bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excess mortality analysis for Germany for all three COVID-19 waves in 2020 - 2021
Authors: Weber Alexej 
Published: July 2021

AbstractBackground and AimsThe excess mortality has been used as a metric to estimate the impact of COVID-19 across countries. For Germany, we observe that during the second half of the first and second COVID-19 waves, the COVID-19 deaths are significantly higher than the excess mortality. We attribute the difference to the pre-dying effect. We then compare the excess mortality to the official COVID-19 death numbers and calculate the infection fatality rates (IFRs) and the percentage of infected individuals from excess mortality for different age bands. We also compare the impact of COVID-19 to past influenza waves and analyze the vaccination effect on excess mortality.MethodsWe forecast the baseline mortality from official data on deaths in Germany. Distributing a part of excess mortality into the near future, we lower the baseline simulating the pre-dying effect. From the observed mortality deficit, we estimate the percentage of infected individuals and then estimate the age-dependent IFRs.ResultsIn the first wave, we find an overall excess mortality of ca. 8 000. For the second wave, the overall excess mortality adds up to ca. 56 000. We find, that the pre-dying effect explains the difference between the official COVID-19 deaths and excess mortality in the second half of the waves to a high degree. Attributing the whole excess mortality to COVID-19, we find that the IFRs are significantly higher in the second wave. In the third wave, the overall excess mortality is ca. 5 000. We find an excess mortality in mid-age bands which cannot be explained by the official COVID-19 deaths. For the senior band 80+, we find results in favor of a strong and positive vaccination effect for the third COVID-19 wave.ConclusionsWe conclude that in the first and second COVID-19 waves, the COVID-19 deaths explain almost all excess mortality when the pre-dying effect is taken into account. In the third wave in 2021, the excess mortality is not very pronounced for the 80+ age band, probably due to vaccination. The partially unvaccinated 40-80 age group experiences a pronounced excess mortality in the third wave while there are too few official COVID-19 deaths to explain the excess. The no-vaccination scenario for the 80+ age band results in a similarly high excess mortality as for the more younger age bands, suggesting a very positive vaccination effect on reduction of COVID-19 deaths.
COVID-19 deaths and hospitalizations averted by rapid vaccination rollout in the United States
Authors: Moghadas Seyed M. , Sah Pratha , Fitzpatrick Meagan C. , Shoukat Affan , Pandey Abhishek , Vilches Thomas N. , Singer Burton H. , Schneider Eric C. , Galvani Alison P. 
Published: July 2021

AbstractImportanceRandomized clinical trials have shown that the COVID-19 vaccines currently approved in the US are highly efficacious. However, more evidence is needed to understand the population-level impact of the US vaccination rollout in the face of the changing landscape of COVID-19 pandemic in the US, including variants with higher transmissibility and immune escape.ObjectiveTo quantify the population-level impact of the US vaccination campaign in averting cases, hospitalizations and deaths from December 12, 2020 to June 28, 2021.DesignAge-stratified agent-based model which included transmission dynamics of the Alpha, Gamma and Delta variants in addition to the original Wuhan-1 variant.SettingOur model was calibrated to COVID-19 outbreak and vaccine rollout in the US. Model predictions were made at the country level.ParticipantsSimulated age-stratified population representing US demographics.Main Outcomes and MeasuresCases, hospitalizations and deaths averted by vaccination against COVID-19 in the US, compared to the counterfactuals of no vaccination and vaccination administered at half the actual pace.ResultsThe swift vaccine rollout in the US curbed a potential resurgence of cases in April 2021, which would have been otherwise fuelled by the Alpha variant. Compared to the scenario without vaccines, we estimated that the actual vaccination program averted more than 26 million cases, 1.2 million hospitalizations and saved 279,000 lives. A vaccination campaign with half the actual rollout rate would have led to an additional 460,000 hospitalizations and 121,000 deaths.Conclusions and RelevanceThe COVID-19 vaccination campaign in the US has had an extraordinary impact on reducing disease burden despite the emergence of highly transmissible variants. These findings highlight that the pace of vaccination was essential for mitigating COVID-19 in the US, and underscore the urgent need to close the vaccine coverage gaps in communities across the country.Key PointsQuestionHow effective was the United States (US) vaccination campaign in suppressing COVID-19 burden?FindingsThe vaccination campaign was highly effective in curbing the COVID-19 outbreak in the US. We estimated that the vaccine rollout saved over 275,000 lives and averted 1.2 million hospitalizations.MeaningThe swift vaccine rollout in the US averted a remarkable number of cases, hospitalizations and deaths despite the emergence of highly transmissible variants.
Phylogenomic evidence for the Origin of Obligately Anaerobic Anammox Bacteria around the Great Oxidation Event
Authors: Liao Tianhua , Wang Sishuo , Stüeken Eva E. , Luo Haiwei 
Published: July 2021

AbstractThe anaerobic ammonium oxidation (anammox) bacteria could transform ammonium and nitrite to dinitrogen gas, and this obligate anaerobic process accounts for up to half of the global nitrogen loss in surface environments. Yet its origin and evolution, which may give important insights into the biogeochemistry of early Earth, remains enigmatic. Here, we performed comprehensive phylogenomic analysis and showed a single origin of anammox bacteria within the phylum Planctomycetes. After accommodating the uncertainties and factors influencing time estimates, which includes implementing both a traditional cyanobacteria-based and a recently developed mitochondria-based approach, we estimated that anammox bacteria originated at early Proterozoic and most likely around the so-called Great Oxidation Event (GOE; 2.32 to 2.5 billion years ago [Ga]) which fundamentally changed global biogeochemical cycles. We further showed that during the origin of anammox bacteria, genes involved in oxidative stress, bioenergetics and anammox granules formation were recruited, which might have contributed to their survival on an increasingly oxic Earth. Our findings suggest the rising levels of atmospheric oxygen, which made nitrite increasingly available, was a potential driving force for the emergence of anammox bacteria. This is one of the first studies that link the GOE to the evolution of obligate anaerobic bacteria.
The role of posterior ventral stream areas for viewpoint-invariant object recognition
Authors: Nestmann Sophia , Karnath Hans-Otto , Rennig Johannes 
Published: July 2021

AbstractObject constancy is one of the most crucial mechanisms of the human visual system enabling viewpoint invariant object recognition. However, the neuronal foundations of object constancy are widely unknown. Research has shown that the ventral visual stream is involved in processing of various kinds of object stimuli and that several regions along the ventral stream are possibly sensitive to the orientation of an object in space. To systematically address the question of viewpoint sensitive object perception, we conducted a study with stroke patients as well as an fMRI experiment with healthy participants applying object stimuli in several spatial orientations, for example in typical and atypical viewing conditions. In the fMRI experiment, we found stronger BOLD signals and above-chance classification accuracies for objects presented in atypical viewing conditions in fusiform face sensitive and lateral occipito-temporal object preferring areas. In the behavioral patient study, we observed that lesions of the right fusiform gyrus were associated with lower performance in object recognition for atypical views. The complementary results from both experiments emphasize the contributions of fusiform and lateral-occipital areas to visual object constancy and indicate that visual object constancy is particularly enabled through increased neuronal activity and specific activation patterns for objects in demanding viewing conditions.
A behavioral architecture for realistic simulations ofDrosophilalarva locomotion and foraging
Authors: Sakagiannis Panagiotis , Jürgensen Anna-Maria , Nawrot Martin Paul 
Published: July 2021

AbstractTheDrosophilalarva is extensively used as model organism in neuroethological studies where precise behavioral tracking enables the statistical analysis of individual and population-level behavioral metrics that can inform mathematical models of larval behavior. Here, we propose a hierarchical model architecture comprising three layers to facilitate modular model construction, closed-loop simulations, and direct comparisons between empirical and simulated data. At the basic layer, the autonomous locomotory model is capable of performing exploration. Based on novel kinematic analyses our model features intermittent forward crawling that is phasically coupled to lateral bending. At the second layer, navigation is achieved via active sensing in a simulated environment and top-down modulation of locomotion. At the top layer, behavioral adaptation entails associative learning. We evaluate virtual larval behavior across agent-based simulations of autonomous free exploration, chemotaxis, and odor preference testing. Our behavioral architecture is ideally suited for the modular combination of neuromechanical, neural or mere statistical model components, facilitating their evaluation, comparison, extension and integration into multifunctional control architectures.
Inhibition of cholinergic interneurons potentiates corticostriatal transmission in D1 receptor-expressing medium-sized spiny neurons and restores motor learning in parkinsonian condition
Authors: Laverne Gwenaelle , Pesce Jonathan , Reynders Ana , Melon Christophe , Goff Lydia Kerkerian-Le , Maurice Nicolas , Beurrier Corinne 
Published: July 2021

SUMMARYStriatal cholinergic interneurons (CINs) respond to salient or reward prediction-related stimuli after conditioning with brief pauses in their activity, implicating them in learning and action selection. This pause is lost in animal models of Parkinson’s disease. How this signal regulates the functioning of the striatum remains an open question. To address this issue, we examined the impact of CIN firing inhibition on glutamatergic transmission between the cortex and the medium-sized spiny projection neurons expressing dopamine D1 receptors (D1 MSNs). Brief interruption of CIN activity had no effect in control condition whereas it increased glutamatergic responses in D1 MSNs after nigrostriatal dopamine denervation. This potentiation was dependent upon M4 muscarinic receptor and protein kinase A. Decreasing CIN firing by opto/chemogenetic strategies in vivo rescued long-term potentiation in some MSNs and alleviated motor learning deficits in parkinsonian mice. Taken together, our findings demonstrate that the control exerted by CINs on corticostriatal transmission and striatal-dependent motor-skill learning depends on the integrity of dopaminergic inputs.
Motion/direction-sensitive thalamic neurons project extensively to the middle layers of primary visual cortex
Authors: Zhuang Jun , Wang Yun , Ouellette Naveen D. , Turschak Emily , Larsen Rylan S. , Takasaki Kevin T. , Daigle Tanya L. , Tasic Bosiljka , Waters Jack , Zeng Hongkui , Reid R. Clay 
Published: July 2021

AbstractThe motion/direction-sensitive and location-sensitive neurons are two major functional types in mouse visual thalamus that project to the primary visual cortex (V1). It has been proposed that the motion/direction-sensitive neurons mainly target the superficial layers in V1, in contrast to the location-sensitive neurons which mainly target the middle layers. Here, by imaging calcium activities of motion/direction-sensitive and location-sensitive axons in V1, we find no evidence for these cell-type specific laminar biases at population level. Furthermore, using a novel approach to reconstruct single-axon structures with identified in vivo response types, we show that, at single-axon level, the motion/direction-sensitive axons have middle layer preferences and project more densely to the middle layers than the location-sensitive axons. Overall, our results demonstrate that Motion/direction-sensitive thalamic neurons project extensively to the middle layers of V1, challenging the current view of the thalamocortical organizations in the mouse visual system.
Reflective mirror-based line-scan adaptive optics OCT
Authors: Pandiyan Vimal Prabhu , Jiang Xiaoyun , Kuchenbecker James A. , Sabesan Ramkumar 
Published: July 2021

AbstractLine-scan OCT, incorporated with adaptive optics (AO), offers high resolution, speed and sensitivity for imaging retinal structure and function in vivo. Here, we introduce its implementation with reflective mirror-based afocal telescopes, optimized for imaging light-induced retinal activity (optoretinography) and weak retinal reflections at the cellular scale. A non-planar optical design was followed based on previous recommendations with key differences specific to a line-scan geometry. The three beam paths fundamental to an OCT system – illumination/sample, detection, and reference – were modeled in Zemax optical design software to yield theoretically diffraction-limited performance over a 2.2 deg. field-of-view and 1.5 D vergence range at the eye’s pupil. The performance for imaging retinal structure was exemplified by cellular-scale visualization of retinal ganglion cells, macrophages, foveal cones, and rods in human observers. The performance for functional imaging was exemplified by resolving the light-evoked optical changes in foveal cone photoreceptors where the spatial resolution was sufficient for cone spectral classification at an eccentricity 0.3 deg. from the foveal center. This enabled the first in vivo demonstration of reduced S-cone (short-wavelength cone) density in the human foveola, thus far observed only in ex vivo histological preparations. Together, the feasibility for high resolution imaging of retinal structure and function demonstrated here holds significant potential for basic science and translational applications.
Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic eEF2K
Authors: Beretta Stefania , Ponzoni Luisa , Gritti Laura , Scalmani Paolo , Mantegazza Massimo , Sala Mariaelvina , Verpelli Chiara , Sala Carlo 
Published: July 2021

AbstractDravet Syndrome is a severe childhood pharmacoresistant epileptic disorder caused mainly by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. In Scn1a+/- mice, a mouse model of the Dravet syndrome, we found that the activity of eEF2K/eEF2 pathway was enhanced. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were able to reduce the epileptic phenotype of Scn1a+/- mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a+/- mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.
FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability
Authors: Liu Wenpeng , Polaczek Piotr , Roubal Ivan , Meng Yuan , Choe Won-chae , Caron Marie-Christine , Sedgeman Carl A. , Xi Yu , Liu Changwei , Wu Qiong , Zheng Li , Masson Jean-Yves , Shen Binghui , Campbell Judith L. 
Published: July 2021

SummaryFANCD2 protein, a key coordinator and effector of the interstrand crosslink repair pathway, is also required to prevent excessive nascent strand degradation at hydroxyurea-induced stalled forks. The RAD51 recombinase has also been implicated in regulation of resection at stalled replication forks. The mechanistic contributions of these proteins to fork protection are not well understood. Here, we used purified FANCD2 and RAD51 to study how each protein regulates DNA resection at stalled forks. We showed that FANCD2 inhibits fork degradation in two ways: 1) the N-terminal domain of FANCD2 inhibits DNA2 nuclease activity by directly binding to DNA2. 2) independent of dimerization with FANCI, FANCD2 itself stabilizes RAD51 filaments to inhibit multiple nucleases, including DNA2, MRE11, and EXO1. Unexpectedly, we uncovered a new FANCD2 function: by stabilizing RAD51 filaments, FANCD2 acts as a “RAD51 modulator” to stimulate the strand exchange activity of RAD51. Our work biochemically explains non-canonical mechanisms by which FANCD2 and RAD51 protect stalled forks. We propose a model in which the strand exchange activity of FANCD2 provides a simple molecular explanation for genetic interactions between FANCD2 and the BRCA2 mediator in the FA/BRCA pathway of fork protection
Profiling chromatin accessibility in formalin-fixed paraffin-embedded samples
Authors: Polavarapu Vamsi Krishna , Xing Pengwei , Zhang Hua , Zhao Miao , Mathot Lucy , Zhao Linxuan , Rosen Gabriela , Swartling Fredrik J. , Sjöblom Tobias , Chen Xingqi 
Published: July 2021

ABSTRACTArchived formalin-fixed paraffin-embedded (FFPE) samples are the global standard format for preservation of the majority of biopsies in both basic research and translational cancer studies, and profiling chromatin accessibility in the archived FFPE tissues is fundamental to understanding gene regulation. Accurate mapping of chromatin accessibility from FFPE specimens is challenging because of the high degree of DNA damage. Here, we first showed that standard ATAC-seq can be applied to purified FFPE nuclei but yields lower library complexity and a smaller proportion of long DNA fragments. We then present FFPE-ATAC, the first highly sensitive method for decoding chromatin accessibility in FFPE tissues that combines Tn5-mediated transposition and T7 in vitro transcription. The FFPE-ATAC generates high-quality chromatin accessibility profiles with 500 nuclei from a single FFPE tissue section, enables the dissection of chromatin profiles from the regions of interest with the aid of hematoxylin and eosin (H&E) staining, and reveals disease-associated chromatin regulation from the human colorectal cancer FFPE tissue archived for more than 10 years. In summary, the approach allows decoding of the chromatin states that regulate gene expression in archival FFPE tissues, thereby permitting investigators, to better understand epigenetic regulation in cancer and precision medicine.
Multiplexed identification of RAS paralog imbalance as a driver of lung cancer growth
Authors: Tang Rui , Shuldiner Emily G. , Kelly Marcus , Murray Christopher W. , Hebert Jess D. , Andrejka Laura , Tsai Min K. , Hughes Nicholas W. , Parker Mitchell I , Cai Hongchen , Li Yao-Cheng , Wahl Geoffrey M. , Dunbrack Roland L. , Jackson Peter K. , Petrov Dmitri A. , Winslow Monte M. 
Published: July 2021

ABSTRACTOncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the positive and negative regulators of RAS signaling is incomplete. To uncover the functional impact of diverse KRAS-interacting proteins on lung cancer growth in vivo, we used multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumor barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung tumors, we identified HRAS and NRAS as key suppressors of KRASG12D-driven tumor growth in vivo and confirmed these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogs interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signaling. HRAS mutations identified in KRAS-driven human tumors partially abolished this effect. Comparison of the tumor-suppressive effects of HRAS and NRAS in KRAS- and BRAF-driven lung cancer models confirmed that RAS paralogs are specific suppressors of oncogenic KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role of RAS paralog imbalance in oncogenic KRAS-driven lung cancer.
Structure and Mechanism of Hedgehog Acyl Transferase
Authors: Coupland Claire E. , Andrei Sebastian A. , Ansell T. Bertie , Carrique Loic , Kumar Pramod , Sefer Lea , Schwab Rebekka A , Byrne Eamon F.X. , Pardon Els , Steyaert Jan , Magee Anthony I. , Lanyon-Hogg Thomas. , Sansom Mark S. P. , Tate Edward W. , Siebold Christian 
Published: July 2021

SUMMARYThe iconic Sonic Hedgehog (SHH) morphogen pathway is a fundamental orchestrator of embryonic development and stem cell maintenance, and is implicated in cancers in various organs. A key step in signalling is transfer of a palmitate group to the N-terminal cysteine residue of SHH, catalysed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT) resident in the endoplasmic reticulum (ER). Here, we present the high-resolution cryo-EM structure of HHAT bound to substrate analogue palmityl-coenzyme A and a SHH mimetic megabody. Surprisingly, we identified a heme group bound to an HHAT cysteine residue and show that this modification is essential for HHAT structure and function. A structure of HHAT bound to potent small molecule inhibitor IMP-1575 revealed conformational changes in the active site which occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the novel mechanism by which HHAT adapts the membrane environment to transfer a long chain fatty acid across the ER membrane from cytosolic acyl-CoA to a luminal protein substrate. This structure of a member of the protein-substrate membrane-bound O-acyltransferase (MBOAT) superfamily provides a blueprint for other protein substrate MBOATs, such as WNT morphogen acyltransferase Porcupine and ghrelin O-acyltransferase GOAT, and a template for future drug discovery.