nils-herrmann/clean_scirepeval huggingface dataset:
Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring
Venue: Cell

Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biological and chemical exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geographical locations. We found that individuals are potentially exposed to thousands of pan-domain species and chemical compounds, including insecticides and carcinogens. Personal biological and chemical exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geographical region. Integrated analysis of biological and chemical exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.
Structural Basis for the RNA-Guided Ribonuclease Activity of CRISPR-Cas13d
Venue: Cell

CRISPR-Cas endonucleases directed against foreign nucleic acids mediate prokaryotic adaptive immunity and have been tailored for broad genetic engineering applications. Type VI-D CRISPR systems contain the smallest known family of single effector Cas enzymes, and their signature Cas13d ribonuclease employs guide RNAs to cleave matching target RNAs. To understand the molecular basis for Cas13d function and explain its compact molecular architecture, we resolved cryoelectron microscopy structures of Cas13d-guide RNA binary complex and Cas13d-guide-target RNA ternary complex to 3.4 and 3.3 Å resolution, respectively. Furthermore, a 6.5 Å reconstruction of apo Cas13d combined with hydrogen-deuterium exchange revealed conformational dynamics that have implications for RNA scanning. These structures, together with biochemical and cellular characterization, provide insights into its RNA-guided, RNA-targeting mechanism and delineate a blueprint for the rational design of improved transcriptome engineering technologies.
Multi-level Proteomics Identifies CT45 as a Chemosensitivity Mediator and Immunotherapy Target in Ovarian Cancer
Venue: Cell

Most high-grade serous ovarian cancer (HGSOC) patients develop resistance to platinum-based chemotherapy and recur, but 15% remain disease free over a decade. To discover drivers of long-term survival, we quantitatively analyzed the proteomes of platinum-resistant and -sensitive HGSOC patients from minute amounts of formalin-fixed, paraffin-embedded tumors. This revealed cancer/testis antigen 45 (CT45) as an independent prognostic factor associated with a doubling of disease-free survival in advanced-stage HGSOC. Phospho- and interaction proteomics tied CT45 to DNA damage pathways through direct interaction with the PP4 phosphatase complex. In vitro, CT45 regulated PP4 activity, and its high expression led to increased DNA damage and platinum sensitivity. CT45-derived HLA class I peptides, identified by immunopeptidomics, activate patient-derived cytotoxic T cells and promote tumor cell killing. This study highlights the power of clinical cancer proteomics to identify targets for chemo- and immunotherapy and illuminate their biological roles.
Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells
Venue: Cell

The mechanisms underlying sterol transport in mammalian cells are poorly understood. In particular, how cholesterol internalized from HDL is made available to the cell for storage or modification is unknown. Here, we describe three ER-resident proteins (Aster-A, -B, -C) that bind cholesterol and facilitate its removal from the plasma membrane. The crystal structure of the central domain of Aster-A broadly resembles the sterol-binding fold of mammalian StARD proteins, but sequence differences in the Aster pocket result in a distinct mode of ligand binding. The Aster N-terminal GRAM domain binds phosphatidylserine and mediates Aster recruitment to plasma membrane-ER contact sites in response to cholesterol accumulation in the plasma membrane. Mice lacking Aster-B are deficient in adrenal cholesterol ester storage and steroidogenesis because of an inability to transport cholesterol from SR-BI to the ER. These findings identify a nonvesicular pathway for plasma membrane to ER sterol trafficking in mammals.
A Novel Class of ER Membrane Proteins Regulates ER-Associated Endosome Fission
Venue: Cell

Endoplasmic reticulum (ER) membrane contact sites (MCSs) mark positions where endosomes undergo fission for cargo sorting. To define the role of ER at this unique MCS, we targeted a promiscuous biotin ligase to cargo-sorting domains on endosome buds. This strategy identified the ER membrane protein TMCC1, a member of a conserved protein family. TMCC1 concentrates at the ER-endosome MCSs that are spatially and temporally linked to endosome fission. When TMCC1 is depleted, endosome morphology is normal, buds still form, but ER-associated bud fission and subsequent cargo sorting to the Golgi are impaired. We find that the endosome-localized actin regulator Coronin 1C is required for ER-associated fission of actin-dependent cargo-sorting domains. Coronin 1C is recruited to endosome buds independently of TMCC1, while TMCC1/ER recruitment requires Coronin 1C. This link between TMCC1 and Coronin 1C suggests that the timing of TMCC1-dependent ER recruitment is tightly regulated to occur after cargo has been properly sequestered into the bud.
Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma
Venue: Cell

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.
An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis
Venue: Cell

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors
Venue: Cell

Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.
A Bacterial Chromosome Structuring Protein Binds Overtwisted DNA to Stimulate Type II Topoisomerases and Enable DNA Replication
Venue: Cell

When DNA is unwound during replication, it becomes overtwisted and forms positive supercoils in front of the translocating DNA polymerase. Unless removed or dissipated, this superhelical tension can impede replication elongation. Topoisomerases, including gyrase and topoisomerase IV in bacteria, are required to relax positive supercoils ahead of DNA polymerase but may not be sufficient for replication. Here, we find that GapR, a chromosome structuring protein in Caulobacter crescentus, is required to complete DNA replication. GapR associates in vivo with positively supercoiled chromosomal DNA, and our biochemical and structural studies demonstrate that GapR forms a dimer-of-dimers that fully encircles overtwisted DNA. Further, we show that GapR stimulates gyrase and topo IV to relax positive supercoils, thereby enabling DNA replication. Analogous chromosome structuring proteins that locate to the overtwisted DNA in front of replication forks may be present in other organisms, similarly helping to recruit and stimulate topoisomerases during DNA replication.
C. elegans AWA Olfactory Neurons Fire Calcium-Mediated All-or-None Action Potentials
Venue: Cell

Neurons in Caenorhabditis elegans and other nematodes have been thought to lack classical action potentials. Unexpectedly, we observe membrane potential spikes with defining characteristics of action potentials in C. elegans AWA olfactory neurons recorded under current-clamp conditions. Ion substitution experiments, mutant analysis, pharmacology, and modeling indicate that AWA fires calcium spikes, which are initiated by EGL-19 voltage-gated CaV1 calcium channels and terminated by SHK-1 Shaker-type potassium channels. AWA action potentials result in characteristic signals in calcium imaging experiments. These calcium signals are also observed when intact animals are exposed to odors, suggesting that natural odor stimuli induce AWA spiking. The stimuli that elicit action potentials match AWA's specialized function in climbing odor gradients. Our results provide evidence that C. elegans neurons can encode information through regenerative all-or-none action potentials, expand the computational repertoire of its nervous system, and inform future modeling of its neural coding and network dynamics.
ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P
Venue: Cell

Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.
Pursuing the Secrets of Histone Proteins: An Amazing Journey with a Remarkable Supporting Cast
Venue: Cell

Receiving any award for achievements in basic biomedical research, let alone one as prestigious as a Lasker Award, prompts me to ask a simple question: how did I get here?My answer has two parts: not by design and certainly not alone. When I entered the field of histone biology as a postdoc, a rich older literature suggested that histone proteins might be worth a career investment. This was a gamble, but in short, I found histone proteins interesting. While relatively poor in molecular weight, histones were potentially rich in biologically meaningful information, as different gel systems revealed a large variety of patterns in electrophoretic properties. But was any of this heterogeneity physiologically relevant? That histones might be important was supported by their highly conserved nature and their undisputed role as fundamental protein organizers of the chromatin. Well before my time, numerous labs had documented a wealth of post-translational modifications (PTMs) on histones and hypothesized that these PTMs might alter chromatin structure and function by influencing histone-DNA and histone-histone contacts. Eukaryotic genomes demanded packaging within a chromatin environment, but was this packaging anything more than just nature’s clever way to make sure large genomes fit into tight nuclear spaces? I was hoping that there was more gold left to be mined from these ‘‘simple’’ proteins and their welldocumented covalent decorations. I had no plan B, and nothing could have been further from my mind than a Lasker Award.
Leading and Inspiring by Example
Venue: Cell

Joan Steitz radiates a passion for science. Whether she's teaching an undergraduate course, mentoring a grad student or post-doc, or speaking at a scientific conference, her enthusiasm and curiosity for all things RNA is infectious. Joan, the recipient of the 2018 Lasker-Koshland Special Achievement Award in Medical Science, spoke with Cell editor (and her former post-doc) Lara Szewczak about how she came to be an advocate for women in science and shared advice for young scientists entering the research community today. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.
Balancing Tricks and Mini-pigs: Steps along the Road to Propofol
Venue: Cell

I grew up on a 50-acre farm on the Island of Arran in the Firth of Clyde in Scotland. We looked across to theMull of Kintyre, and on a clear day, we could see the coast of Northern Ireland. It was a quiet life, and I can recall the day in 1952whenmains electricity reached our farm.We had cattle, pigs, sheep, and hens, and I decided to study veterinary medicine at Glasgow University. At that time, I envisaged a life driving round the countryside examining and treating farm animals. However, by the time I had completed the undergraduate course in 1963, I decided that I would like to stay within the university environment and begin an academic career, attracted by the opportunity that the university facilities provided to investigate cases more thoroughly. My first opportunity was to join Professor Ian McIntyre and a group from Glasgow University who were running a ‘‘conversion course’’ for diplomates from the veterinary college in Kenya to allow them to upgrade to internationally recognized degree status. My role there was to provide a veterinary service to local Kikuyu farmers and to identify suitable cases to be brought into the college for clinical teaching. I enjoyed playing rugby with the Impala club in Nairobi and played for a Kenyan team against Tanzania in Dar es Salaam. After a year, I returned to Glasgow as a house surgeon in
Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization
Venue: Cell

The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.
Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
Venue: Cell

Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies."
Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations
Venue: Cell

(Cell 174, 521–535.e1–e13; July 26, 2018) Our paper reported that activation of KCC2 transporters in interneurons promotes functional recovery from spinal injury in mice. We have identified four minor errors in the Results section of the manuscript. Two sentences originally read: "They included baclofen, a GABA receptor agonist; bumetanide, an inhibitor of the Na+/2Cl /K+ co-transporter (NKCC); CLP290, an agonist of the neuron-specific K+-Cl co-transporter (KCC2), also called SLC12A5; L838,417, a GABAA-positive allosteric modulator; CP101606, an NMDA receptor antagonist; 8-OHDPAT, a 5HT1A/7 agonist; and quipazine, a 5HT2A/C agonist (Figures 1E and S1A).One of these treatments resulted in significant improvements in stepping ability within the first 2–3weeks after daily treatment.’’ However, they should read: ‘‘They included baclofen, a GABA receptor agonist; bumetanide, an inhibitor of the Na+/2Cl /K+ co-transporter (NKCC1); CLP290, an agonist of the neuron-specific K+-Cl co-transporter (KCC2), also called SLC12A5; L838,417, a GABAA-positive allosteric modulator; CP101606, an NMDA receptor antagonist; 8-OHDPAT, a 5HT1A/7 agonist; and quipazine, a 5HT2A/C agonist (Figures 1E and S1A).None of these treatments resulted in significant improvements in stepping ability within the first 2–3 weeks after daily treatment.’’ The third text error appears in the sentence, "As shown in Figure S6B, expression of this depolarizing hM3Dq in excitatory spinal neurons (AAV9-FLEX-hM3Dq-mCherry into Vglut2-Cre), combined with daily CNO delivery, failed to illicit functional recovery within 8 weeks of daily CNO treatment." It should read "As shown in Figure S6B, expression of this depolarizing hM3Dq in excitatory spinal neurons (AAV9-FLEX-hM3Dq-mCherry into Vglut2-Cre), combined with daily CNO delivery, failed to elicit functional recovery within 8 weeks of daily CNO treatment.’’ The final error is the paragraph beginning with the subheading "CLP290/KCC2 Alters Excitability and Relay Formation." "GABAA" should have appeared as "GABAA". These errors have now been corrected in the online version of the paper. We apologize for any inconvenience they may have caused to the readers.
Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks
Venue: Cell

Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.
Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT
Venue: Cell

Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.