tbuckley/cabot-search huggingface dataset:
Reduced Nephron Endowment in Six2-TGC tg Mice Is Due to Six3 Misexpression by Aberrant Enhancer–Promoter Interactions in the Transgene
Authors: Alison J. Perl, Han Liu, Matthew Hass, Nirpesh Adhikari, Praneet Chaturvedi, Yueh-Chiang Hu, Rulang Jiang, Yaping Liu, Raphael Kopan
Journal: Journal of the American Society of Nephrology (2024)

Key Points Aberrant enhancer–promoter interactions detected by Hi-C drive ectopic expression of Six3 in the Six2TGCtg line. Disruption of Six3 in the Six2TGCtg line restores nephron number, implicating SIX3 interference with SIX2 function in nephron progenitor cell renewal. Background Lifelong kidney function relies on the complement of nephrons generated during mammalian development from a mesenchymal nephron progenitor cell population. Low nephron endowment confers increased susceptibility to CKD. Reduced nephron numbers in the popular Six2TGC transgenic mouse line may be due to disruption of a regulatory gene at the integration site and/or ectopic expression of a gene(s) contained within the transgene. Methods Targeted locus amplification was performed to identify the integration site of the Six2TGC transgene. Genome-wide chromatin conformation capture (Hi-C) datasets were generated from nephron progenitor cells isolated from the Six2TGC +/tg mice, the Cited1 CreERT2/+ control mice, and the Six2TGC +/tg ; Tsc1 +/Flox mice that exhibited restored nephron number compared with Six2TGC +/tg mice. Modified transgenic mice lacking the C-terminal domain of Six3 were used to evaluate the mechanism of nephron number reduction in the Six2TGC +/tg mouse line. Results Targeted locus amplification revealed integration of the Six2TGC transgene within an intron of Cntnap5a on chr1, and Hi-C analysis mapped the precise integration of Six2TGC and Cited1 CreERT2 transgenes to chr1 and chr14, respectively. No changes in topology, accessibility, or expression were observed within the 50-megabase region centered on Cntnap5a in Six2TGC +/tg mice compared with control mice. By contrast, we identified an aberrant regulatory interaction between a Six2 distal enhancer and the Six3 promoter contained within the transgene. Increasing the Six2TGC tg to Six2 locus ratio or removing one Six2 allele in Six2TGC +/tg mice caused severe renal hypoplasia. Furthermore, clustered regularly interspaced short palindromic repeats disruption of Six3 within the transgene ( Six2TGC ∆Six3CT ) restored nephron endowment to wild-type levels and abolished the stoichiometric effect. Conclusions These findings broadly demonstrate the utility of Hi-C data in mapping transgene integration sites and architecture. Data from genetic and biochemical studies together suggest that in Six2TGC kidneys, SIX3 interferes with SIX2 function in nephron progenitor cell renewal through its C-terminal domain.
Associations of residential greenness with bone mineral density and osteoporosis: the modifying effect of genetic susceptibility
Authors: Tingting Tan, Linxi Tang, Xiaoning Guo, Tao Li, Yaohua Tian, Zhengxiao Ouyang
Journal: Annals of the Rheumatic Diseases (2024)

To investigate the associations of residential greenness with bone mineral density and incident osteoporosis, and further evaluate the potential modifying effect of genetic susceptibility.
Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement
Authors: Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, Sasha R Howard
Journal: Endocrine Reviews (2024)

Abstract There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second—termed “mini-puberty”—in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic “mini-puberty” in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.
A simplified algorithm to evaluate the risk of submucosal invasive cancer in large (≥20 mm) nonpedunculated colonic polyps
Authors: Timothy O'Sullivan, Ana Craciun, Karen Byth, Sunil Gupta, Julia Louisa Gauci, Oliver Cronin, Anthony Whitfield, Muhammad Abuarisha, Stephen John Williams, Eric Yong Tat Lee, Nicholas Graeme Burgess, Michael J. Bourke
Journal: Endoscopy (2024)

Abstract Background Recognition of submucosal invasive cancer (SMIC) in large (≥20 mm) nonpedunculated colonic polyps (LNPCPs) informs selection of the optimal resection strategy. LNPCP location, morphology, and size influence the risk of SMIC; however, currently no meaningful application of this information has simplified the process to make it accessible and broadly applicable. We developed a decision-making algorithm to simplify the identification of LNPCP subtypes with increased risk of potential SMIC. Methods Patients referred for LNPCP resection from September 2008 to November 2022 were enrolled. LNPCPs with SMIC were identified from endoscopic resection specimens, lesion biopsies, or surgical outcomes. Decision tree analysis of lesion characteristics identified in multivariable analysis was used to create a hierarchical classification of SMIC prevalence. Results 2451 LNPCPs were analyzed: 1289 (52.6%) were flat, 1043 (42.6%) nodular, and 118 (4.8%) depressed. SMIC was confirmed in 273 of the LNPCPs (11.1%). It was associated with depressed and nodular vs. flat morphology (odds ratios [ORs] 35.7 [95%CI 22.6–56.5] and 3.5 [95%CI 2.6–4.9], respectively; P&lt;0.001); rectosigmoid vs. proximal location (OR 3.2 [95%CI 2.5–4.1]; P&lt;0.001); nongranular vs. granular appearance (OR 2.4 [95%CI 1.9–3.1]; P&lt;0.001); and size (OR 1.12 per 10-mm increase [95%CI 1.05–1.19]; P&lt;0.001). Decision tree analysis targeting SMIC identified eight terminal nodes: SMIC prevalence was 62% in depressed LNPCPs, 19% in nodular rectosigmoid LNPCPs, and 20% in nodular proximal colon nongranular LNPCPs. Conclusions This decision-making algorithm simplifies identification of LNPCPs with an increased risk of potential SMIC. When combined with surface optical evaluation, it facilitates accurate lesion characterization and resection choices.
Efficacy and safety of endoscopic ultrasound-guided hepaticogastrostomy: a meta-regression analysis
Authors: Cecilia Binda, Elton Dajti, Paolo Giuffrida, Margherita Trebbi, Chiara Coluccio, Alessandro Cucchetti, Alessandro Fugazza, Barbara Perini, Giulia Gibiino, Andrea Anderloni, Alessandro Repici, Carlo Fabbri
Journal: Endoscopy (2024)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is a valid option for EUS-guided biliary drainage that has been increasingly used in the last decade. The aims of this study were to provide a systematic review with meta-analysis and meta-regression of the features and outcomes of this procedure.
Human neutrophils drive skin autoinflammation by releasing interleukin (IL)-26
Authors: Alessia Baldo, Jeremy Di Domizio, Ahmad Yatim, Sophie Vandenberghe-Dürr, Raphael Jenelten, Anissa Fries, Lorenzo Grizzetti, François Kuonen, Carle Paul, Robert L. Modlin, Curdin Conrad, Michel Gilliet
Journal: The Journal of Experimental Medicine (2024)

Autoinflammation is a sterile inflammatory process resulting from increased neutrophil infiltration and overexpression of IL-1 cytokines. The factors that trigger these events are, however, poorly understood. By investigating pustular forms of psoriasis, we show that human neutrophils constitutively express IL-26 and abundantly release it from granular stores upon activation. In pustular psoriasis, neutrophil-derived IL-26 drives the pathogenic autoinflammation process by inducing the expression of IL-1 cytokines and chemokines that further recruit neutrophils. This occurs via activation of IL-26R in keratinocytes and via the formation of complexes between IL-26 and microbiota DNA, which trigger TLR9 activation of neutrophils. Thus our findings identify neutrophils as an important source of IL-26 and point to IL-26 as the key link between neutrophils and a self-sustaining autoinflammation loop in pustular psoriasis.
A randomized double‐blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia
Authors: Vanessa Short, Richard Allen, Christopher J. Earley, Huzefa Bahrain, Stella Rineer, Kiumarce Kashi, Jesse Gerb, Michael Auerbach
Journal: American Journal of Hematology (2024)

Abstract Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five‐ to six‐fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open‐label trials have demonstrated symptomatic improvement in RLS following treatment of IDA using oral or intravenous iron supplementation. To date, there have been no randomized double‐blind controlled trials of intravenous iron compared with oral iron for the treatment of RLS patients with IDA. In the current study, oral ferrous sulfate and ferumoxytol were compared for efficacy and speed of response for treatment of RLS occurring in patients with IDA. The planned recruitment for this study was 70 patients with RLS and IDA, to be randomly assigned 1:1 to oral or intravenous iron, using double‐blind, double‐dummy procedures. At Week 6, the primary outcomes of Clinical Global Impression—Improvement score and change from baseline in the International Restless Legs Syndrome Study Group rating scale score were assessed. Due to challenges, performing the clinical trial during the COVID‐19 pandemic, final‐week data were found missing for 30 patients. As a result, in order to maintain the prespecified statistical analysis, an additional 30 patients were recruited. Both IV and oral iron were associated with a marked improvement in RLS symptoms, with no statistically significant difference between treatment groups. No serious adverse events were observed in either treatment group.
The exceptions that prove the rule—a historical view of bedaquiline susceptibility
Authors: Paolo Miotto, Daniela M Cirillo, Thomas Schön, Claudio U Köser
Journal: Genome Medicine (2024)

Abstract In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 ( Rv0678 ), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve the design and analysis of clinical trials, as well as the World Health Organization catalogue of resistance mutations, the global reference for interpreting genotypic antimicrobial susceptibility testing results.
High burden of clonal mast cell disorders and hereditary α‐tryptasemia in patients who need <i>Hymenoptera</i> venom immunotherapy
Authors: Peter Korošec, Gunter J. Sturm, Jonathan J. Lyons, Tinkara Pirc Marolt, Manca Svetina, Mitja Košnik, Mihaela Zidarn, Mark Kačar, Nina Frelih, Nika Lalek, Ajda Demšar Luzar, Samo Zver, Matevž Škerget, Ewa Czarnobilska, Wojciech Dyga, Sanja Popović Grle, Miroslav Samarzija, Lisa Arzt‐Gradwohl, Urban Čerpes, Grzegorz Porebski, Branko Pevec, Eva Schadelbauer, Peter Kopač, Julij Šelb, Matija Rijavec
Journal: Allergy (2024)

Abstract Background In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long‐term effectiveness of VIT. Methods 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms. Results 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [ n = 207 of 610] with Ring‐Messmer grade 3–4 vs. 11% [ n = 78 of 709] with Grade 1–2; p &lt; .0001), whereas only 1.3% ( n = 2 of 152) of controls with LLR and none with asymptomatic sensitization ( n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [ n = 207] in Grade 3–4 vs. 0.001% [ n = 78] in Grade 1–2; p &lt; .0001), and the majority had normal baseline serum tryptase levels (69% [ n = 196 of 285]). All KIT p.D816V‐positive individuals ( n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms ( p &lt; .01), and remarkably, 31.0% ( n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p &lt; .01). Conclusions By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.
<scp>RNA</scp>‐sequencing of paired tape‐strips and skin biopsies in atopic dermatitis reveals key differences
Authors: Blaine Fritz, Anne‐Sofie Halling, Isabel Díaz‐Pinés Cort, Maria Oberländer Christensen, Amalie Thorsti Møller Rønnstad, Caroline Meyer Olesen, Mette Hjorslev Knudgaard, Claus Zachariae, Steffen Heegaard, Jacob P. Thyssen, Thomas Bjarnsholt
Journal: Allergy (2024)

Abstract Background Skin tape‐strips and biopsies are widely used methods for investigating the skin in atopic dermatitis (AD). Biopsies are more commonly used but can cause scarring and pain, whereas tape‐strips are noninvasive but sample less tissue. The study evaluated the performance of skin tape‐strips and biopsies for studying AD. Methods Whole‐transcriptome RNA‐sequencing was performed on paired tape‐strips and biopsies collected from lesional and non‐lesional skin from AD patients ( n = 7) and non‐AD controls ( n = 5). RNA yield, mapping efficiency, and differentially expressed genes (DEGs) for the two methods (tape‐strip/biopsy) and presence of AD (AD/non‐AD) were compared. Results Tape‐strips demonstrated a lower RNA yield (22 vs. 4596 ng) and mapping efficiency to known genes (28% vs. 93%) than biopsies. Gene‐expression profiles of paired tape‐strips and biopsies demonstrated a medium correlation ( R 2 = 0.431). Tape‐strips and biopsies demonstrated systematic differences in measured expression levels of 6483 genes across both AD and non‐AD samples. Tape‐strips preferentially detected many itch (CCL3/CCL4/OSM) and immune‐response (CXCL8/IL4/IL5/IL22) genes as well as markers of epidermal dendritic cells (CD1a/CD207), while certain cytokines (IL18/IL37), skin‐barrier genes (KRT2/FLG2), and dermal fibroblasts markers (COL1A/COL3A) were preferentially detected by biopsies. Tape‐strips identified more DEGs between AD and non‐AD (3157 DEGs) then biopsies (44 DEGs). Tape‐strips also detected higher levels of bacterial mRNA than biopsies. Conclusions This study concludes that tape‐strips and biopsies each demonstrate respective advantages for measuring gene‐expression changes in AD. Thus, the specific skin layers and genes of interest should be considered before selecting either method.
Stem Cell Transplants Might Boost Lung Function in People With COPD
Authors: Samantha Anderer
Journal: JAMA (2024)

An early clinical trial involving 20 participants in China suggests that pulmonary stem cell transplants could benefit patients with chronic obstructive pulmonary disease (COPD). The participants had stage 2 to stage 4 COPD and were between the ages of 40 and 75 years.
Drug-Resistant <i>E coli</i> in Pet Dogs Could Pose Risk to People
Authors: Samantha Anderer
Journal: JAMA (2024)

In a recent study of pet dogs in China, researchers detected the presence of multidrug-resistant (MDR) Escherichia coli in more than half of the bacteria sampled. Because dogs' fecal matter sheds bacteria, these MDR E coli pose a health risk to their owners, the study authors noted in PLOS One.
Mental Well-Being Among Adversity-Exposed Adolescents During the COVID-19 Pandemic
Authors: Julia H. Raney, Shayna Weinstein, Kyle T. Ganson, Alexander Testa, Dylan B. Jackson, Matthew Pantell, David V. Glidden, Claire D. Brindis, Jason M. Nagata
Journal: JAMA Network Open (2024)

Importance Further research is needed to understand factors associated with well-being during the COVID-19 pandemic among adolescents who have experienced adverse childhood experiences (ACEs). Objective To explore factors associated with improved mental health during the COVID-19 pandemic among adolescents who have experienced ACEs. Design, Setting, and Participants This cross-sectional study used data from the baseline (2016-2018) and sixth (March 2021) COVID Rapid Response Research (RRR) surveys of the Adolescent Brain Cognitive Development study, which includes 21 sites across the US. Adolescents aged 11 to 15 years who completed the COVID RRR mental health measures were included. Data analyses were conducted from June to August 2023. Exposures School-based factors (eg, in-person school) and 8 coping behaviors (eg, exercise). Main Outcomes and Measures The primary outcomes were adolescent-reported positive affect (PA) and perceived stress (PS). Adolescents were stratified by no ACEs, low-to-intermediate ACEs (1-3), and high ACEs (≥4). Linear regressions estimated associations between factors and mental health, adjusting for potential confounders. Unstandardized beta coefficients (B) were compared with equality of coefficients tests. Results The 4515 adolescents in this study (mean [SD] age, 13.3 [0.88] years; 51% [95% CI, 50% to 53%] female) were racially and ethnically diverse (American Indian/Alaska Native, 2% [95% CI, 2% to 3%]; Asian, 8% [95% CI, 7% to 9%]; Black, 11% [95% CI, 10% to 12%]; Latino or Hispanic, 17% [95% CI, 15% to 18%]; White, 61% [95% CI, 60% to 63%]; other, 1% [95% CI, 0% to 2%]). For youths with high ACEs, caring for one’s body (PA B = 4.02 [95% CI, 1.39 to 6.66]; PS B = −0.92 [95% CI, −1.84 to 0.00]), exercising (PA B = 3.19 [95% CI, 0.46 to 5.92]; PS B = −1.41 [95% CI, −2.40 to −0.43]), and engaging in healthy behaviors (PA B = 4.07 [95% CI, 1.28 to 6.84]; PS B = −1.01 [95% CI, −1.98 to −0.05]) were associated with higher PA and lower PS scores. In-person schooling had a greater impact on PA scores for youths with high ACEs (B = 5.55 [95% CI, 2.08 to 9.01]) than youths with low-to-intermediate ACEs (B = 1.27 [95% CI, 0.27 to 2.27]). Conclusions and Relevance These findings suggest that in-person schooling and several coping behaviors (caring for one’s body, exercising, and engaging in healthy behaviors) were associated with significantly higher PA and lower PS during the COVID-19 pandemic among adolescents with high ACEs. Adolescents with high ACEs demonstrated especially greater mental health scores when they reported in-person schooling. Future studies should build on these findings to identify clinical and school-based mental health protective factors for adolescents with high ACE risk.
Adolescent Psychedelic Use and Psychotic or Manic Symptoms
Authors: Otto Simonsson, Miriam A. Mosing, Walter Osika, Fredrik Ullén, Henrik Larsson, Yi Lu, Laura W. Wesseldijk
Journal: JAMA Psychiatry (2024)

Importance While psychedelic-assisted therapy has shown promise in the treatment of certain psychiatric disorders, little is known about the potential risk of psychotic or manic symptoms following naturalistic psychedelic use, especially among adolescents. Objective To investigate associations between naturalistic psychedelic use and self-reported psychotic or manic symptoms in adolescents using a genetically informative design. Design, Setting, and Participants This study included a large sample of adolescent twins (assessed at age 15, 18, and 24 years) born between July 1992 and December 2005 from the Swedish Twin Registry and cross-sectionally evaluated the associations between past psychedelic use and psychotic or manic symptoms at age 15 years. Individuals were included if they answered questions related to past use of psychedelics. Data were analyzed from October 2022 to November 2023. Main Outcomes and Measures Primary outcome measures were self-reported psychotic and manic symptoms at age 15 years. Lifetime use of psychedelics and other drugs was also assessed at the same time point. Results Among the 16 255 participants included in the analyses, 8889 were female and 7366 were male. Among them, 541 participants reported past use of psychedelics, most of whom (535 of 541 [99%]) also reported past use of other drugs (ie, cannabis, stimulants, sedatives, opioids, inhalants, or performance enhancers). When adjusting for substance-specific and substance-aggregated drug use, psychedelic use was associated with reduced psychotic symptoms in both linear regression analyses (β , −0.79; 95% CI, −1.18 to −0.41 and β , −0.39; 95% CI, −0.50 to −0.27, respectively) and co-twin control analyses (β , −0.89; 95% CI, −1.61 to −0.16 and β , −0.24; 95% CI, −0.48 to −0.01, respectively). In relation to manic symptoms, likewise adjusting for substance-specific and substance-aggregated drug use, statistically significant interactions were found between psychedelic use and genetic vulnerability to schizophrenia (β , 0.17; 95% CI, 0.01 to 0.32 and β , 0.17; 95% CI, 0.02 to 0.32, respectively) or bipolar I disorder (β , 0.20; 95% CI, 0.04 to 0.36 and β , 0.17; 95% CI, 0.01 to 0.33, respectively). Conclusions and Relevance The findings in this study suggest that, after adjusting for other drug use, naturalistic use of psychedelic may be associated with lower rates of psychotic symptoms among adolescents. At the same time, the association between psychedelic use and manic symptoms seems to be associated with genetic vulnerability to schizophrenia or bipolar I disorder. These findings should be considered in light of the study’s limitations and should therefore be interpreted with caution.