    Understanding the computations that take place in neural circuits requires identifying how neurons in those circuits are connected to one another. In addition, recent research indicates that aberrant neuronal wiring may be the cause of several neurodevelopmental disorders, further emphasizing the importance of identifying the wiring diagrams of brain circuits. To address this issue, several new approaches have been recently developed. In this review, we describe several methods that are currently available to investigate the structure and connectivity of the brain, and discuss their strengths and limitations.
  • RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data.

    Movassagh, Mercedeh; Alomran, Nawaf; Mudvari, Prakriti; Dede, Merve; Dede, Cem; Kowsari, Kamran; Restrepo, Paula; Cauley, Edmund; Bahl, Sonali; Li, Muzi; et al. (Oxford University Press, 2016-12-15)
    We introduce RNA2DNAlign, a computational framework for quantitative assessment of allele counts across paired RNA and DNA sequencing datasets. RNA2DNAlign is based on quantitation of the relative abundance of variant and reference read counts, followed by binomial tests for genotype and allelic status at SNV positions between compatible sequences. RNA2DNAlign detects positions with differential allele distribution, suggesting asymmetries due to regulatory/structural events. Based on the type of asymmetry, RNA2DNAlign outlines positions likely to be implicated in RNA editing, allele-specific expression or loss, somatic mutagenesis or loss-of-heterozygosity (the first three also in a tumor-specific setting). We applied RNA2DNAlign on 360 matching normal and tumor exomes and transcriptomes from 90 breast cancer patients from TCGA. Under high-confidence settings, RNA2DNAlign identified 2038 distinct SNV sites associated with one of the aforementioned asymetries, the majority of which have not been linked to functionality before. The performance assessment shows very high specificity and sensitivity, due to the corroboration of signals across multiple matching datasets. RNA2DNAlign is freely available from http://github.com/HorvathLab/NGS as a self-contained binary package for 64-bit Linux systems.
  • Probabilistic bias analysis in pharmacoepidemiology and comparative effectiveness research: a systematic review

    Hunnicutt, Jacob N.; Ulbricht, Christine M.; Chrysanthopoulou, Stavroula A.; Lapane, Kate L. (Wiley, 2016-12-01)
    PURPOSE: We systematically reviewed pharmacoepidemiologic and comparative effectiveness studies that use probabilistic bias analysis to quantify the effects of systematic error including confounding, misclassification, and selection bias on study results. METHODS: We found articles published between 2010 and October 2015 through a citation search using Web of Science and Google Scholar and a keyword search using PubMed and Scopus. Eligibility of studies was assessed by one reviewer. Three reviewers independently abstracted data from eligible studies. RESULTS: Fifteen studies used probabilistic bias analysis and were eligible for data abstraction-nine simulated an unmeasured confounder and six simulated misclassification. The majority of studies simulating an unmeasured confounder did not specify the range of plausible estimates for the bias parameters. Studies simulating misclassification were in general clearer when reporting the plausible distribution of bias parameters. Regardless of the bias simulated, the probability distributions assigned to bias parameters, number of simulated iterations, sensitivity analyses, and diagnostics were not discussed in the majority of studies. CONCLUSION: Despite the prevalence and concern of bias in pharmacoepidemiologic and comparative effectiveness studies, probabilistic bias analysis to quantitatively model the effect of bias was not widely used. The quality of reporting and use of this technique varied and was often unclear. Further discussion and dissemination of the technique are warranted.
  • Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via Stimulator of Interferon Genes.

    Iracheta-Vellve, Arvin; Petrasek, Jan; Gyongyosi, Benedek; Satishchandran, Abhishek; Lowe, Patrick; Kodys, Karen; Catalano, Donna; Calenda, Charles D.; Kurt-Jones, Evelyn A.; Fitzgerald, Kate A.; et al. (American Society for Biochemistry and Molecular Biology, 2016-11-03)
    Fibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon Regulatory Factor 3 (IRF3) regulates hepatocyte apoptosis and production of Type-I interferons (IFNs). In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the ER adapter, Stimulator of Interferon Genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically-induced liver fibrogenesis. To test this, we performed acute or chronic carbontetrachloride (CCl4) administration to WT, IRF3-, TRAM-, TRIF-, and STING-deficient mice. We report that acute CCl4 administration to WT mice resulted in early ER stress, activation of IRF3 and Type-I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl4. Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl4. In contrast, mice deficient in Type-I IFN receptors or in TLR4-signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis suggesting that the pro-apoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis, and indicate that innate immune signaling modulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.
  • Functional status predicts postoperative mortality after liver transplantation

    Dolgin, Natasha H.; Martins, Paulo N.A.; Movahedi, Babak; Lapane, Kate L.; Anderson, Frederick A. Jr.; Bozorgzadeh, Adel (2016-11-01)
    BACKGROUND: Frail patients are more vulnerable to perioperative stressors of liver transplantation (LT). Program Specific Reports, used in transplant center auditing, risk-adjust for frailty using the Karnofsky Performance Status (KPS) scale. We evaluate the extent to which functional impairment/disability is associated with increased risk of postoperative death. METHODS: We included 24 505 first-time LT recipients from the Scientific Registry of Transplant Recipients (2006-2011). We categorized patients as Severe, Moderate, or Normal function/disability using the KPS scale and evaluated risk of 30- and 90-day mortality. Analyses took potential center-specific differences in KPS measurement protocols into account using hierarchal logistic modeling. RESULTS: Over one-quarter of our population was Severely impaired/disabled, and 30.5% had no functional limitations. Severely and Moderately impaired/disabled patients had 2.56 (95% CI 1.91-3.44) and 1.40 (95% CI 1.10-1.78) times the odds of 30-day mortality, respectively, after adjusting for key recipient and donor factors. Estimates remained consistent regardless of Model for End-Stage Liver Disease score, medical condition, or clustering analyses by center. Technical/operative complications and multiorgan failure/hemorrhage were more common causes of death among more Severely disabled patients than in higher functioning groups. CONCLUSIONS: Pre-transplant functional status, assessed using the KPS scale, is a reliable predictor of post-LT mortality in the United States.

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