Miracle-dz/UniFAR-FTUs huggingface dataset:
Extended Co-Expression of Inhibitory Receptors by Human CD8 T-Cells Depending on Differentiation, Antigen-Specificity and Anatomical Localization

Inhibitory receptors mediate CD8 T-cell hyporesponsiveness against cancer and infectious diseases. PD-1 and CTLA-4 have been extensively studied, and blocking antibodies have already shown clinical benefit for cancer patients. Only little is known on extended co-expression of inhibitory receptors and their ligands. Here we analyzed the expression of eight inhibitory receptors by tumor-antigen specific CD8 T-cells. We found that the majority of effector T-cells simultaneously expressed four or more of the inhibitory receptors BTLA, TIM-3, LAG-3, KRLG-1, 2B4, CD160, PD-1 and CTLA-4. There were major differences depending on antigen-specificity, differentiation and anatomical localization of T-cells. On the other hand, naive T-cells were only single or double positive for BTLA and TIM-3. Extended co-expression is likely relevant for effector T-cells, as we found expression of multiple ligands in metastatic lesions of melanoma patients. Together, our data suggest that naive T-cells are primarily regulated by BTLA and TIM-3, whereas effector cells interact via larger numbers of inhibitory receptors. Blocking multiple inhibitory receptors simultaneously or sequentially may improve T-cell based therapies, but further studies are necessary to clarify the role of each receptor-ligand pair.
Predicting Zika virus structural biology: Challenges and opportunities for intervention

Background Zika virus is an emerging crisis as infection is implicated in severe neurological disorders—Guillain–Barré syndrome and fetal microcephaly. There are currently no treatment options available for Zika virus infection. This virus is part of the flavivirus genus and closely related to Dengue Fever Virus, West Nile Virus, and Japanese Encephalitis Virus. Like other flaviviruses, the Zika virus genome encodes three structural proteins (capsid, precursor membrane, and envelope) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Currently, no structural information exists on these viral proteins to facilitate vaccine design and rational drug discovery. Methods Structures for all Zika virus viral proteins were predicted using experimental templates available from closely related viruses using the online SwissModel server. These homology models were compared to drug targets from other viruses using Visual Molecular Dynamics Multiseq software. Sequential alignment of all Zika virus polyproteins was performed using Clustal Omega to identify mutations in specific viral proteins implicated in pathogenesis. Results The precursor membrane, envelope, and NS1 proteins are unique to Zika virus highlighting possible challenges in vaccine design. Sequential differences between Zika virus strains occur at critical positions on precursor membrane, envelope, NS2A, NS3, NS4B, and NS5 as potential loci for differential pathogenesis. Druggable pockets in Dengue Fever Virus and West Nile Virus NS3 and NS5 are retained in predicted Zika virus structures. Conclusions Lead candidates for Zika virus can likely be established using NS3 and NS5 inhibitors from other flaviviruses, and the structures presented can provide opportunities for Zika virus intervention strategies.
Identification of in vivo Sulci on the External Surface of Eight Adult Chimpanzee Brains: Implications for Interpreting Early Hominin Endocasts

The only direct source of information about hominin brain evolution comes from the fossil record of endocranial casts (endocasts) that reproduce details of the external morphology of the brain imprinted on the walls of the braincase during life. Surface traces of sulci that separate the brain’s convolutions (gyri) are reproduced sporadically on early hominin endocasts. Paleoneurologists rely heavily on published descriptions of sulci on brains of great apes, especially chimpanzees (humans’ phylogenetically closest living relatives), to guide their identifications of sulci on ape-sized hominin endocasts. However, the few comprehensive descriptions of cortical sulci published for chimpanzees usually relied on post mortem brains, (now) antiquated terminology for some sulci, and photographs or line drawings from limited perspectives (typically right or left lateral views). The shortage of adequate descriptions of chimpanzee sulcal patterns partly explains why the identities of certain sulci on australopithecine endocasts (e.g., the inferior frontal and middle frontal sulci) have been controversial. Here, we provide images of lateral and dorsal surfaces of 16 hemispheres from 4 male and 4 female adult chimpanzee brains that were obtained using in vivo magnetic resonance imaging. Sulci on the exposed surfaces of the frontal, parietal, temporal, and occipital lobes are identified on the images based on their locations, positions relative to each other, and homologies known from comparative studies of cytoarchitecture in primates. These images and sulcal identifications exceed the quantity and quality of previously published illustrations of chimpanzee brains with comprehensively labeled sulci and, thus, provide a larger number of examples for identifying sulci on hominin endocasts than hitherto available. Our findings, even in a small sample like the present one, overturn published claims that australopithecine endocasts reproduce derived configurations of certain sulci in their frontal lobes that never appear on chimpanzee brains. The sulcal patterns in these new images also suggest that changes in two gyri that bridge between the parietal and occipital lobes may have contributed to cortical reorganization in early hominins. It is our hope that these labeled in vivo chimpanzee brains will assist future researchers in identifying sulci on hominin endocasts, which is a necessary first step in the quest to learn how and when the external morphology of the human cerebral cortex evolved from apelike precursors.
Maxillary overdentures supported by four or six implants in the anterior region: 5‐year results from a randomized controlled trial

Abstract Objective To compare a four‐ and six‐implant maxillary overdenture after an observation period of 5 years. Material and methods Fifty subjects with functional problems concerning their maxillary denture, who had ample bone volume in the anterior region to place four or six implants, were included and randomly assigned to either group. Implant and overdenture survival, clinical performance, marginal bone loss and patient satisfaction were assessed. Results Forty‐six patients completed the 5‐year follow‐up. One implant failed in the six implants group (99.2% survival) and none in the four implants group (100% survival). No overdentures had to be replaced during the observation period and the number of complications was limited. Clinical function was good, with no difference in clinical parameters between the groups. Mean marginal bone resorption was 0.50 ± 0.37 and 0.52 ± 0.43 mm in the four and six implant group respectively. Conclusion In patients with functional complaints of their maxillary denture, bar‐supported overdentures on four implants in the anterior maxillary region were not inferior to overdentures supported by six implants after 5 years of function. Implant survival and patient satisfaction were high, clinical parameters favourable, bone loss and complications to the denture were minor in both groups (Clinical trial registration number: NTR2969).
Key Research Issues for Privacy Protection and Preservation in Cloud Computing

Cloud computing promises an open and promising environment where customers or users can utilise and deploy IT services in a pay-as-you-go style while saving huge capital investments on their own IT infrastructure. The openness and virtualisation features in cloud environments make privacy protection and preservation be a challenging issue. Currently, in existing privacy protection and preservation fields, many approaches and methods have been investigated and presented to withstand different kinds of attackers and risks. On the basis of this, many researchers start to consider these in cloud environments. But current work is still at the early stage. Therefore, a systematic investigation and an overall classification of key issues in cloud privacy protection and preservation are necessary to keep current research on the right track while reducing unnecessary work as much as possible. Hence, in this paper, we investigate and classify various privacy issues in cloud environments. Especially, we focus on some key areas of cloud privacy protection and preservation from the perspective of cloud roles and cloud service levels. This paper can help to provide an overall picture of cloud privacy protection and preservation and point out potential key areas in cloud privacy protection and preservation.
Viruses and Human Cancers: a Long Road of Discovery of Molecular Paradigms

SUMMARY About a fifth of all human cancers worldwide are caused by infectious agents. In 12% of cancers, seven different viruses have been causally linked to human oncogenesis: Epstein-Barr virus, hepatitis B virus, human papillomavirus, human T-cell lymphotropic virus, hepatitis C virus, Kaposi's sarcoma herpesvirus, and Merkel cell polyomavirus. Here, we review the many molecular mechanisms of oncogenesis that have been discovered over the decades of study of these viruses. We discuss how viruses can act at different stages in the complex multistep process of carcinogenesis. Early events include their involvement in mutagenic events associated with tumor initiation such as viral integration and insertional mutagenesis as well as viral promotion of DNA damage. Also involved in tumor progression is the dysregulation of cellular processes by viral proteins, and we describe how this has been investigated by studies in cell culture and in experimental animals and by molecular cellular approaches. Also important are the molecular mechanisms whereby viruses interact with the immune system and the immune evasion strategies that have evolved.
Guiding blind transmitters for K-user MISO interference relay channels with Imperfect channel knowledge

This paper proposes a novel multi-antenna relay-aided interference management technique that can use imperfect channel knowledge for interference relay channels. Using the proposed method, it is shown that KM/K+M-1 degrees of freedom (DoF) are achievable in a K-user multiple-input-single-output interference relay channel when the relay has M antennas with a certain type of limited channel knowledge. By leveraging this result, it is demonstrated that the interference-free DoF of K are asymptotically achieved as M approaches infinity. One major implication of these results is that even under this limited channel knowledge, the use of massive antennas at the relay is sufficient to recover the optimal DoF for relay-aided interference networks with perfect channel knowledge.
Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

Significance Infection with Leishmania (Viannia) parasites can have different manifestations, ranging from localized cutaneous to disseminated and mucocutaneous leishmaniasis, that are prone to relapse after the healing. We previously described the association of the endosymbiont Leishmania RNA virus 1 (LRV1) with increased disease severity. Here, we showed that coinfection with the lymphocytic choriomeningitis virus (LCMV) or Toscana virus exacerbated the outcome of Leishmania guyanensis-induced murine leishmaniasis, favoring parasite persistence and dissemination resulting in metastasis. Both endogenous and exogenous coinfections were dependent upon type I interferon responses. Strikingly, LCMV coinfection after the healing of leishmaniasis induced disease reactivation, overriding the protective adaptive immune response. Thus, viral infections may be a significant risk factor contributing to the pathological spectrum of human leishmaniasis. The presence of the endogenous Leishmania RNA virus 1 (LRV1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. Here, we show that the disease-exacerbatory role of LRV1 relies on type I IFN (type I IFNs) production by macrophages and signaling in vivo. Moreover, infecting mice with the LRV1-cured Leishmania guyanensis (LgyLRV1−) strain of parasites followed by type I IFN treatment increased lesion size and parasite burden, quantitatively reproducing the LRV1-bearing (LgyLRV1+) infection phenotype. This finding suggested the possibility that exogenous viral infections could likewise increase pathogenicity, which was tested by coinfecting mice with L. guyanensis and lymphocytic choriomeningitis virus (LCMV), or the sand fly-transmitted arbovirus Toscana virus (TOSV). The type I IFN antiviral response increased the pathology of L. guyanensis infection, accompanied by down-regulation of the IFN-γ receptor normally required for antileishmanial control. Further, LCMV coinfection of IFN-γ–deficient mice promoted parasite dissemination to secondary sites, reproducing the LgyLRV1+ metastatic phenotype. Remarkably, LCMV coinfection of mice that had healed from L. guyanensis infection induced reactivation of disease pathology, overriding the protective adaptive immune response. Our findings establish that type I IFN-dependent responses, arising from endogenous viral elements (dsRNA/LRV1), or exogenous coinfection with IFN-inducing viruses, are able to synergize with New World Leishmania parasites in both primary and relapse infections. Thus, viral infections likely represent a significant risk factor along with parasite and host factors, thereby contributing to the pathological spectrum of human leishmaniasis.
Apathy and Cognitive Deficits in Patients with Transient Global Ischemia After Cardiac Arrest

Background and Objective: Despite the extensive literature on cognitive deficits in the course of transient global ischemia after cardiac arrest with delayed resuscitation, apathy has been studied less frequently and systematically. We aimed to evaluate the frequency of apathy, defined as changes in drive or lack of motivation, and its relation to cognition as well as depression in people with transient global ischemia after cardiac arrest. Methods: In a retrospective study using the clinical data of 38 cardiac arrest survivors, we analyzed the frequency and severity of deficits in four cognitive domains (attention, memory spans, long-term memory, and executive functions) as well as apathy. Results: As in previous studies, long-term memory problems were predominant, but occurred rarely in isolation. Problems in drive were frequent and correlated with the severity of deficits in all cognitive domains except memory spans (and executive functions only as a trend). Influences of apathy were independent of the presence of a depressive syndrome. Conclusions: Transient global ischemia after cardiac arrest generally leads to a broad pattern of cognitive decline with predominating memory deficits. Apathy is a frequent sequela and is associated with cognitive deficits, independent of depression. Studies investigating the cognitive profile after cardiac arrest should account for modulating influences of apathy.
p53 and NF‐κB: different strategies for responding to stress lead to a functional antagonism

The p53 transcription factor responds to a variety of intrinsic stresses, such as DNA damage, hypoxia, and even oncogene activation. NFκB responds to a large number of extrinsic stresses such as cytokine activation and infectious diseases. The p53 tumor suppressor limits the consequences of stress by initiating cell death, senescence, or cell cycle arrest and promotes metabolic patterns in the cell to favor oxidative phosphorylation. NF‐κB, the oncogene, promotes cell division, which initiates the innate and adaptive immune responses utilizing large amounts of glucose in aerobic glycolysis, resulting in the synthesis of substrates for cell division. Thus these two transcription factors, both of which have evolved to respond to different types of stress, have adopted opposite strategies and cannot function in the same cell at the same time. On activation of one of these transcription factors, the other is inactivated. This is achieved at several places in the p53 and NF‐κB pathways where regulatory proteins act on both p53 and NF‐κB with opposite functional consequences. These internodal sites create core regulatory circuits essential for integrating two central pathways in cells. —Ak, P., Levine, A. J. p53 and NF‐κB: different strategies for responding to stress lead to a functional antagonism. FASEB J. 24, 3643–3652 (2010). www.fasebj. org
Knee extensor fatigue developed during high-intensity exercise limits lower-limb power production

ABSTRACT We investigated the association between changes in vastii electromyography (EMG) and knee extensor fatigue during high-intensity cycling, and the subsequent effect on lower-limb power and intermuscular coordination during all-out cycling. On two separate days, participants completed 30-s all-out cycling or 10-min of high-intensity cycling followed by 30-s all-out cycling. EMG for gluteus maximus (GMAX), rectus femoris (RF), vastii (VAS), hamstrings (HAM) and gastrocnemius (GAS); co-activation for GMAX/RF, VAS/HAM and VAS/GAS; isometric maximal voluntary force (IMVF) and resting twitch (RT) of the knee extensors were measured. VAS EMG increases during high-intensity cycling (6% to 14%, P < 0.05) were negatively correlated (r = −0.791, P < 0.05) with knee extensor IMVF decreases (−2% to−36%, P < 0.05) following the exercise. Knee extensor IMVF decreases were positively correlated (r = 0.757, P < 0.05) with all-out cycling power reductions (0% to −27%, P < 0.05). VAS/GAS co-activation did not change (P > 0.05) during all-out cycling while VAS and GAS EMG decreased. Larger increase in VAS EMG during high-intensity cycling was associated with greater knee extensor fatigue and larger power reduction during all-out cycling. High VAS/GAS co-activation potentially limited power reduction induced by knee extensor fatigue during all-out cycling.
Consensus guidelines for the detection of immunogenic cell death

Apoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named “immunogenic cell death” (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.
In vitro model to study the effects of matrix stiffening on Ca2+ handling and myofilament function in isolated adult rat cardiomyocytes

This paper describes a novel model that allows exploration of matrix‐induced cardiomyocyte adaptations independent of the passive effect of matrix rigidity on cardiomyocyte function. Detachment of adult cardiomyocytes from the matrix enables the study of matrix effects on cell shortening, Ca2+ handling and myofilament function. Cell shortening and Ca2+ handling are altered in cardiomyocytes cultured for 24 h on a stiff matrix. Matrix stiffness‐impaired cardiomyocyte contractility is reversed upon normalization of extracellular stiffness. Matrix stiffness‐induced reduction in unloaded shortening is more pronounced in cardiomyocytes isolated from obese ZSF1 rats with heart failure with preserved ejection fraction compared to lean ZSF1 rats.
An Evaluation of the Impacts of Changing Firearms Legislation on Australian Female Firearm Homicide Victimization Rates

Reducing lethal violence against women requires comprehensive measures addressing individual, social, economic, cultural, and situational factors. Regarding situational factors, access to weapons—and firearm access in particular—has received notable research attention. However, most study comes from the United States of America, and findings may not apply elsewhere. The current study examines whether changing gun laws in Australia affected female firearm homicide victimization. Female firearm homicide victimization may have been affected; however, no significant impacts were found for male firearm homicide victimization. Findings suggest there may be value in preventing legal access to firearms by persons who have a history of intimate partner violence, although considerable further study is required.
Framework for gradual progression of cell ontogeny in the Arabidopsis root meristem

Significance Plants have the ability to live and grow for many thousands of years due to the activity of groups of cells called meristems. Meristems contain stem cells that can survive the entire life of the plant and ensure the continuous supply of new cells. Stem cells are thought to be qualitatively different compared with their neighboring daughter cells. Here we show that in the case of the proximal root meristem, there does not seem to be such an on-off type of organization. We show that the majority of transcripts, together with other cellular properties, gradually transition from stem cell activity to differentiation, by opposing gradients. This impacts our understanding of meristem organization and will determine the direction of future research. In plants, apical meristems allow continuous growth along the body axis. Within the root apical meristem, a group of slowly dividing quiescent center cells is thought to limit stem cell activity to directly neighboring cells, thus endowing them with unique properties, distinct from displaced daughters. This binary identity of the stem cells stands in apparent contradiction to the more gradual changes in cell division potential and differentiation that occur as cells move further away from the quiescent center. To address this paradox and to infer molecular organization of the root meristem, we used a whole-genome approach to determine dominant transcriptional patterns along root ontogeny zones. We found that the prevalent patterns are expressed in two opposing gradients. One is characterized by genes associated with development, the other enriched in differentiation genes. We confirmed these transcript gradients, and demonstrate that these translate to gradients in protein accumulation and gradual changes in cellular properties. We also show that gradients are genetically controlled through multiple pathways. Based on these findings, we propose that cells in the Arabidopsis root meristem gradually transition from stem cell activity toward differentiation.