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Enhancing Vascularized Composite Allograft Supercooling Preservation: A Multifaceted Approach with CPA Optimization, Thermal Tracking, and Stepwise Loading Techniques. 增强血管化复合异体移植物的过冷保护:采用 CPA 优化、热跟踪和逐步加载技术的多层面方法。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4431685/v1
Irina Filz von Reiterdank, Antonia T Dinicu, Curtis L Cetrulo, J H Coert, Aebele B Mink van der Molen, Korkut Uygun
{"title":"Enhancing Vascularized Composite Allograft Supercooling Preservation: A Multifaceted Approach with CPA Optimization, Thermal Tracking, and Stepwise Loading Techniques.","authors":"Irina Filz von Reiterdank, Antonia T Dinicu, Curtis L Cetrulo, J H Coert, Aebele B Mink van der Molen, Korkut Uygun","doi":"10.21203/rs.3.rs-4431685/v1","DOIUrl":"10.21203/rs.3.rs-4431685/v1","url":null,"abstract":"<p><p>Vascularized composite allografts (VCAs) present unique challenges in transplant medicine, owing to their complex structure and vulnerability to ischemic injury. Innovative preservation techniques are crucial for extending the viability of these grafts, from procurement to transplantation. This study addresses these challenges by integrating cryoprotectant agent (CPA) optimization, advanced thermal tracking, and stepwise CPA loading strategies within an ex vivo rodent model. CPA optimization focused on various combinations, identifying those that effectively suppress ice nucleation while mitigating cytotoxicity. Thermal dynamics were monitored using invasive thermocouples and non-invasive FLIR imaging, yielding detailed temperature profiles crucial for managing warm ischemia time and optimizing cooling rates. The efficacy of stepwise CPA loading versus conventional flush protocols demonstrated that stepwise (un)loading significantly improved arterial resistance and weight change outcomes. In summary, this study presents comprehensive advancements in VCA preservation strategies, combining CPA optimization, precise thermal monitoring, and stepwise loading techniques. These findings hold potential implications for refining transplantation protocols and improving graft viability in VCA transplantation.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
UW Supplementation with AP39 Improves Liver Viability Following Static Cold Storage. 华大补充 AP39 可提高静态冷藏后的肝脏活力
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4487319/v1
S Taggart McLean, Saige Holkup, Alexandra Tchir, Mohammadreza Mojoudi, Madeeha Hassan, Christopher Taveras, S Ozgur Ozge, F Markmann James, Heidi Yeh, Korkut Uygun, Alban Longchamp
{"title":"UW Supplementation with AP39 Improves Liver Viability Following Static Cold Storage.","authors":"S Taggart McLean, Saige Holkup, Alexandra Tchir, Mohammadreza Mojoudi, Madeeha Hassan, Christopher Taveras, S Ozgur Ozge, F Markmann James, Heidi Yeh, Korkut Uygun, Alban Longchamp","doi":"10.21203/rs.3.rs-4487319/v1","DOIUrl":"10.21203/rs.3.rs-4487319/v1","url":null,"abstract":"<p><p>Static cold storage of donor livers at 4°C incompletely arrests metabolism, ultimately leading to decreases in ATP levels, oxidative stress, cell death, and organ failure. Hydrogen Sulfide (H<sub>2</sub>S) is an endogenously produced gas, previously demonstrated to reduce oxidative stress, reduce ATP depletion, and protect from ischemia and reperfusion injury. H<sub>2</sub>S is difficult to administer due to its rapid release curve, resulting in cellular death at high concentrations. AP39, a mitochondrially targeted, slow-release H<sub>2</sub>S donor, has been shown to reduce ischemia-reperfusion injury in hearts and kidneys. Thus, we investigated whether the addition of AP39 during 3-day static cold storage can improve liver graft viability. At the end of storage, livers underwent six hours of acellular normothermic machine perfusion, a model of transplantation. During simulated transplantation, livers stored with AP39 showed reduced resistance, reduced cellular damage (ALT and AST), and reduced apoptosis. Additionally, bile production and glucose, as well as energy charge were improved by the addition of AP39. These results indicate that AP39 supplementation improves liver viability during static cold storage.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Use of Real-World Data and Machine Learning to Screen for Maternal and Paternal Characteristics Associated with Cardiac Malformations. 利用真实世界数据和机器学习筛选与心脏畸形相关的母体和父体特征。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4490534/v1
Jeremy Brown, Krista Huybrechts, Loreen Straub, Dominik Heider, Brian Bateman, Sonia Hernandez-Diaz
{"title":"Use of Real-World Data and Machine Learning to Screen for Maternal and Paternal Characteristics Associated with Cardiac Malformations.","authors":"Jeremy Brown, Krista Huybrechts, Loreen Straub, Dominik Heider, Brian Bateman, Sonia Hernandez-Diaz","doi":"10.21203/rs.3.rs-4490534/v1","DOIUrl":"10.21203/rs.3.rs-4490534/v1","url":null,"abstract":"<p><p>Effective prevention of cardiac malformations, a leading cause of infant morbidity, is constrained by limited understanding of etiology. The study objective was to screen for associations between maternal and paternal characteristics and cardiac malformations. We selected 720,381 pregnancies linked to live-born infants (n=9,076 cardiac malformations) in 2011-2021 MarketScan US insurance claims data. Odds ratios were estimated with clinical diagnostic and medication codes using logistic regression. Screening of 2,000 associations selected 81 associated codes at the 5% false discovery rate. Grouping of selected codes, using latent semantic analysis and the Apriori-SD algorithm, identified elevated risk with known risk factors, including maternal diabetes and chronic hypertension. Less recognized potential signals included maternal fingolimod or azathioprine use. Signals identified might be explained by confounding, measurement error, and selection bias and warrant further investigation. The screening methods employed identified known risk factors, suggesting potential utility for identifying novel risk factors for other pregnancy outcomes.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antibiotic treatment induces microbiome dysbiosis and reduction of neuroinflammation following traumatic brain injury in mice. 抗生素治疗可诱导小鼠脑外伤后微生物群失调并减轻神经炎症。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4475195/v1
Hannah Flinn, Austin Marshall, Morgan Holcomb, Leonardo Cruz, Sirena Soriano, Todd J Treangen, Sonia Villapol
{"title":"Antibiotic treatment induces microbiome dysbiosis and reduction of neuroinflammation following traumatic brain injury in mice.","authors":"Hannah Flinn, Austin Marshall, Morgan Holcomb, Leonardo Cruz, Sirena Soriano, Todd J Treangen, Sonia Villapol","doi":"10.21203/rs.3.rs-4475195/v1","DOIUrl":"10.21203/rs.3.rs-4475195/v1","url":null,"abstract":"<p><strong>Background: </strong>The gut microbiome is linked to brain pathology in cases of traumatic brain injury (TBI), yet the specific bacteria that are implicated are not well characterized. To address this gap, in this study, we induced traumatic brain injury (TBI) in male C57BL/6J mice using the controlled cortical impact (CCI) injury model. After 35 days, we administered a broad-spectrum antibiotics (ABX) cocktail (ampicillin, gentamicin, metronidazole, vancomycin) through oral gavage for 2 days to diminish existing microbiota. Subsequently, we inflicted a second TBI on the mice and analyzed the neuropathological outcomes five days later.</p><p><strong>Results: </strong>Longitudinal analysis of the microbiome showed significant shifts in the diversity and abundance of bacterial genera during both acute and chronic inflammation. These changes were particularly dramatic following treatment with ABX and after the second TBI. ABX treatment did not affect the production of short-chain fatty acids (SCFA) but did alter intestinal morphology, characterized by reduced villus width and a lower count of goblet cells, suggesting potential negative impacts on intestinal integrity. Nevertheless, diminishing the intestinal microbiome reduced cortical damage, apoptotic cell density, and microglial/macrophage activation in the cortical and thalamic regions of the brain.</p><p><strong>Conclusions: </strong>Our findings suggest that eliminating colonized gut bacteria via broad-spectrum ABX reduces neuroinflammation and enhances neurological outcomes in TBI despite implications to gut health.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endothelial cell Notch signaling programs cancer-associated fibroblasts to promote tumor immune evasion. 内皮细胞 Notch 信号传导程序可使癌症相关成纤维细胞促进肿瘤免疫逃避。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4538031/v1
Yu Zhu, Menglan Xiang, Kevin F Brulois, Nicole H Lazarus, Junliang Pan, Eugene C Butcher
{"title":"Endothelial cell Notch signaling programs cancer-associated fibroblasts to promote tumor immune evasion.","authors":"Yu Zhu, Menglan Xiang, Kevin F Brulois, Nicole H Lazarus, Junliang Pan, Eugene C Butcher","doi":"10.21203/rs.3.rs-4538031/v1","DOIUrl":"10.21203/rs.3.rs-4538031/v1","url":null,"abstract":"<p><p>Stromal cells within the tumor tissue promote immune evasion as a critical strategy for cancer development and progression, but the underlying mechanisms remain poorly understood. In this study, we explore the role of endothelial cells (ECs) in the regulation of the immunosuppressive tumor microenvironment. Using mouse pancreatic ductal adenocarcinoma (PDAC) models, we found that canonical Notch signaling in endothelial cells suppresses the recruitment of antitumor T cells and promotes tumor progression by inhibiting the pro-inflammatory functions of cancer-associated fibroblasts (CAFs). Abrogation of endothelial Notch signaling modulates EC-derived angiocrine factors to enhance the pro-inflammatory activities of CAFs, which drive CXCL9/10-CXCR3-mediated T cell recruitment to inhibit tumor growth. Additionally, abrogation of endothelial Notch unleashed interferon gamma responses in the tumor microenvironment, upregulated PDL1 expression on tumor cells, and sensitized PDAC to PD1-based immunotherapy. Collectively, these data uncover a pivotal role of endothelial cells in shaping the immunosuppressive microenvironment, and suggest the potential of targeting EC-CAF interaction as a novel therapeutic modality to boost antitumor immunity.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of Tyr34 in proton-coupled electron transfer of human manganese superoxide dismutase. Tyr34 在人锰超氧化物歧化酶质子耦合电子传递中的作用。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4494128/v1
Gloria Borgstahl, Jahaun Azadmanesh, Katelyn Slobodnik, Lucas Struble, Erika Cone, Medhanjali Dasgupta, William Lutz, Siddhartha Kumar, Amarnath Natarajan, Leighton Coates, Kevin Weiss, Dean Myles, Thomas Kroll
{"title":"The role of Tyr34 in proton-coupled electron transfer of human manganese superoxide dismutase.","authors":"Gloria Borgstahl, Jahaun Azadmanesh, Katelyn Slobodnik, Lucas Struble, Erika Cone, Medhanjali Dasgupta, William Lutz, Siddhartha Kumar, Amarnath Natarajan, Leighton Coates, Kevin Weiss, Dean Myles, Thomas Kroll","doi":"10.21203/rs.3.rs-4494128/v1","DOIUrl":"10.21203/rs.3.rs-4494128/v1","url":null,"abstract":"<p><p>Human manganese superoxide dismutase (MnSOD) plays a crucial role in controlling levels of reactive oxygen species (ROS) by converting superoxide (O<sub>2</sub> <sup>●-</sup>) to molecular oxygen (O<sub>2</sub>) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) with proton-coupled electron transfers (PCETs). The reactivity of human MnSOD is determined by the state of a key catalytic residue, Tyr34, that becomes post-translationally inactivated by nitration in various diseases associated with mitochondrial dysfunction. We previously reported that Tyr34 has an unusual pK<sub>a</sub> due to its proximity to the Mn metal and undergoes cyclic deprotonation and protonation events to promote the electron transfers of MnSOD. To shed light on the role of Tyr34 MnSOD catalysis, we performed neutron diffraction, X-ray spectroscopy, and quantum chemistry calculations of Tyr34Phe MnSOD in various enzymatic states. The data identifies the contributions of Tyr34 in MnSOD activity that support mitochondrial function and presents a thorough characterization of how a single tyrosine modulates PCET catalysis.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Human Organoids for Rapid Validation of Gene Variants Linked to Cochlear Malformations. 用于快速验证与耳蜗畸形有关的基因变异的人体器官模型。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4474071/v1
Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin
{"title":"Human Organoids for Rapid Validation of Gene Variants Linked to Cochlear Malformations.","authors":"Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin","doi":"10.21203/rs.3.rs-4474071/v1","DOIUrl":"10.21203/rs.3.rs-4474071/v1","url":null,"abstract":"<p><p>Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital deafness. Most patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected <i>FGF3</i> (p.Arg165Gly) and <i>GREB1L</i> (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and <i>PBXIP1</i>(p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed significant developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a tool to rapidly validate the pathogenicity of DNA variants associated with cochlear malformations.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative responses to demethylating therapy in animal models of osteosarcoma. 骨肉瘤动物模型对去甲基化疗法的比较反应。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4451060/v1
Shan Huang, Ling Ren, Jessica A Beck, Sushant Patkar, Maria Angeles Lillo Osuna, Aswini Cherukuri, Christina Mazcko, Susan A Krum, Amy K LeBlanc
{"title":"Comparative responses to demethylating therapy in animal models of osteosarcoma.","authors":"Shan Huang, Ling Ren, Jessica A Beck, Sushant Patkar, Maria Angeles Lillo Osuna, Aswini Cherukuri, Christina Mazcko, Susan A Krum, Amy K LeBlanc","doi":"10.21203/rs.3.rs-4451060/v1","DOIUrl":"10.21203/rs.3.rs-4451060/v1","url":null,"abstract":"<p><strong>Background: </strong>The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown.</p><p><strong>Methods: </strong>Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC <i>in vitro</i> and <i>in vivo</i>, respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry.</p><p><strong>Results: </strong>ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth <i>in vitro</i> and <i>in vivo</i>. Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways.</p><p><strong>Conclusion: </strong>DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Characterization of the family-level Borreliaceae pan-genome and development of an episomal typing protocol. 确定包柔氏菌科级泛基因组的特征并制定外显子分型方案。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4491589/v1
Kayla M Socarras, Mary C Marino, Joshua P Earl, Rachel L Ehrlich, Nicholas A Cramer, Joshua C Mell, Bhaswati Sen, Azad Ahmed, Richard T Marconi, Garth D Ehrlich
{"title":"Characterization of the family-level Borreliaceae pan-genome and development of an episomal typing protocol.","authors":"Kayla M Socarras, Mary C Marino, Joshua P Earl, Rachel L Ehrlich, Nicholas A Cramer, Joshua C Mell, Bhaswati Sen, Azad Ahmed, Richard T Marconi, Garth D Ehrlich","doi":"10.21203/rs.3.rs-4491589/v1","DOIUrl":"10.21203/rs.3.rs-4491589/v1","url":null,"abstract":"<p><strong>Background: </strong>The <i>Borreliaceae</i> family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease and vector-borne relapsing fevers. Infections by the <i>Borreliaceae</i> are difficult to detect by both direct and indirect methods, often leading to delayed and missed diagnoses. Efforts to improve diagnoses center around the development of molecular diagnostics (MDx), but due to deep tissue sequestration of the causative spirochaetes and the lack of persistent bacteremias, even MDx assays suffer from a lack of sensitivity. Additionally, the highly extensive genomic heterogeneity among isolates, even within the same species, contributes to the lack of assay sensitivity as single target assays cannot provide universal coverage. This within-species heterogeneity is partly due to differences in replicon repertoires and genomic structures that have likely arisen to support the complex <i>Borreliaceae</i> lifecycle in which these parasites have to survive in multiple hosts each with unique immune responses.</p><p><strong>Results: </strong>We constructed a <i>Borreliaceae</i> family-level pangenome and characterized the phylogenetic relationships among the constituent taxa which supports the recent taxonomy of splitting the family into at least two genera. Gene content pro les were created for the majority of the <i>Borreliaceae</i> replicons, providing for the first time their unambiguous molecular typing.</p><p><strong>Conclusion: </strong>Our characterization of the <i>Borreliaceae</i> pan-genome supports the splitting of the former <i>Borrelia</i> genus into two genera and provides for the phylogenetic placement of several non-species designated isolates. Mining this family-level pangenome will enable precision diagnostics corresponding to gene content-driven clinical outcomes while also providing targets for interventions.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferences. 南非家长对神经发育障碍基因组研究成果返还的看法:预期影响和偏好。
Research square Pub Date : 2024-06-11 DOI: 10.21203/rs.3.rs-4448155/v1
Angelique Diedericks, Zandré Bruwer, Nakita Laing, Emma Eastman, Jantina De Vries De Vries, Kirsten A Donald, Elise B Robinson, Charles R Newton, Amina Abubakar
{"title":"Parental Perspectives Regarding the Return of Genomic Research Results in Neurodevelopmental Disorders in South Africa: Anticipated Impact and Preferences.","authors":"Angelique Diedericks, Zandré Bruwer, Nakita Laing, Emma Eastman, Jantina De Vries De Vries, Kirsten A Donald, Elise B Robinson, Charles R Newton, Amina Abubakar","doi":"10.21203/rs.3.rs-4448155/v1","DOIUrl":"10.21203/rs.3.rs-4448155/v1","url":null,"abstract":"<p><p>Few policies and little research exist regarding the disclosure of genomic results to research participants in Africa. As understanding participant preferences would be pivotal to the success of the feedback process, this study set out to address this issue by engaging with enrolled participants from an ongoing genomics research project on neurodevelopmental disorders with the aim to assess the anticipated impact of receiving pertinent results and explore the preferences for feedback in a South-African context. Twelve semi-structured interviews were conducted with 17 parents of children participating in the research study. Transcribed interview data and observational notes were analysed using thematic analysis and framework matrices. Participants linked their own meaning to the impact of receiving a pertinent result and perceived the information as useful for reasons other than only clinical utility. These included closure, improved management of their child's condition and information regarding recurrence risks. In terms of preferences for feedback, an in-person result delivery session, conducted by a member of the study team or medical professional familiar with their child was preferred. In addition, participants felt a sense of ownership over their blood or their contribution to the research study, finding meaning even in non-pertinent (secondary findings) or negative results. These findings provide insight into the type of discussions that may be valuable in enabling the development of best practices and guidelines for the return of individual genetic research results, in a culturally appropriate manner, within South-African communities.</p>","PeriodicalId":94282,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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