Nonalcoholic fatty liver disease in CLOCK mutant mice
Nonalcoholic fatty liver disease (NAFLD) is becoming a major health issue as obesity increases around the world. We studied the effect of a circadian locomotor output cycles kaput (CLOCK) mutant (ClkΔ19/Δ19) protein on hepatic lipid metabolism in C57BL/6 Clkwt/wt and apolipoprotein E–deficient (Apoe−/−) mice. Both ClkΔ19/Δ19 and ClkΔ19/Δ19 Apoe−/− mice developed a full spectrum of liver diseases (steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma) recognized in human NAFLD when challenged with a Western diet, lipopolysaccharide, or CoCl2. We...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Xiaoyue Pan, Joyce Queiroz, M. Mahmood Hussain Source Type: research

Posttranslational modifications define course of prion strain adaptation and disease phenotype
Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein (PrPC), tau, and α-synuclein. Alternative self-propagating protein states or strains give rise to different disease phenotypes and display strain-specific subsets of posttranslational modifications. The relationships between strain-specific structure, posttranslational modifications, and disease phenotype are poorly understood. We previously reported that among hundreds of PrPC sialoglycoforms expressed by a cell, individual prion strains recruited PrPC molecules selectively, according t...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Natallia Makarava, Jennifer Chen-Yu Chang, Kara Molesworth, Ilia V. Baskakov Source Type: research

Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity
Fibrinolysis is initiated by tissue-type plasminogen activator (tPA) and inhibited by plasminogen activator inhibitor 1 (PAI-1). In obese humans, plasma PAI-1 and tPA proteins are increased, but PAI-1 dominates, leading to reduced fibrinolysis and thrombosis. To understand tPA–PAI-1 regulation in obesity, we focused on hepatocytes, a functionally important source of tPA and PAI-1 that sense obesity-induced metabolic stress. We showed that obese mice, like humans, had reduced fibrinolysis and increased plasma PAI-1 and tPA, due largely to their increased hepatocyte expression. A decrease in the PAI-1 (SERPINE1) gene c...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Ze Zheng, Keiko Nakamura, Shana Gershbaum, Xiaobo Wang, Sherry Thomas, Marc Bessler, Beth Schrope, Abraham Krikhely, Rui-Ming Liu, Lale Ozcan, José A. López, Ira Tabas Source Type: research

Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in patients with ESCC. RSK4 was found to be a direct...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Ming-Yang Li, Lin-Ni Fan, Dong-Hui Han, Zhou Yu, Jing Ma, Yi-Xiong Liu, Pei-Feng Li, Dan-Hui Zhao, Jia Chai, Lei Jiang, Shi-Liang Li, Juan-Juan Xiao, Qiu-Hong Duan, Jing Ye, Mei Shi, Yong-Zhan Nie, Kai-Chun Wu, Dezhong Joshua Liao, Yu Shi, Yan Wang, Qing- Source Type: research

Genomic landscape of metastatic breast cancer identifies preferentially dysregulated pathways and targets
Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases — MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 — 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of ...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Matt R. Paul, Tien-chi Pan, Dhruv K. Pant, Natalie N.C. Shih, Yan Chen, Kyra L. Harvey, Aaron Solomon, David Lieberman, Jennifer J.D. Morrissette, Danielle Soucier-Ernst, Noah G. Goodman, S. William Stavropoulos, Kara N. Maxwell, Candace Clark, George K. Source Type: research

Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy
Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous CD8+ T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM ...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Lina Such, Fang Zhao, Derek Liu, Beatrice Thier, Vu Thuy Khanh Le-Trilling, Antje Sucker, Christoph Coch, Natalia Pieper, Sebastian Howe, Hilal Bhat, Halime Kalkavan, Cathrin Ritter, Robin Brinkhaus, Selma Ugurel, Johannes Köster, Ulrike Seifert, Ulf Dit Source Type: research

Precision metabolome reprogramming for imprecision therapeutics in retinitis pigmentosa
Retinitis pigmentosa (RP), the most common form of rod-cone dystrophy, is caused by greater than 3100 mutations in more than 71 genes, many of which are preferentially expressed in rod photoreceptors. Cone death generally follows rod loss regardless of the underlying pathogenic mutation. Preventing the secondary loss of cone photoreceptors would preserve central visual acuity and substantially improve patients’ quality of life. In this issue of the JCI, Wang et al. demonstrate that adeno-associated virus–mediated overexpression of TGF-β1 promoted cone survival and function in 3 distinct RP models with rod-...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Salvatore Caruso, Joseph Ryu, Peter M.J. Quinn, Stephen H. Tsang Source Type: research

Taste-related reward is associated with weight loss following bariatric surgery
CONCLUSION The anatomical and/or metabolic changes associated with RYGB may more effectively “reset” the neural processing of reward stimuli, thereby rescuing the blunted activation in the mesolimbic pathway found in patients with obesity. Further, these findings suggest that RYGB may be particularly effective in patients with a preference for sweet foods.FUNDING NIH K23DK100559 and Dalio Philanthropies. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Kimberly R. Smith, Afroditi Papantoni, Maria G. Veldhuizen, Vidyulata Kamath, Civonnia Harris, Timothy H. Moran, Susan Carnell, Kimberley E. Steele Source Type: research

Nck1 is a critical adaptor between proatherogenic blood flow, inflammation, and atherosclerosis
Atherosclerosis is an inflammatory condition of the arteries that has profound incidence and increasing prevalence. Although endothelial cells detect changes in blood flow, how endothelial activation contributes to atherogenic inflammation is not well understood. In this issue of the JCI, Alfaidi et al. used mouse models to explore flow-induced endothelial activation. The authors revealed a role for Nck1 and a specific activator of the innate immune response, the downstream interleukin receptor–associated kinase-1 (IRAK-1) in NF-κB–mediated inflammation and atherosclerosis susceptibility. These results li...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Mary Wines-Samuelson, Sayantani Chowdhury, Bradford C. Berk Source Type: research

Blocking endothelial apoptosis revascularizes the retina in a model of ischemic retinopathy
Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying ve...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Zoe L. Grant, Lachlan Whitehead, Vickie H.Y. Wong, Zheng He, Richard Y. Yan, Abigail R. Miles, Andrew V. Benest, David O. Bates, Claudia Prahst, Katie Bentley, Bang V. Bui, Robert C.A. Symons, Leigh Coultas Source Type: research

AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes
In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus–mediated approach in hepatocytes in vivo reversed AGER1 downregulat...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Ali Dehnad, Weiguo Fan, Joy X. Jiang, Sarah R. Fish, Yuan Li, Suvarthi Das, Gergely Mozes, Kimberly A. Wong, Kristin A. Olson, Gregory W. Charville, Mohammed Ali, Natalie J. Török Source Type: research

Selective role of Nck1 in atherogenic inflammation and plaque formation
Although the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) established the role of treating inflammation in atherosclerosis, our understanding of endothelial activation at atherosclerosis-prone sites remains limited. Disturbed flow at atheroprone regions primes plaque inflammation by enhancing endothelial NF-κB signaling. Herein, we demonstrate a role for the Nck adaptor proteins in disturbed flow–induced endothelial activation. Although highly similar, only Nck1 deletion, but not Nck2 deletion, limited flow-induced NF-κB activation and proinflammatory gene expression. Nck1-knockout mic...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Mabruka Alfaidi, Christina H. Acosta, Dongdong Wang, James G. Traylor, A. Wayne Orr Source Type: research

Microglia modulation by TGF-β1 protects cones in mouse models of retinal degeneration
Retinitis pigmentosa (RP) is a genetically heterogenous group of eye diseases in which initial degeneration of rods triggers secondary degeneration of cones, leading to significant loss of daylight, color, and high-acuity vision. Gene complementation with adeno-associated viral (AAV) vectors is one strategy to treat RP. Its implementation faces substantial challenges, however; for example, the tremendous number of loci with causal mutations. Gene therapy targeting secondary cone degeneration is an alternative approach that could provide a much-needed generic treatment for many patients with RP. Here, we show that microglia...
Source: Journal of Clinical Investigation - July 14, 2020 Category: Biomedical Science Authors: Sean K. Wang, Yunlu Xue, Constance L. Cepko Source Type: research

The molecular biology and immune control of chronic Toxoplasma gondii infection
Toxoplasma gondii is an incredibly successful parasite owing in part to its ability to persist within cells for the life of the host. Remarkably, at least 350 host species of T. gondii have been described to date, and it is estimated that 30% of the global human population is chronically infected. The importance of T. gondii in human health was made clear with the first reports of congenital toxoplasmosis in the 1940s. However, the AIDS crisis in the 1980s revealed the prevalence of chronic infection, as patients presented with reactivated chronic toxoplasmosis, underscoring the importance of an intact immune system for pa...
Source: Journal of Clinical Investigation - July 2, 2020 Category: Biomedical Science Authors: Xiao-Yu Zhao, Sarah E. Ewald Source Type: research

A conversation with Jesse Roth
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - July 2, 2020 Category: Biomedical Science Authors: Ushma S. Neill Source Type: research

The multifaceted nature of HIV latency
Although antiretroviral therapies (ARTs) potently inhibit HIV replication, they do not eradicate the virus. HIV persists in cellular and anatomical reservoirs that show minimal decay during ART. A large number of studies conducted during the past 20 years have shown that HIV persists in a small pool of cells harboring integrated and replication-competent viral genomes. The majority of these cells do not produce viral particles and constitute what is referred to as the latent reservoir of HIV infection. Therefore, although HIV is not considered as a typical latent virus, it can establish a state of nonproductive infection u...
Source: Journal of Clinical Investigation - July 2, 2020 Category: Biomedical Science Authors: Caroline Dufour, Pierre Gantner, Rémi Fromentin, Nicolas Chomont Source Type: research

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome
There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job’s syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delay...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Natalia I. Dmitrieva, Avram D. Walts, Dai Phuong Nguyen, Alex Grubb, Xue Zhang, Xujing Wang, Xianfeng Ping, Hui Jin, Zhen Yu, Zu-Xi Yu, Dan Yang, Robin Schwartzbeck, Clifton L. Dalgard, Beth A. Kozel, Mark D. Levin, Russell H. Knutsen, Delong Liu, Joshua Source Type: research

Maternal diesel particle exposure promotes offspring asthma through NK cell–derived granzyme B
Mothers living near high-traffic roads before or during pregnancy are more likely to have children with asthma. Mechanisms are unknown. Using a mouse model, here we showed that maternal exposure to diesel exhaust particles (DEP) predisposed offspring to allergic airway disease (AAD, murine counterpart of human asthma) through programming of their NK cells; predisposition to AAD did not develop in DEP pups that lacked NK cells and was induced in normal pups receiving NK cells from WT DEP pups. DEP NK cells expressed GATA3 and cosecreted IL-13 and the killer protease granzyme B in response to allergen challenge. Extracellula...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Qian Qian, Bidisha Paul Chowdhury, Zehua Sun, Jerica Lenberg, Rafeul Alam, Eric Vivier, Magdalena M. Gorska Source Type: research

Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis
Gasdermin D (GSDMD) induces pyroptosis via the pore-forming activity of its N-terminal domain, cleaved by activated caspases associated with the release of IL-1β. Here, we report a nonpyroptotic role of full-length GSDMD in guiding the release of IL-1β–containing small extracellular vesicles (sEVs) from intestinal epithelial cells (IECs). In response to caspase-8 inflammasome activation, GSDMD, chaperoned by Cdc37/Hsp90, recruits the E3 ligase, NEDD4, to catalyze polyubiquitination of pro–IL-1β, serving as a signal for cargo loading into secretory vesicles. GSDMD and IL-1β colocalize with th...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Katarzyna Bulek, Junjie Zhao, Yun Liao, Nitish Rana, Daniele Corridoni, Agne Antanaviciute, Xing Chen, Han Wang, Wen Qian, William A. Miller-Little, Shadi Swaidani, Fangqiang Tang, Belinda B. Willard, Keith McCrae, Zizhen Kang, George R. Dubyak, Fabio Com Source Type: research

A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer
Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8 (ceroid lipofuscinosis, neuronal, 8). Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system), which recruits lysosomal enzymes at the ER to promote th...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Lakshya Bajaj, Jaiprakash Sharma, Alberto di Ronza, Pengcheng Zhang, Aiden Eblimit, Rituraj Pal, Dany Roman, John R. Collette, Clarissa Booth, Kevin T. Chang, Richard N. Sifers, Sung Y. Jung, Jill M. Weimer, Rui Chen, Randy W. Schekman, Marco Sardiello Source Type: research

Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation
Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that in...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Xiaofei Li, Jing Zhao, Vivek Kasinath, Mayuko Uehara, Liwei Jiang, Naima Banouni, Martina M. McGrath, Takaharu Ichimura, Paolo Fiorina, Dario R. Lemos, Su Ryon Shin, Carl F. Ware, Jonathan S. Bromberg, Reza Abdi Source Type: research

Senescence of fibroblastic reticular cells in draining lymph nodes: immunoregulation following transplantation
The lymph node (LN) is an intriguing site not only for inducing protective effector immunity but also for inducing tolerance against peripherally encountered antigens such as tissue-specific self-antigens that are regionally drained and through draining lymph nodes (DLNs). The dual functions of DLNs in immunity are attributable at least in part to fibroblastic reticular cells (FRCs), which are a major population of the nonhematopoietic compartment in the LN. In this issue of the JCI, Li, Zhao, and colleagues investigated DLNs in the transplantation setting. The authors demonstrated that, following skin transplantation, the...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Zhaoli Sun, James Burdick Source Type: research

Long-range cis-regulatory elements controlling GDF6 expression are essential for ear development
Molecular mechanisms governing the development of the mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in 3 subjects from 2 families with nonsyndromic cochlear aplasia, we identified homozygous 221-kb and 338-kb deletions in a noncoding region on chromosome 8 with an approximately 200-kb overlapping section. Genomic location of the overlapping deleted region started from approximately 350 kb downstream of GDF6, which codes for growth and differentiation factor 6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual showed reduced ex...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Guney Bademci, Clemer Abad, Filiz B. Cengiz, Serhat Seyhan, Armagan Incesulu, Shengru Guo, Suat Fitoz, Emine Ikbal Atli, Nicholas C. Gosstola, Selma Demir, Brett M. Colbert, Gozde Cosar Seyhan, Claire J. Sineni, Duygu Duman, Hakan Gurkan, Cynthia C. Morto Source Type: research

Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability
Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection ef...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Reihaneh Zarrizi, Martin R. Higgs, Karolin Voßgröne, Maria Rossing, Birgitte Bertelsen, Muthiah Bose, Arne Nedergaard Kousholt, Heike Rösner, the COMPLEXO Network, Bent Ejlertsen, Grant S. Stewart, Finn Cilius Nielsen, Claus S. Sørensen Source Type: research

Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson’s disease
Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson’s disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upr...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Souvarish Sarkar, Hai M. Nguyen, Emir Malovic, Jie Luo, Monica Langley, Bharathi N. Palanisamy, Neeraj Singh, Sireesha Manne, Matthew Neal, Michelle Gabrielle, Ahmed Abdalla, Poojya Anantharam, Dharmin Rokad, Nikhil Panicker, Vikrant Singh, Muhammet Ay, A Source Type: research

Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency
Aging is associated with a high prevalence of hypertension due to elevated susceptibility of BP to dietary salt, but its mechanism is unknown. Serum levels of Klotho, an anti-aging factor, decline with age. We found that high salt (HS) increased BP in aged mice and young heterozygous Klotho-knockout mice and was associated with increased vascular expression of Wnt5a and p-MYPT1, which indicate RhoA activity. Not only the Wnt inhibitor LGK974 and the Wnt5a antagonist Box5 but Klotho supplementation inhibits HS-induced BP elevation, similarly to the Rho kinase inhibitor fasudil, associated with reduced p-MYPT1 expression in ...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Wakako Kawarazaki, Risuke Mizuno, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Daigoro Hirohama, Kohei Ueda, Fumiko Kawakami-Mori, Shigeyoshi Oba, Takeshi Marumo, Toshiro Fujita Source Type: research

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
We report that diet-induced obesity (DIO) in mice increased plasma and vascular Aβ42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aβ42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aβ42 infusion into control diet–fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma Aβ42 correlated with diabetes and endothelial dysfunction. Mechanistically, h...
Source: Journal of Clinical Investigation - June 30, 2020 Category: Biomedical Science Authors: Paul J. Meakin, Bethany M. Coull, Zofia Tuharska, Christopher McCaffery, Ioannis Akoumianakis, Charalambos Antoniades, Jane Brown, Kathryn J. Griffin, Fiona Platt, Claire H. Ozber, Nadira Y. Yuldasheva, Natallia Makava, Anna Skromna, Alan Prescott, Alison Source Type: research

Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier
Fowler syndrome is a rare autosomal recessive brain vascular disorder caused by mutation in FLVCR2 in humans. The disease occurs during a critical period of brain vascular development, is characterized by glomeruloid vasculopathy and hydrocephalus, and is almost invariably prenatally fatal. Here, we sought to gain insights into the process of brain vascularization and the pathogenesis of Fowler syndrome by inactivating Flvcr2 in mice. We showed that Flvcr2 was necessary for angiogenic sprouting in the brain, but surprisingly dispensable for maintaining the blood-brain barrier. Endothelial cells lacking Flvcr2 had altered e...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Nicolas Santander, Carlos O. Lizama, Eman Meky, Gabriel L. McKinsey, Bongnam Jung, Dean Sheppard, Christer Betsholtz, Thomas D. Arnold Source Type: research

The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II–associated (RNA Pol II–associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins — CTCF and cohesins — and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant P...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Susmita G. Ramanand, Yong Chen, Jiapei Yuan, Kelly Daescu, Maryou B.K. Lambros, Kathleen E. Houlahan, Suzanne Carreira, Wei Yuan, GuemHee Baek, Adam Sharp, Alec Paschalis, Mohammed Kanchwala, Yunpeng Gao, Adam Aslam, Nida Safdar, Xiaowei Zhan, Ganesh V. R Source Type: research

Dynamic transcriptome analysis unveils key proresolving factors of chronic inflammatory arthritis
Despite recent advances in understanding chronic inflammation remission, global analyses have not been explored to systematically discover genes or pathways underlying the resolution dynamics of chronic inflammatory diseases. Here, we performed time-course gene expression profiling of mouse synovial tissues along progression and resolution of collagen-induced arthritis (CIA) and identified genes associated with inflammation resolution. Through network analysis of these genes, we predicted 3 key secretory factors responsible for the resolution of CIA: Itgb1, Rps3, and Ywhaz. These factors were predominantly expressed by Tre...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Jin-Sun Kong, Ji-Hwan Park, Seung-Ah Yoo, Ki-Myo Kim, Yeung-Jin Bae, Yune-Jung Park, Chul-Soo Cho, Daehee Hwang, Wan-Uk Kim Source Type: research

Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling
Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo. This response is associated with the aberrant formation of primary cilia, an organelle essential for canonical Hh signaling through smoothened, a transmembrane protein targeted by small-molecule...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Catherine R. Cochrane, Vijesh Vaghjiani, Anette Szczepny, W. Samantha N. Jayasekara, Alvaro Gonzalez-Rajal, Kazu Kikuchi, Geoffrey W. McCaughan, Andrew Burgess, Daniel J. Gough, D. Neil Watkins, Jason E. Cain Source Type: research

Microglia complement astrocytes in neuromyelitis optica
Neuromyelitis optica (NMO) is a central nervous system (CNS) inflammatory autoimmune disease caused by antibodies against aquaporin-4 (AQP4) expressed on astrocytes. Binding of AQP4-specific antibodies (NMO-IgG) triggers activation of the complement cascade, which is responsible for astrocyte loss and secondary demyelination. Although the role for the cytolytic complement proteins in astrocyte destruction in NMO is well established, little is known regarding the initial phase of astrocyte injury. In this issue of the JCI, Chen and colleagues evaluated the precytolytic phase when NMO-IgG binds astrocytes in vivo in the abse...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Zahra Moinfar, Scott S. Zamvil Source Type: research

Complement factor H–deficient mice develop spontaneous hepatic tumors
Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH–/–) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH–/– males. Examination of fH–/– ...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Jennifer Laskowski, Brandon Renner, Matthew C. Pickering, Natalie J. Serkova, Peter M. Smith-Jones, Eric T. Clambey, Raphael A. Nemenoff, Joshua M. Thurman Source Type: research

Is innate immunity our best weapon for flattening the curve?
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Leonard Angka, Marisa Market, Michele Ardolino, Rebecca C. Auer Source Type: research

Astrocyte-microglia interaction drives evolving neuromyelitis optica lesion
Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. Activation of cytolytic complement has been implicated as the major effector of tissue destruction that secondarily involves myelin. We investigated early precytolytic events in the evolving pathophysiology of NMO in mice by continuously infusing IgG (NMO patient serum–derived or AQP4-specific mouse monoclonal), without exogenous complement, into the spinal subarachnoid space. Motor impairment and sublytic NMO-compatible immunopathology were IgG...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Tingjun Chen, Vanda A. Lennon, Yong U. Liu, Dale B. Bosco, Yujiao Li, Min-Hee Yi, Jia Zhu, Shihui Wei, Long-Jun Wu Source Type: research

Gut microbiome communication with bone marrow regulates susceptibility to amebiasis
The microbiome provides resistance to infection. However, the underlying mechanisms are poorly understood. We demonstrate that colonization with the intestinal bacterium Clostridium scindens protects from Entamoeba histolytica colitis via innate immunity. Introduction of C. scindens into the gut microbiota epigenetically altered and expanded bone marrow granulocyte-monocyte progenitors (GMPs) and resulted in increased intestinal neutrophils with subsequent challenge with E. histolytica. Introduction of C. scindens alone was sufficient to expand GMPs in gnotobiotic mice. Adoptive transfer of bone marrow from C. scindens&nda...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Stacey L. Burgess, Jhansi L. Leslie, Jashim Uddin, David N. Oakland, Carol Gilchrist, G. Brett Moreau, Koji Watanabe, Mahmoud Saleh, Morgan Simpson, Brandon A. Thompson, David T. Auble, Stephen D. Turner, Natasa Giallourou, Jonathan Swann, Zhen Pu, Jennie Source Type: research

Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome
Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier. Here, we report the characterizations of Mfsd7c-KO mice and compare these characterizations to phenotypic findings in humans with biallelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late-gestation lethality, likely due to CNS phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c-KO embryos was inhibited in cortical ventricu...
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Pazhanichamy Kalailingam, Kai Qi Wang, Xiu Ru Toh, Toan Q. Nguyen, Madhuvanthi Chandrakanthan, Zafrul Hasan, Clair Habib, Aharon Schif, Francesca Clementina Radio, Bruno Dallapiccola, Karin Weiss, Long N. Nguyen Source Type: research

Neuroimaging of hypothalamic mechanisms related to glucose metabolism in anorexia nervosa and obesity
CONCLUSION These results indicate that blunted hypothalamic glucose reactivity might be related to the pathophysiology of AN. This study provides insights for future research, as it is an extended perspective of the traditional primary nonhomeostatic understanding of the disease.FUNDING This study was supported by a grant from the DFG (SI 2087/2-1). (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Joe J. Simon, Marion A. Stopyra, Esther Mönning, Sebastian Sailer, Nora Lavandier, Lars P. Kihm, Martin Bendszus, Hubert Preissl, Wolfgang Herzog, Hans-Christoph Friederich Source Type: research

Cannabis and the developing brain challenge risk perception
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Yasmin L. Hurd Source Type: research

COVID-19, microangiopathy, hemostatic activation, and complement
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - June 23, 2020 Category: Biomedical Science Authors: Wen-Chao Song, Garret A. FitzGerald Source Type: research

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and c...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Marta Palomo-Irigoyen, Encarni Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira-Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia, Daniela Medrano, David Fernández-Ramos, Juan José Lozano, Satoshi Okawa, J Source Type: research

Immune profiling of pediatric solid tumors
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive ...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Rachael L. Terry, Deborah Meyran, David S. Ziegler, Michelle Haber, Paul G. Ekert, Joseph A. Trapani, Paul J. Neeson Source Type: research

Human CRY1 variants associate with attention deficit/hyperactivity disorder
Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeut...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, Source Type: research

Circular RNA-ZNF532 regulates diabetes-induced retinal pericyte degeneration and vascular dysfunction
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Vascular pericyte degeneration is the predominant clinical manifestation of DR, yet the mechanism governing pericyte degeneration is poorly understood. Circular RNAs (circRNAs) play important roles in multiple biological processes and disease progression. Here, we investigated the role of circRNA in pericyte biology and diabetes-induced retinal vascular dysfunction. cZNF532 expression was upregulated in pericytes under diabetic stress, in the retinal vessels of a diabetic murine model, and in the vitreous humor of diabetic patients. cZNF532 ...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Qin Jiang, Chang Liu, Chao-Peng Li, Shan-Shan Xu, Mu-Di Yao, Hui-Min Ge, Ya-Nan Sun, Xiu-Miao Li, Shu-Jie Zhang, Kun Shan, Bai-Hui Liu, Jin Yao, Chen Zhao, Biao Yan Source Type: research

H. pylori infection alters repair of DNA double-strand breaks via SNHG17
Chronic infections can lead to carcinogenesis through inflammation-related mechanisms. Chronic infection of the human gastric mucosa with Helicobacter pylori is a well-known risk factor for gastric cancer. However, the mechanisms underlying H. pylori–induced gastric carcinogenesis are incompletely defined. We aimed to screen and clarify the functions of long noncoding RNAs (lncRNAs) that are differentially expressed in H. pylori–related gastric cancer. We found that lncRNA SNHG17 was upregulated by H. pylori infection and markedly increased the levels of double-strand breaks (DSBs). SNHG17 overexpression correl...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Taotao Han, Xiaohui Jing, Jiayu Bao, Lianmei Zhao, Aidong Zhang, Renling Miao, Hui Guo, Baoguo Zhou, Shang Zhang, Jiazeng Sun, Juan Shi Source Type: research

Ebola virus glycoprotein stimulates IL-18–dependent natural killer cell responses
CONCLUSION This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein.TRIAL REGISTRATION ClinicalTrials.gov NCT02313077.FUNDING United Kingdom Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (grant 115861) and Crucell Holland (now Janssen Vaccines and Prevention B.V.), European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations ...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Helen R. Wagstaffe, Elizabeth A. Clutterbuck, Viki Bockstal, Jeroen N. Stoop, Kerstin Luhn, Macaya Douoguih, Georgi Shukarev, Matthew D. Snape, Andrew J. Pollard, Eleanor M. Riley, Martin R. Goodier Source Type: research

Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activatio...
Source: Journal of Clinical Investigation - June 16, 2020 Category: Biomedical Science Authors: Min-Hee Oh, Im-Hong Sun, Liang Zhao, Robert D. Leone, Im-Meng Sun, Wei Xu, Samuel L. Collins, Ada J. Tam, Richard L. Blosser, Chirag H. Patel, Judson M. Englert, Matthew L. Arwood, Jiayu Wen, Yee Chan-Li, Lukáš Tenora, Pavel Majer, Rana Rais, Barbara S. Source Type: research

Crosstalk between maternal perinatal obesity and offspring dopaminergic circuitry
The mechanism by which maternal obesity influences fetal brain development and behavior is not well understood. In this issue of the JCI, Lippert et al. showed that feeding maternal mice a high-fat diet (HFD) during lactation attenuated the activity of dopamine (DA) midbrain neurons and altered the DA-related behavioral phenotype seen in the offspring. The authors further suggested that the altered excitatory and inhibitory balance between D1 medium spiny neurons (MSN) and D2 MSN mediates this behavioral phenotype. These mechanisms may provide strategies for preventing the negative effects of maternal obesity on offspring ...
Source: Journal of Clinical Investigation - June 10, 2020 Category: Biomedical Science Authors: Yuki Yasumoto, Tamas L. Horvath Source Type: research

Crosstalk between maternal perinatal obesity and offspring dopaminergic circuity
The mechanism by which maternal obesity influences fetal brain development and behavior is not well understood. In this issue of the JCI, Lippert et al. showed that feeding maternal mice a high-fat diet (HFD) during lactation attenuated the activity of dopamine (DA) midbrain neurons and altered the DA-related behavioral phenotype seen in the offspring. The authors further suggested that the altered excitatory and inhibitory balance between D1 medium spiny neurons (MSN) and D2 MSN mediates this behavioral phenotype. These mechanisms may provide strategies for preventing the negative effects of maternal obesity on offspring ...
Source: Journal of Clinical Investigation - June 9, 2020 Category: Biomedical Science Authors: Yuki Yasumoto, Tamas L. Horvath Source Type: research

T follicular regulatory cells and IL-10 promote food antigen–specific IgE
Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell–deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in ...
Source: Journal of Clinical Investigation - June 9, 2020 Category: Biomedical Science Authors: Markus M. Xie, Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Soheila J. Maleki, Barry K. Hurlburt, Joan Cook-Mills, Mark H. Kaplan, Alexander L. Dent Source Type: research