Fault-Tolerant Computing With Biased-Noise Superconducting Qubits

We present a universal scheme of pulsed operations for the IBM oscillator-stabilized flux qubit comprising the CPHASE gate, single-qubit preparations and measurements. Based on numerical simulations, we argue that the error rates for these operations can be as low as about .5% and that noise is highly biased, with phase errors being stronger than all other types of errors by a factor of nearly 10^3. In contrast, the design of a CNOT gate for this system with an error rate of less than about 1.2% seems extremely challenging. We propose a special encoding which exploits the noise bias allowing us to implement a logical CNOT gate where phase errors and all other types of errors have nearly balanced rates of about .4%. Our results illustrate how the design of an encoding scheme can be adjusted and optimized according to the available physical operations and the particular noise characteristics of experimental devices.Comment: 15 pages, 7 figure

Nationwide population-based death certificate study

BACKGROUND: Most people would prefer to die at home as opposed to hospital; therefore, understanding mortality patterns by place of death is essential for health resources allocation. AIM: We examined trends and risk factors for hospital death in conditions needing palliative care in a country without integrated palliative care. DESIGN: This is a death certificate study. We examined factors associated with hospital death using logistic regression. SETTING/PARTICIPANTS: All adults (1,045,381) who died between 2003 and 2012 in Portugal were included. We identified conditions needing palliative care from main causes of death: cancer, heart/cerebrovascular, renal, liver, respiratory and neurodegenerative diseases, dementia/Alzheimer's/senility and HIV/AIDS. RESULTS: Conditions needing palliative care were responsible for 70.7% deaths ( N = 738,566, median age 80); heart and cerebrovascular diseases (43.9%) and cancer (32.2%) accounted for most. There was a trend towards hospital death (standardised percentage: 56.3% in 2003, 66.7% in 2012; adjusted odds ratio: 1.04, 95% confidence interval: 1.04-1.04). Hospital death risk was higher for those aged 18-39 years (3.46, 3.25-3.69 vs aged 90+), decreasing linearly with age; lower in dementia/Alzheimer's/senility versus cancer (0.13, 0.13-0.13); and higher for the married and in HIV/AIDS (3.31, 3.00-3.66). Effects of gender, working status, weekday and month of death, hospital beds availability, urbanisation level and deprivation were small. CONCLUSION: The upward hospital death trend and fact that being married are risk factors for hospital death suggest that a reliance on hospitals may coexist with a tradition of extended family support. The sustainability of this model needs to be assessed within the global transition pattern in where people die.publishersversionpublishe

Foot-and-Mouth Disease Infection Dynamics in Contact-Exposed Pigs Are Determined by the Estimated Exposure Dose

The quantitative relationship between the exposure dose of foot-and-mouth disease virus (FMDV) and subsequent infection dynamics has been demonstrated through controlled inoculation studies in various species. However, similar quantitation of viral doses has not been achieved during contact exposure experiments due to the intrinsic difficulty of measuring the virus quantities exchanged between animals. In the current study, novel modeling techniques were utilized to investigate FMDV infection dynamics in groups of pigs that had been contact-exposed to FMDV-infected donors shedding varying levels of virus, as well as in pigs inoculated via the intra-oropharyngeal (IOP) route. Estimated virus exposure doses were modeled and were found to be statistically significantly associated with the dynamics of FMDV RNA detection in serum and oropharyngeal fluid (OPF), and with the time to onset of clinical disease. The minimum estimated shedding quantity in OPF that defined infectiousness of donor pigs was 6.55 log10 genome copy numbers (GCN)/ml (95% CI 6.11, 6.98), which delineated the transition from the latent to infectious phase of disease which occurred during the incubation phase. This quantity corresponded to a minimum estimated exposure dose of 5.07 log10 GCN/ml (95% CI 4.25, 5.89) in contact-exposed pigs. Thus, we demonstrated that a threshold quantity of FMDV detection in donor pigs was necessary in order to achieve transmission by direct contact. The outcomes from this investigation demonstrate that variability of infection dynamics which occurs during the progression of FMD in naturally exposed pigs can be partially attributed to variations in exposure dose. Moreover, these modeling approaches for dose-quantitation may be retrospectively applied to contact-exposure experiments or field scenarios. Hence, robust information could be incorporated into models used to evaluate FMD spread and control

Transmission of foot-and-mouth disease SAT2 viruses at the wildlife-livestock interface of two major transfrontier conservation areas in Southern Africa

Over a decade ago, foot-and-mouth disease (FMD) re-emerged in Southern Africa specifically in beef exporting countries that had successfully maintained disease-free areas in the past. FMD virus (FMDV) serotype SAT2 has been responsible for a majority of these outbreaks. Epidemiological studies have revealed the importance of the African buffalo as the major wildlife FMD reservoir in the region. We used phylogeographic analysis to study dynamics of FMD transmission between buffalo and domestic cattle at the interface of the major wildlife protected areas in the region currently encompassing two largest Transfrontier conservation areas: Kavango–Zambezi (KAZA) and Great Limpopo (GL). Results of this study showed restricted local occurrence of each FMDV SAT2 topotypes I, II, and III, with occasional virus migration from KAZA to GL. Origins of outbreaks in livestock are frequently attributed to wild buffalo, but our results suggest that transmission from cattle to buffalo also occurs. We used coalescent Bayesian skyline analysis to study the genetic variation of the virus in cattle and buffalo, and discussed the association of these genetic changes in the virus and relevant epidemiological events that occurred in this area. Our results show that the genetic diversity of FMDV SAT2 has decreased in buffalo and cattle population during the last decade. This study contributes to understand the major dynamics of transmission and genetic variation of FMDV SAT2 in Southern Africa, which will could ultimately help in designing efficient strategies for the control of FMD at a local and regional levelThis project was funded in part by grants from the USDA/ARS and CORUS (French Ministry of Foreign Affairs). The FMD virus database was compiled with funds from the SADC FMD Project.http://www.frontiersin.orgam2016Zoology and Entomolog

Transmission of foot-and-mouth disease SAT2 viruses at the wildlife-livestock interface of two major transfrontier conservation areas in Southern Africa

Over a decade ago, foot-and-mouth disease (FMD) re-emerged in Southern Africa specifically in beef exporting countries that had successfully maintained disease-free areas in the past. FMD virus (FMDV) serotype SAT2 has been responsible for a majority of these outbreaks. Epidemiological studies have revealed the importance of the African buffalo as the major wildlife FMD reservoir in the region. We used phylogeographic analysis to study dynamics of FMD transmission between buffalo and domestic cattle at the interface of the major wildlife protected areas in the region currently encompassing two largest Transfrontier conservation areas: Kavango–Zambezi (KAZA) and Great Limpopo (GL). Results of this study showed restricted local occurrence of each FMDV SAT2 topotypes I, II, and III, with occasional virus migration from KAZA to GL. Origins of outbreaks in livestock are frequently attributed to wild buffalo, but our results suggest that transmission from cattle to buffalo also occurs. We used coalescent Bayesian skyline analysis to study the genetic variation of the virus in cattle and buffalo, and discussed the association of these genetic changes in the virus and relevant epidemiological events that occurred in this area. Our results show that the genetic diversity of FMDV SAT2 has decreased in buffalo and cattle population during the last decade. This study contributes to understand the major dynamics of transmission and genetic variation of FMDV SAT2 in Southern Africa, which will could ultimately help in designing efficient strategies for the control of FMD at a local and regional levelThis project was funded in part by grants from the USDA/ARS and CORUS (French Ministry of Foreign Affairs). The FMD virus database was compiled with funds from the SADC FMD Project.http://www.frontiersin.orgam2016Zoology and Entomolog

Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment

© Author(s) (or their employer(s)) 2022.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.C and RCA are supported by the Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) (PhD grants PD/BD/128238/2016 (RCA) and SFRH/BD/131969/2017 (BC)). The authors thank the funding received from the European Structural & Investment Funds through the COMPETE Programme and from National Funds through FCT under the Programme grant LISBOA-01-0145-FEDER016405 - SAICTPAC/0019/2015 (HF and RCG). HFF and RCA received additional support from FCT-MCTES (UIDB/04138/2020, PTDC/BTM-SAL/4350/2021 and UTAPEXPL/NPN/0041/2021; EXPL/MED-QUI/1316/2021, respectively). The MultiNano@MBM project was supported by The Israeli Ministry of Health, and FCTMCTES, under the frame of EuroNanoMed-II (ENMed/0051/2016; HF and RS-F). HF and RS-F thank the generous financial support from ‘La Caixa’ Foundation under the framework of the Healthcare Research call 2019 (NanoPanther; LCF/PR/HR19/52160021), as well as CaixaImpulse (Co-Vax; LCF/TR/CD20/52700005). MP thanks the financial support from Liga Portuguesa Contra o Cancro – Nucleo Regional do Sul and ‘iNOVA4Health – UIDB/04462/2020’, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência. RS-F thanks the following funding agencies for their generous support: the European Research Council (ERC) Advanced Grant Agreement No. (835227)–3DBrainStrom, ERC PoC Grant Agreement no. 862580 – 3DCanPredict, The Israel Science Foundation (Grant No. 1969/18), The Melanoma Research Alliance (MRA Established Investigator Award n°615808), the Israel Cancer Research Fund (ICRF) Professorship award (n° PROF-18-682), and the Morris Kahn Foundation.info:eu-repo/semantics/publishedVersio

Morphological and Transcriptional Changes in Human Bone Marrow During Natural Plasmodium vivax Malaria Infections.

--- - Label: BACKGROUND NlmCategory: BACKGROUND content: The presence of Plasmodium vivax malaria parasites in the human bone marrow (BM) is still controversial. However, recent data from a clinical case and experimental infections in splenectomized nonhuman primates unequivocally demonstrated the presence of parasites in this tissue. - Label: METHODS NlmCategory: METHODS content: In the current study, we analyzed BM aspirates of 7 patients during the acute attack and 42 days after drug treatment. RNA extracted from CD71+ cell suspensions was used for sequencing and transcriptomic analysis. - Label: RESULTS NlmCategory: RESULTS content: We demonstrated the presence of parasites in all patients during acute infections. To provide further insights, we purified CD71+ BM cells and demonstrated dyserythropoiesis and inefficient erythropoiesis in all patients. In addition, RNA sequencing from 3 patients showed that genes related to erythroid maturation were down-regulated during acute infections, whereas immune response genes were up-regulated. - Label: CONCLUSIONS NlmCategory: CONCLUSIONS content: This study thus shows that during P. vivax infections, parasites are always present in the BM and that such infections induced dyserythropoiesis and ineffective erythropoiesis. Moreover, infections induce transcriptional changes associated with such altered erythropoietic response, thus highlighting the importance of this hidden niche during natural infections

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors