Miracle-dz/UniFAR-FTUs huggingface dataset:
EGFR Amplification in Metastatic Colorectal Cancer.

BACKGROUND EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies (mAbs). Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified metastatic colorectal cancer (mCRC). METHODS In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs. 1459 EGFR non-amplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs. 439 EGFR non-amplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples. RESULTS EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 non-amplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared to EGFR non-amplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months; 95% confidence interval [CI] = 50.7-NA) vs. EGFR non-amplified ones (24.0 months; 95% CI = 22.8-25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20-0.44, P<.001; adjusted HR = 0.46, 95%CI = 0.30-0.69, P<.001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months [95% CI = 35.2-NA] vs. 29.1 months [95% CI = 27.0-31.9], respectively; HR = 0.46, 95%CI = 0.28-0.76, P=.002). CONCLUSION Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR targeting strategies beyond single-agent monoclonal antibodies.
Transmission characteristics of respiratory droplets aerosol in indoor environment: an experimental study

ABSTRACT Transmission of droplets has been recognized as an important form of infection for the respiratory diseases. This study investigated the distribution of human respiratory droplets and assessed the effects of air change rate and generated velocity on droplet transmission using an active agent in an enclosed chamber (46 m3). Results revealed that the higher the air change rate was, the fewer viable droplets were detected in the range of <3.3 μm with ventilation; an increased air change rate can increase the attenuation of droplet aerosol. Without ventilation, the viable droplet size was observed to mainly distribute greater than 3.3 μm, which occupied up 87.5% of the total number. When the generated velocity was increased to 20 m/s, 29.38% of the viable droplets were detected at the position of 2.0 m. The findings are excepted to be useful for developing the technology of reducing droplet propagation and providing data verification for simulation research.
Repositioning and extraction of stylet‐driven pacing leads with extendable helix used for left bundle branch area pacing

Conventional stylet‐driven leads with extendable helix can be implanted successfully for left bundle branch area pacing (LBBAP) with a low acute complication rate. We report two cases in which lead repositioning after a first unsuccessful attempt to LBBAP was associated with fracture of the helix rotating mechanism and failure to fully extract the pacing lead.
Careful use to minimize adverse events of oral antidiabetic medications in the elderly

ABSTRACT Introduction An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population. Areas covered This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins). Expert opinion Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.
Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation

T cell receptor (TCR) triggering by antigen results in metabolic reprogramming that, in turn, facilitates the exit of T cells from quiescence. The increased nutrient requirements of activated lymphocytes are met, in part, by upregulation of cell surface transporters and enhanced uptake of amino acids, fatty acids, and glucose from the environment. However, the role of intracellular pathways of amino acid biosynthesis in T cell activation is relatively unexplored. Asparagine is a nonessential amino acid that can be synthesized intracellularly through the glutamine-hydrolyzing enzyme asparagine synthetase (ASNS). We set out to define the requirements for uptake of extracellular asparagine and ASNS activity in CD8+ T cell activation. At early time points of activation in vitro, CD8+ T cells expressed little or no ASNS, and, as a consequence, viability and TCR-stimulated growth, activation, and metabolic reprogramming were substantially impaired under conditions of asparagine deprivation. At later time points (more than 24 hours of activation), TCR-induced mTOR-dependent signals resulted in ASNS upregulation that endowed CD8+ T cells with the capacity to function independently of extracellular asparagine. Thus, our data suggest that the coordinated upregulation of ASNS expression and uptake of extracellular asparagine is involved in optimal T cell effector responses.
Development of Individual Variability in Brain Functional Connectivity and Capability across the Adult Lifespan.

Individual variability exists in both brain function and behavioral performance. However, changes in individual variability in brain functional connectivity and capability across adult development and aging have not yet been clearly examined. Based on resting-state functional magnetic resonance imaging data from a large cohort of participants (543 adults, aged 18-88 years), brain functional connectivity was analyzed to characterize the spatial distribution and differences in individual variability across the adult lifespan. Results showed high individual variability in the association cortex over the adult lifespan, whereas individual variability in the primary cortex was comparably lower in the initial stage but increased with age. Individual variability was also negatively correlated with the strength/number of short-, medium-, and long-range functional connections in the brain, with long-range connections playing a more critical role in increasing global individual variability in the aging brain. More importantly, in regard to specific brain regions, individual variability in the motor cortex was significantly correlated with differences in motor capability. Overall, we identified specific patterns of individual variability in brain functional structure during the adult lifespan and demonstrated that functional variability in the brain can reflect behavioral performance. These findings advance our understanding of the underlying principles of the aging brain across the adult lifespan and suggest how to characterize degenerating behavioral capability using imaging biomarkers.
C1q-like 1 is frequently up-regulated in lung adenocarcinoma and contributes to the proliferation and invasion of tumor cells

This study aims to investigate the effects of C1q-like 1 (C1QL1) on the growth and migration of lung adenocarcinoma (LUAD) cells and the underlying mechanism. The expression of C1QL1 in LUAD tissues and its prognostic value were analyzed using the data from The Cancer Genome Atlas (TCGA) database. To investigate the function of C1QL1, loss-of-function and gain-of-function assays were conducted in Calu-3 cells and LTEP-a-2 cells, respectively. Cell growth was evaluated by CCK-8 and colony formation assays. Transwell assays were performed to assess cell invasive and migratory abilities. qRT-PCR and Western blotting were performed to detect RNA and protein expression, respectively. Firstly, we found that C1QL1 was highly expressed and predicted poor outcomes in LUAD patients from TCGA database. Moreover, the mRNA and protein expression levels of C1QL1 were higher in LUAD cells than that in normal lung cells. Results of functional experiments illustrated that depletion of C1QL1 restrained the growth, invasion and migration of Calu-3 cells, meanwhile over-expression of C1QL1 presented the opposite results in LTEP-a-2 cells. Furthermore, we discovered that down-regulation of C1QL1 elevated the protein level of E-cadherin and reduced the protein levels of N-cadherin, Vimentin and Snail in Calu-3 cells, whereas over-expression of C1QL1 led to the opposite outcomes in LTEP-a-2 cells. Our data indicated that C1QL1 functioned as a crucial driver in LUAD cell growth and motility, which might be achieved by modulating epithelial–mesenchymal transition (EMT). These consequences are of important relevance for the design of therapeutic strategies for LUAD.
Sexual incentive delay in the scanner: Sexual cue and reward processing, and links to problematic porn consumption and sexual motivation

Abstract Background and aims The use of pornography, while unproblematic for the majority, can grow into addiction-like behavior which in its extreme form is labeled as compulsive sexual behavioral disorder in the ICD-11 (WHO, 2018). The aim of this study was to investigate the addiction-specific reactivity to cues in order to better understand underlying mechanisms in the development of this disorder. Methods We have used an optimized Sexual Incentive Delay Task to study brain activity in reward associated brain areas during an anticipation phase (with cues predicting pornographic videos, control videos or no videos) and a corresponding delivery phase in healthy men. Correlations to indicators of problematic pornography use, the time spent on pornography use, and trait sexual motivation were analyzed. Results The results of 74 men showed that reward-related brain areas (amygdala, dorsal cingulate cortex, orbitofrontal cortex, nucleus accumbens, thalamus, putamen, caudate nucleus, and insula) were significantly more activated by both the pornographic videos and the pornographic cues than by control videos and control cues, respectively. However, we found no relationship between these activations and indicators of problematic pornography use, time spent on pornography use, or with trait sexual motivation. Discussion and conclusions The activity in reward-related brain areas to both visual sexual stimuli as well as cues indicates that optimization of the Sexual Incentive Delay Task was successful. Presumably, associations between reward-related brain activity and indicators for problematic or pathological pornography use might only occur in samples with increased levels and not in a rather healthy sample used in the present study.
Genetic and clinical spectrums in Korean Charcot‐Marie‐Tooth disease patients with myelin protein zero mutations

Charcot‐Marie‐Tooth disease (CMT) is the most common disorder of inherited peripheral neuropathies characterized by distal muscle weakness and sensory loss. CMT is usually classified into three types, demyelinating, axonal, and intermediate neuropathies. Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells as a major component of peripheral myelin have been reported to cause various type of CMT.
Oxytocin, Neural Plasticity, and Social Behavior.

Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Spons & Shields: practical isolation for trusted execution

Trusted execution environments (TEEs) promise a cost-effective, “lift-and-shift” solution for deploying security-sensitive applications in untrusted clouds. For this, they must support rich, multi-component applications, but a large trusted computing base (TCB) inside the TEE risks that attackers can compromise application security. Fine-grained compartmentalisation can increase security through defense-in-depth, but current solutions either run all software components unprotected in the same TEE, lack efficient shared memory support, or isolate application processes using separate TEEs, impacting performance and compatibility. We describe the Spons & Shields framework (SSF) for Intel SGX TEEs, which offers intra-TEE compartmentalisation using two new abstraction, Spons and Shields. Spons and Shields generalise process, library and user/kernel isolation inside the TEE while allowing for efficient memory sharing. When users deploy unmodified multi-component applications in a TEE, SSF dynamically creates Spons (one per POSIX process or library) and Shields (to enforce a given security policy for memory accesses). Applications can be hardened with minor code changes, e.g., by using a separate Shield to isolate an SSL library. SSF uses compiler instrumentation to protect Shield boundaries, exploiting MPX instructions if available. We evaluate SSF using a complex application service (NGINX, PHP interpreter and PostgreSQL) and show that its overhead is comparable to process isolation.
Swift shadow paging (SSP): no write-protection but following TLB flushing

Virtualization is a key technique for supporting cloud services and memory virtualization is a major component of virtualization technology. Common memory virtualization mechanisms include shadow paging and hardware-assisted paging. The shadow paging model needs to synchronize shadow/guest page tables whenever there is a guest page table update. In the design of traditional shadow paging (TSP), the guest page table pages are write-protected so the updates can be intercepted by the hypervisor to ensure synchronization. Frequent page table updates cause lots of VM_Exits. Researchers have developed hardware-assisted paging to eliminate this overhead. However, address translation needs to walk a two-dimensional page table. This design significantly increases the overhead of page walk. This paper proposes SSP, a Swift Shadow Paging model which leverages the privileged hardware mode. In this design, the write protection mechanism is no longer needed. Rather, SSP accomplishes lazy page table synchronization by intercepting TLB flushing, which must be initiated by the guest OS when there is a page table update. The hardware mode, such as RISC-V’s machine mode and Sunway’s hardware mode, with the highest privilege, opens a new door for communication between the host OS and a guest OS. In addition, by using a shadow page table base address buffer, SSP eliminates the VM_Exits generated by guest process context switching. SSP inherits the advantage of TSP as it remains as a software-only solution and does not incur the excessive overhead of page walk when compared to hardware-assisted paging. We implement SSP in a Sunway machine. Our evaluation demonstrates SSP’s advantage for multiple workloads. Compared with TSP, SSP reduces VM_Exits caused by memory virtualization by 23%-56%. And the virtualization overhead of SSP is less than 5.5% for all workloads.
Human-modified landscapes alter home range and movement patterns of capybaras

The expansion of human activity forces species to co-exist with people in human-modified landscapes (HMLs). However, living in HMLs demands behavioral adaptations, and the proximity between wildlife and people heightens human–wildlife conflicts. Capybara (Hydrochoerus hydrochaeris) is a thriving rodent species in HMLs in Brazil and as such, is involved in human–wildlife conflicts, such as vehicle collisions and transmission of Brazilian spotted fever (BSF). Despite their public importance, the effects of HMLs on capybara movement behavior have never been investigated. Our study aimed to investigate changes in home range, ranging pattern, and activity, for capybaras in six HMLs and two natural landscapes (NLs) by monitoring capybaras with GPS collars. We found home ranges 2.43 times greater in NLs than in HMLs and differences in ranging pattern in HMLs. Capybaras tended to be more nocturnal and move shorter distances across HMLs than NLs. Our results confirm the impacts of the HMLs altering capybara movement. The aggregation of capybaras in very small home ranges might imply on greater risks of tick infestations. In addition, capybara–vehicle collision may be increased during capybaras' nocturnal activity. Therefore, we recommend that transportation agencies avoid the construction of transportation infrastructures (roads, railways, airstrips) in capybaras' home ranges, which should be of restricted access to people in BSF endemic areas.
Subspecies Identification of Captive Gentoo Penguins in Japan, Using Mitochondrial DNA Phylogeny for Their Pedigree Management

Abstract The Gentoo Penguins Pygoscelis papua has been classified into two subspecies, Northern P. papua papua and Southern P. papua ellsworthi. In Japan, where a breeding program exists for Gentoo Penguins, the Japanese Association of Zoos and Aquariums (JAZA) has recognized three categories of species in its pedigree ledger: Northern (from the islands of South Georgia), Southern (from the South Shetland Islands), and Unknown (when their origins are not clear). Phylogenetic analyses of the mitochondrial DNA (mtDNA) D-loop region of Gentoo Penguins in their natural habitat have differentiated them as belonging to the Kerguelen Islands (Indian Ocean), Falkland Islands (Atlantic Ocean), and South Georgia (Atlantic Ocean), and categorized some as Northern and others as Southern subspecies. However, the identification of a third subspecies has been suggested. Therefore, reclassification of captive Gentoo Penguins using phylogenetic analysis is necessary for domestic subspecies pedigree management. In this study, we determined five mtDNA haplotype sequences using seven Gentoo Penguins (considered morphologically as three Northern, three Southern, and one Unknown) and characterized their phylogenetic relationships among subspecies and among geographical distributions including 56 published mtDNA sequences. The phylogenetic tree showed three major lineages, Kerguelen Islands, Falkland Islands, and Scotia Arc/Antartica. The five haplotype sequences of the seven captive Gentoo Penguins were classified unexpectedly to one lineage, the Scotia Arc/Antartica, which contains the nucleotide sequences derived from Southern P. papua ellsworthi. Therefore, the mtDNA phylogeny of the seven captive penguins suggests that all captive Gentoo Penguins in Japan belong to the Southern subspecies. If so, then more comprehensive genetic testing of Gentoo Penguins in Japanese aquariums and zoos is required for the management of successful breeding programs.
The Impact of Agricultural Activities on Habitat Use by the Wood Sandpiper and Common Greenshank in Rice Fields

Abstract Rice fields provide important inland stopover sites for migratory shorebirds. However, stopover duration and habitat use depend on the environmental conditions in the rice fields, which constantly change due to agricultural activities. This study determined the characteristics of habitat use in two shorebird species, the Wood Sandpiper Tringa glareola and Common Greenshank T. nebularia, in rice fields with different habitat conditions resulting from physical changes (field type: fields flooded after plowing, with high water levels after harrowing, or with low water levels after harrowing) and chemical changes (pesticide use: environmentally friendly or conventional farming) from agricultural activities around the time the migratory shorebirds arrive. The study was conducted during the spring stopover periods of these shorebird species in 2015 (May 2–20, 19 days) and 2016 (May 2–21, 20 days), during which we observed the characteristics of their habitat use and estimated the densities of potential prey. Both Wood Sandpiper and Common Greenshank were observed to use flooded fields with low water levels after harrowing. As for pesticide use, potential prey animals were most densely populated in environmentally friendly fields, for which only the large-bodied Common Greenshanks showed selection. This species-specific habitat use seems to be closely associated with body size-dependent prey availability and prey species selection. The small-bodied Wood Sandpiper was more affected by physical than chemical factors. These findings suggest that rice fields—major inland stopover sites for shorebirds—provide different habitats depending on agricultural activities. The study results also have practical implications for future improvement of inland shorebird habitat through efficient rice field management sensitive to the needs of migratory shorebirds.