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  • ItemOpen Access
    Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.
    (NeuroImage, 2023-12) Zhu, Xi; Kim, Yoojean; Ravid, Orren; He, Xiaofu; Suarez-Jimenez, Benjamin; Zilcha-Mano, Sigal; Lazarov, Amit; Lee, Seonjoo; Abdallah, Chadi G; Angstadt, Michael; Averill, Christopher L; Baird, C Lexi; Baugh, Lee A; Blackford, Jennifer U; Bomyea, Jessica; Bruce, Steven E; Bryant, Richard A; Cao, Zhihong; Choi, Kyle; Cisler, Josh; Cotton, Andrew S; Daniels, Judith K; Davenport, Nicholas D; Davidson, Richard J; DeBellis, Michael D; Dennis, Emily L; Densmore, Maria; deRoon-Cassini, Terri; Disner, Seth G; Hage, Wissam El; Etkin, Amit; Fani, Negar; Fercho, Kelene A; Fitzgerald, Jacklynn; Forster, Gina L; Frijling, Jessie L; Geuze, Elbert; Gonenc, Atilla; Gordon, Evan M; Gruber, Staci; Grupe, Daniel W; Guenette, Jeffrey P; Haswell, Courtney C; Herringa, Ryan J; Herzog, Julia; Hofmann, David Bernd; Hosseini, Bobak; Hudson, Anna R; Huggins, Ashley A; Ipser, Jonathan C; Jahanshad, Neda; Jia-Richards, Meilin; Jovanovic, Tanja; Kaufman, Milissa L; Kennis, Mitzy; King, Anthony; Kinzel, Philipp; Koch, Saskia BJ; Koerte, Inga K; Koopowitz, Sheri M; Korgaonkar, Mayuresh S; Krystal, John H; Lanius, Ruth; Larson, Christine L; Lebois, Lauren AM; Li, Gen; Liberzon, Israel; Lu, Guang Ming; Luo, Yifeng; Magnotta, Vincent A; Manthey, Antje; Maron-Katz, Adi; May, Geoffery; McLaughlin, Katie; Mueller, Sven C; Nawijn, Laura; Nelson, Steven M; Neufeld, Richard WJ; Nitschke, Jack B; O'Leary, Erin M; Olatunji, Bunmi O; Olff, Miranda; Peverill, Matthew; Phan, K Luan; Qi, Rongfeng; Quidé, Yann; Rektor, Ivan; Ressler, Kerry; Riha, Pavel; Ross, Marisa; Rosso, Isabelle M; Salminen, Lauren E; Sambrook, Kelly; Schmahl, Christian; Shenton, Martha E; Sheridan, Margaret; Shih, Chiahao; Sicorello, Maurizio; Sierk, Anika; Simmons, Alan N; Simons, Raluca M; Simons, Jeffrey S; Sponheim, Scott R; Stein, Murray B; Stein, Dan J; Stevens, Jennifer S; Straube, Thomas; Sun, Delin; Théberge, Jean; Thompson, Paul M; Thomopoulos, Sophia I; van der Wee, Nic JA; van der Werff, Steven JA; van Erp, Theo GM; van Rooij, Sanne JH; van Zuiden, Mirjam; Varkevisser, Tim; Veltman, Dick J; Vermeiren, Robert RJM; Walter, Henrik; Wang, Li; Wang, Xin; Weis, Carissa; Winternitz, Sherry; Xie, Hong; Zhu, Ye; Wall, Melanie; Neria, Yuval; Morey, Rajendra A

    Background

    Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.

    Methods

    We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.

    Results

    We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance.

    Conclusion

    These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.
  • ItemOpen Access
    Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity.
    (Nature communications, 2018-04) Joas, Simone; Parrish, Erica H; Gnanadurai, Clement W; Lump, Edina; Stürzel, Christina M; Parrish, Nicholas F; Learn, Gerald H; Sauermann, Ulrike; Neumann, Berit; Rensing, Kerstin Mätz; Fuchs, Dietmar; Billingsley, James M; Bosinger, Steven E; Silvestri, Guido; Apetrei, Cristian; Huot, Nicolas; Garcia-Tellez, Thalia; Müller-Trutwin, Michaela; Hotter, Dominik; Sauter, Daniel; Stahl-Hennig, Christiane; Hahn, Beatrice H; Kirchhoff, Frank
    HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.
  • ItemOpen Access
    Bronchoalveolar Tregs are associated with duration of mechanical ventilation in acute respiratory distress syndrome.
    (Journal of translational medicine, 2020-11) Norton, Dustin L; Ceppe, Agathe; Tune, Miriya K; McCravy, Matthew; Devlin, Thomas; Drummond, M Bradley; Carson, Shannon S; Vincent, Benjamin G; Hagan, Robert S; Dang, Hong; Doerschuk, Claire M; Mock, Jason R

    Background

    Foxp3+ regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4+ T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples.

    Methods

    We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48-96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4+ T cells that were Tregs.

    Results

    The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood.

    Conclusion

    Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4+ cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.
  • ItemOpen Access
    Wood smoke particle exposure in mice reduces the severity of influenza infection.
    (Toxicology and applied pharmacology, 2021-09) Vose, Aaron; McCravy, Matthew; Birukova, Anastasiya; Yang, Zhonghui; Hollingsworth, John W; Que, Loretta G; Tighe, Robert M
    Elevated ambient temperatures and extreme weather events have increased the incidence of wildfires world-wide resulting in increased wood smoke particle (WSP). Epidemiologic data suggests that WSP exposure associates with exacerbations of respiratory diseases, and with increased respiratory viral infections. To assess the impact of WSP exposure on host response to viral pneumonia, we performed WSP exposures in rodents followed by infection with mouse adapted influenza (HINI-PR8). C57BL/6 male mice aged 6-8 weeks were challenged with WSP or PBS by oropharyngeal aspiration in acute (single dose) or sub-acute exposures (day 1, 3, 5, 7 and 10). Additional groups underwent sub-acute exposure followed by infection by influenza or heat-inactivated (HI) virus. Following exposures/infection, bronchoalveolar lavage (BAL) was performed to assess for total cell counts/differentials, total protein, protein carbonyls and hyaluronan. Lung tissue was assessed for viral counts by real time PCR. When compared to PBS, acute WSP exposure associated with an increase in airspace macrophages. Alternatively, sub-acute exposure resulted in a dose dependent increase in airspace neutrophils. Sub-acute WSP exposure followed by influenza infection was associated with improved respiratory viral outcomes including reduced weight loss and increased blood oxygen saturation, and decreased protein carbonyls and viral titers. Flow cytometry demonstrated dynamic changes in pulmonary macrophage and T cell subsets based on challenge with WSP and influenza. This data suggests that sub-acute WSP exposure can improve host response to acute influenza infection.
  • ItemOpen Access
    Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions.
    (Blood advances, 2024-02) Bracken, Sonali J; Suthers, Amy N; DiCioccio, Rachel A; Su, Hsuan; Anand, Sarah; Poe, Jonathan C; Jia, Wei; Visentin, Jonathan; Basher, Fahmin; Jordan, Collin Z; McManigle, William C; Li, Zhiguo; Hakim, Frances T; Pavletic, Steven Z; Bhuiya, Nazmim S; Ho, Vincent T; Horwitz, Mitchell E; Chao, Nelson J; Sarantopoulos, Stefanie

    Abstract

    Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.
  • ItemOpen Access
    Single-cell landscape analysis unravels molecular programming of the human B cell compartment in chronic GVHD.
    (JCI insight, 2023-06) Poe, Jonathan C; Fang, Jiyuan; Zhang, Dadong; Lee, Marissa R; DiCioccio, Rachel A; Su, Hsuan; Qin, Xiaodi; Zhang, Jennifer Y; Visentin, Jonathan; Bracken, Sonali J; Ho, Vincent T; Wang, Kathy S; Rose, Jeremy J; Pavletic, Steven Z; Hakim, Frances T; Jia, Wei; Suthers, Amy N; Curry-Chisolm, Itaevia M; Horwitz, Mitchell E; Rizzieri, David A; McManigle, William C; Chao, Nelson J; Cardones, Adela R; Xie, Jichun; Owzar, Kouros; Sarantopoulos, Stefanie
    Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.
  • ItemOpen Access
    Anatomy of provincial level inequality in maternal mortality in China during 2004-2016: a new decomposition analysis.
    (BMC public health, 2020-05) Zhang, Xinyu; Ye, Yingfeng; Fu, Chaowei; Dou, Guanshen; Ying, Xiaohua; Qian, Mengcen; Tang, Shenglan

    Background

    The maternal mortality ratio (MMR) is an important indicator of maternal health and socioeconomic development. Although China has experienced a large decline in MMR, substantial disparities across regions are still apparent. This study aims to explore causes of socioeconomic related inequality in MMR at the province-level in China from 2004 to 2016.

    Methods

    We collected data from various issues of the China Health Statistics Yearbook, China Statistics Yearbook, and China Population and Employment Statistics Yearbook to construct a longitudinal sample of all provinces in China. We first examined determinants of the MMR using province fixed-effect models, accounted for socioeconomic condition, health resource allocation, and access to health care. We then used the concentration index (CI) to measure MMR inequality and employed the direct decomposition method to estimate the marginal impact of the determinants on the inequality index. Importance of the determinants were compared based on logworth values.

    Results

    During our study period, economically more deprived provinces experienced higher MMR than better-off ones. There was no evidence of improved socioeconomic related inequality in MMR. Illiteracy proportion was positively associated with the MMR (p < 0.01). In contrast, prenatal check-up rate (p = 0.05), hospital delivery rate (p < 0.01) and rate of delivery attended by professionals (p = 0.02) were negatively associated with the MMR. We also find that higher maternal health profile creation rate (p < 0.01) was associated with a pro-poor change of MMR inequality.

    Conclusion

    Access to healthcare was the most important factor in explaining the persistent MMR inequality in China, followed by socioeconomic condition. We do not find evidence that health resource allocation was a contributing factor.
  • ItemOpen Access
    The pilot of a new patient classification-based payment system in China: The impact on costs, length of stay and quality
    (Social Science & Medicine, 2021-11) Qian, Mengcen; Zhang, Xinyu; Chen, Yajing; Xu, Su; Ying, Xiaohua
  • ItemOpen Access
    Pathway to Adjustment of Relative Weight in DRG Payment System Reform in Shanghai
    (Chinese Health Resources, 2022-01-20) Zhang, Xinyu; Lyu, Dawei; Qian, Mengcen; Yan, Jiaqi; Xu, Hong; Shen, Yi; Ying, Xiaohua
  • ItemOpen Access
    How do inpatients’ costs, length of stay, and quality of care vary across age groups after a new case-based payment reform in China? An interrupted time series analysis
    (BMC Health Services Research) Chen, Ya-Jing; Zhang, Xin-Yu; Tang, Xue; Yan, Jia-Qi; Qian, Meng-Cen; Ying, Xiao-Hua
    Abstract Context A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. Objective This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. Methods An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18–64 years) and an older group (≥ 65 years), further stratified into young-old (65–79 years) and oldest-old (≥ 80 years) groups. Results The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. Conclusion Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.
  • ItemOpen Access
    Variations in the impact of the new case-based payment reform on medical costs, length of stay, and quality across different hospitals in China: an interrupted time series analysis
    (BMC Health Services Research) Tang, Xue; Zhang, Xinyu; Chen, Yajing; Yan, Jiaqi; Qian, Mengcen; Ying, Xiaohua
    AbstractBackgroundIn 2018, an innovative case-based payment scheme called Diagnosis-Intervention Packet (DIP) was piloted in a large developed city in southern China. This study aimed to investigate the impact of the new payment method on total medical expenditure per case, length of stay (LOS), and in-hospital mortality rate across different hospitals.MethodsWe used the de-identified patient-level discharge data of hospitalized patients from 2016 to 2019 in our study city. The interrupted time series model was used to examine the impact of the DIP payment reform on inflation-adjusted total expenditure per case, LOS, and in-hospital mortality rate across different hospitals, which were stratified into different hospital ownerships (public and private) and hospital levels (tertiary, secondary, and primary).ResultsWe included 2.08 million and 2.98 million discharge cases of insured patients before and after the DIP payment reform, respectively. The DIP payment reform resulted in a significant increase of the monthly trend of adjusted total expenditure per case in public (1.1%,P = 0.000), tertiary (0.6%,P = 0.000), secondary (0.4%,P = 0.047) and primary hospitals (0.9%,P = 0.039). The monthly trend of LOS increased significantly in public (0.022 days,P = 0.041) and primary (0.235 days,P = 0.032) hospitals. The monthly trend of in-hospital mortality rate decreased significantly in private (0.083 percentage points,P = 0.002) and secondary (0.037 percentage points,P = 0.002) hospitals.ConclusionsWe conclude that implementing the DIP payment reform yields inconsistent consequences across different hospitals. DIP reform encouraged public hospitals and high-level hospitals to treat patients with higher illness severities and requiring high treatment intensity, resulting in a significant increase in total expenditure per case. The inconsistencies between public and private hospitals may be attributed to their different baseline levels prior to the reform and their different responses to the incentives created by the reform.
  • ItemOpen Access
    Impact of Diagnosis-Intervention Packet Payment in S City on the Healthcare Quality of Diseases Concerned by the National Public Hospital Performance Assessment
    (Chinese Journal of Health Policy, 2023-04-25) Zhang, Xinyu; Yan, Jiaqi; Wang, Ruixin; Lyu, Dawei; Qian, Mengcen; Ying, Xiaohua
  • ItemOpen Access
    Study on Impact of Diagnosis-Intervention Packet Reform on the Quality of Healthcare
    (Chinese Hospital Management, 2023-12-05) Zhang, Xinyu; Yan, Jiaqi; Wang, Ruixin; Lyu, Dawei; Qian, Mengcen; Ying, Xiaohua
  • ItemOpen Access
    Hospital response to a new case-based payment system in China: the patient selection effect.
    (Health policy and planning, 2024-05) Zhang, Xinyu; Tang, Shenglan; Wang, Ruixin; Qian, Mengcen; Ying, Xiaohua; Maciejewski, Matthew L
    Providers have intended and unintended responses to payment reforms, such as China's new case-based payment system, i.e. Diagnosis-Intervention Packet (DIP) under global budget, that classified patients based on the combination of principal diagnosis and procedures. Our study explores the impact of DIP payment reform on hospital selection of patients undergoing total hip/knee arthroplasty (THA/TKA) or with arteriosclerotic heart disease (AHD) from July 2017 to June 2021 in a large city. We used a difference-in-differences approach to compare the changes in patient age, severity reflected by the Charlson Comorbidity Index (CCI), and a measure of treatment intensity [relative weight (RW)] in hospitals that were and were not subject to DIP incentives before and after the DIP payment reform in July 2019. Compared with non-DIP pilot hospitals, trends in patient age after the DIP reform were similar for DIP and non-DIP hospitals for both conditions, while differences in patient severity grew because severity in DIP hospitals increased more for THA/TKA (P = 0.036) or dropped in non-DIP hospitals for AHD (P = 0.011) following DIP reform. Treatment intensity (measured via RWs) for AHD patients in DIP hospitals increased 5.5% (P = 0.015) more than in non-DIP hospitals after payment reform, but treatment intensity trends were similar for THA/TKA patients in DIP and non-DIP hospitals. When the DIP payment reform in China was introduced just prior to the pandemic, hospitals subject to this reform responded by admitting sicker patients and providing more treatment intensity to their AHD patients. Policymakers need to balance between cost containment and the unintended consequences of prospective payment systems, and the DIP payment could also be a new alternative payment system for other countries.
  • ItemOpen Access
    Footprint evidence of early hominin locomotor diversity at Laetoli, Tanzania.
    (Nature, 2021-12) McNutt, Ellison J; Hatala, Kevin G; Miller, Catherine; Adams, James; Casana, Jesse; Deane, Andrew S; Dominy, Nathaniel J; Fabian, Kallisti; Fannin, Luke D; Gaughan, Stephen; Gill, Simone V; Gurtu, Josephat; Gustafson, Ellie; Hill, Austin C; Johnson, Camille; Kallindo, Said; Kilham, Benjamin; Kilham, Phoebe; Kim, Elizabeth; Liutkus-Pierce, Cynthia; Maley, Blaine; Prabhat, Anjali; Reader, John; Rubin, Shirley; Thompson, Nathan E; Thornburg, Rebeca; Williams-Hatala, Erin Marie; Zimmer, Brian; Musiba, Charles M; DeSilva, Jeremy M
    Bipedal trackways discovered in 1978 at Laetoli site G, Tanzania and dated to 3.66 million years ago are widely accepted as the oldest unequivocal evidence of obligate bipedalism in the human lineage1-3. Another trackway discovered two years earlier at nearby site A was partially excavated and attributed to a hominin, but curious affinities with bears (ursids) marginalized its importance to the paleoanthropological community, and the location of these footprints fell into obscurity3-5. In 2019, we located, excavated and cleaned the site A trackway, producing a digital archive using 3D photogrammetry and laser scanning. Here we compare the footprints at this site with those of American black bears, chimpanzees and humans, and we show that they resemble those of hominins more than ursids. In fact, the narrow step width corroborates the original interpretation of a small, cross-stepping bipedal hominin. However, the inferred foot proportions, gait parameters and 3D morphologies of footprints at site A are readily distinguished from those at site G, indicating that a minimum of two hominin taxa with different feet and gaits coexisted at Laetoli.
  • ItemOpen Access
    Homo naledi, a new species of the genus Homo from the Dinaledi Chamber, South Africa.
    (eLife, 2015-09) Berger, Lee R; Hawks, John; de Ruiter, Darryl J; Churchill, Steven E; Schmid, Peter; Delezene, Lucas K; Kivell, Tracy L; Garvin, Heather M; Williams, Scott A; DeSilva, Jeremy M; Skinner, Matthew M; Musiba, Charles M; Cameron, Noel; Holliday, Trenton W; Harcourt-Smith, William; Ackermann, Rebecca R; Bastir, Markus; Bogin, Barry; Bolter, Debra; Brophy, Juliet; Cofran, Zachary D; Congdon, Kimberly A; Deane, Andrew S; Dembo, Mana; Drapeau, Michelle; Elliott, Marina C; Feuerriegel, Elen M; Garcia-Martinez, Daniel; Green, David J; Gurtov, Alia; Irish, Joel D; Kruger, Ashley; Laird, Myra F; Marchi, Damiano; Meyer, Marc R; Nalla, Shahed; Negash, Enquye W; Orr, Caley M; Radovcic, Davorka; Schroeder, Lauren; Scott, Jill E; Throckmorton, Zachary; Tocheri, Matthew W; VanSickle, Caroline; Walker, Christopher S; Wei, Pianpian; Zipfel, Bernhard
    Homo naledi is a previously-unknown species of extinct hominin discovered within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths. Cranial morphology of H. naledi is unique, but most similar to early Homo species including Homo erectus, Homo habilis or Homo rudolfensis. While primitive, the dentition is generally small and simple in occlusal morphology. H. naledi has humanlike manipulatory adaptations of the hand and wrist. It also exhibits a humanlike foot and lower limb. These humanlike aspects are contrasted in the postcrania with a more primitive or australopith-like trunk, shoulder, pelvis and proximal femur. Representing at least 15 individuals with most skeletal elements repeated multiple times, this is the largest assemblage of a single species of hominins yet discovered in Africa.
  • ItemOpen Access
    Geological and taphonomic context for the new hominin species Homo naledi from the Dinaledi Chamber, South Africa.
    (eLife, 2015-09) Dirks, Paul HGM; Berger, Lee R; Roberts, Eric M; Kramers, Jan D; Hawks, John; Randolph-Quinney, Patrick S; Elliott, Marina; Musiba, Charles M; Churchill, Steven E; de Ruiter, Darryl J; Schmid, Peter; Backwell, Lucinda R; Belyanin, Georgy A; Boshoff, Pedro; Hunter, K Lindsay; Feuerriegel, Elen M; Gurtov, Alia; Harrison, James du G; Hunter, Rick; Kruger, Ashley; Morris, Hannah; Makhubela, Tebogo V; Peixotto, Becca; Tucker, Steven
    We describe the physical context of the Dinaledi Chamber within the Rising Star cave, South Africa, which contains the fossils of Homo naledi. Approximately 1550 specimens of hominin remains have been recovered from at least 15 individuals, representing a small portion of the total fossil content. Macro-vertebrate fossils are exclusively H. naledi, and occur within clay-rich sediments derived from in situ weathering, and exogenous clay and silt, which entered the chamber through fractures that prevented passage of coarser-grained material. The chamber was always in the dark zone, and not accessible to non-hominins. Bone taphonomy indicates that hominin individuals reached the chamber complete, with disarticulation occurring during/after deposition. Hominins accumulated over time as older laminated mudstone units and sediment along the cave floor were eroded. Preliminary evidence is consistent with deliberate body disposal in a single location, by a hominin species other than Homo sapiens, at an as-yet unknown date.
  • ItemOpen Access
    A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity.
    (eLife, 2019-11) Palmer, Adam C; Chidley, Christopher; Sorger, Peter K
    Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.
  • ItemOpen Access
    An enhanced isothermal amplification assay for viral detection.
    (Nature communications, 2020-11) Qian, Jason; Boswell, Sarah A; Chidley, Christopher; Lu, Zhi-Xiang; Pettit, Mary E; Gaudio, Benjamin L; Fajnzylber, Jesse M; Ingram, Ryan T; Ward, Rebecca H; Li, Jonathan Z; Springer, Michael
    Rapid, inexpensive, robust diagnostics are essential to control the spread of infectious diseases. Current state of the art diagnostics are highly sensitive and specific, but slow, and require expensive equipment. Here we report the development of a molecular diagnostic test for SARS-CoV-2 based on an enhanced recombinase polymerase amplification (eRPA) reaction. eRPA has a detection limit on patient samples down to 5 viral copies, requires minimal instrumentation, and is highly scalable and inexpensive. eRPA does not cross-react with other common coronaviruses, does not require RNA purification, and takes ~45 min from sample collection to results. eRPA represents a first step toward at-home SARS-CoV-2 detection and can be adapted to future viruses within days of genomic sequence availability.
  • ItemOpen Access
    A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
    (Nature cell biology, 2024-05) Chidley, Christopher; Darnell, Alicia M; Gaudio, Benjamin L; Lien, Evan C; Barbeau, Anna M; Vander Heiden, Matthew G; Sorger, Peter K
    Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.

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