julilili42/papers huggingface dataset:
Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness
2021-02-19

Abstract A balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.
HESS J1858+020: A GeV-TeV source possibly powered by cosmic rays from SNR G35.6-0.4
2021-02-19

Context. The supernova remnant (SNR) G35.6−0.4 shows a non-thermal radio shell, however, no γ-ray or X-ray counterparts have been found for it thus far. One TeV source, HESS J1858+020, was found near the SNR and this source is spatially associated with some clouds at 3.6 kpc. Aims. To attain a better understanding of the origin of HESS J1858+020, we further investigate the association between SNR cosmic rays (CRs) and the clouds through the Fermi-LAT analysis and hadronic modeling. Methods. We performed the Fermi-LAT analysis to explore the GeV emission in and around the SNR. We explored the SNR physics with previously observed multi-wavelength data. We built a hadronic model using runaway CRs of the SNR to explain the GeV-TeV observation. Results. We found a hard GeV source (SrcX2) that is spatially coincident with both HESS J1858+020 and a molecular cloud complex at 3.6 kpc. In addition, a soft GeV source (SrcX1) was found at the northern edge of the SNR. The GeV spectrum of SrcX2 connects well with the TeV spectrum of HESS J1858+020. The entire γ-ray spectrum ranges from several GeV up to tens of TeV and it follows a power-law with an index of ~2.15. We discuss several pieces of observational evidence to support the middle-aged SNR argument. Using runaway CRs from the SNR, our hadronic model explains the GeV-TeV emission at HESS J1858+020, with a diffusion coefficient that is much lower than the Galactic value.
SARS-CoV-2 Mutations in Brazil: From Genomics to Clinical Conditions
2021-02-19

Due to the high rate of transmissibility, Brazil became the new COVID-19 outbreak epicenter, being a reference region to monitor how SARS-CoV-2 is mutating and spreading. Here, we combined genomic and structural biology analysis evaluate genomes isolated from different regions of Brazil. We showed that the most prevalent mutations were located in the S, N, ORF3a and ORF6 genes, which are involved in different stages of viral life cycle and its interaction with the host cells. Structural analysis brought to light the positions of these mutations on protein structures, helping studies of structure-based drug discovery and vaccine development.
SARS-CoV-2 Mutations in Brazil: From Genomics to Clinical Conditions
2021-02-19

Due to the high rate of transmissibility, Brazil became the new COVID-19 outbreak epicenter, being a reference region to monitor how SARS-CoV-2 is mutating and spreading. Here, we combined genomic and structural biology analysis evaluate genomes isolated from different regions of Brazil. We showed that the most prevalent mutations were located in the S, N, ORF3a and ORF6 genes, which are involved in different stages of viral life cycle and its interaction with the host cells. Structural analysis brought to light the positions of these mutations on protein structures, helping studies of structure-based drug discovery and vaccine development.&lt;br&gt;&lt;div&gt;&lt;/div&gt;
Stable behavioral state-specific large scale activity patterns in the developing cortex of neonates
2021-02-19

Abstract Endogenous neuronal activity is a hallmark of the developing brain. In rodents, a handful of such activities were described in different cortical areas but the unifying macroscopic perspective is still lacking. Here we combined large-scale in vivo Ca 2+ imaging of the dorsal cortex in non-anesthetized neonatal mice with advanced mathematical analyses to reveal unique behavioral state-specific maps of endogenous activity. These maps were remarkably stable over time within and across experiments and used patches of correlated activity with little hemispheric symmetry as well as stationary and propagating waves as building blocks. Importantly, the maps recorded during motion and rest were almost inverse, with sensory-motor areas active during motion and posterior-lateral areas active at rest. The retrosplenial cortex engaged in both resting- and motion-related activities, building functional long-range connections with respective cortical areas. The data obtained bind different region-specific activity patterns described so far into a single consistent picture and set the stage for future inactivation studies, probing the exact function of this complex activity pattern for cortical wiring in neonates.
My two “big” Additions to Science: Cryodynamics and Smile-Theory
2021-02-19

Cryodynamics is the equal-rights sister of venerable deterministic Thermodynamics; and the smile theory crowns deductive biology. The former enables an economic bonanza because it renders interactively controllable fusion reactors possible. The latter enables non-human persons to be kissed awake. Both options appear to be devoid of general interest, however, no matter how unlikely this sounds. For example, the waging of wars becomes impossible in the wake of the smile theory since all persons (born out of the smile) have the same legal rights on the planet. The requisite money is coming from the controllable fusion reactors enabled by Cryodynamics. And the motivation comes from the formerly autistic children saved by the smile theory. The money can be used to finance the democratic peace on earth enabled by the Smile theory`s moving all hearts. Especially that of all children who understand me immediately. I apologize to the reader for my palpable naiveté which nonetheless is realistic, I feel for one. What I need most is an enemy. Only then can the smile theory show its full strength.
Diurnal Fe(II)/Fe(III) cycling and enhanced O2 production in a simulated Archean marine oxygen oasis
2021-02-19

This dataset was used to generate the figures in the abovementioned paper, accepted for publication in Nature Communications. Paper abstract: The oxygenation of early Earth’s atmosphere during the Great Oxidation Event, is generally accepted to have been caused by oceanic Cyanobacterial oxygenic photosynthesis. Recent studies suggest that Fe(II) toxicity delayed the Cyanobacterial expansion necessary for the GOE. This study investigates the effects of Fe(II) on two Cyanobacteria,<em> Pseudanabaena </em>sp. PCC7367 and <em>Synechococcus </em>sp. PCC7336, in a simulated shallow-water marine Archean environment. A similar Fe(II) toxicity response was observed as reported for closed batch cultures. This toxicity was not observed in cultures provided with continuous gaseous exchange that showed significantly shorter doubling times than the closed-culture system, even with repeated nocturnal addition of Fe(II) for 12 days. The green rust formed under high Fe(II) conditions, was not found to be directly toxic to <em>Pseudanabaena </em>sp. PCC7367. In summary, we present evidence of diurnal Fe cycling in a simulated shallow-water marine environment for two ancestral strains of Cyanobacteria, with increased O<sub>2</sub> production under anoxic conditions.
Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
2021-02-20

Abstract In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD–mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
Comparative Embryogenesis in Angiosperms: Activation and Patterning of Embryonic Cell Lineages
2021-02-20

Following fertilization in flowering plants (angiosperms), egg and sperm cells unite to form the zygote, which generates an entire new organism through a process called embryogenesis. In this review, we provide a comparative perspective on early zygotic embryogenesis in flowering plants by using the Poaceae maize and rice as monocot grass and crop models as well as Arabidopsis as a eudicot model of the Brassicaceae family. Beginning with the activation of the egg cell, we summarize and discuss the process of maternal-to-zygotic transition in plants, also taking recent work on parthenogenesis and haploid induction into consideration. Aspects like imprinting, which is mainly associated with endosperm development and somatic embryogenesis, are not considered. Controversial findings about the timing of zygotic genome activation as well as maternal versus paternal contribution to zygote and early embryo development are highlighted. The establishment of zygotic polarity, asymmetric division, and apical and basal cell lineages represents another chapter in which we also examine and compare the role of major signaling pathways, cell fate genes, and hormones in early embryogenesis. Except for the model Arabidopsis, little is known about embryopatterning and the establishment of the basic body plan in angiosperms. Using available in situ hybridization, RNA-sequencing, and marker data, we try to compare how and when stem cell niches are established. Finally, evolutionary aspects of plant embryo development are discussed.
Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.
2021-02-20

308 Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving progression-free survival (PFS; HR 0.51, P &lt; 0.0001), overall survival (OS; HR 0.60, P = 0.0010), and objective response rate (ORR; 55.7% vs 27.1%; P &lt; 0.0001) vs SUN in patients (pts) with aRCC in CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor prognoses. Methods: In this phase III open-label trial, adults with confirmed aRCC (with a clear cell component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40 mg PO QD vs SUN 50 mg PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local pathology report, and outcomes in these pts were evaluated via prespecified supportive subset analyses. Results: The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall, 75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%). Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table). Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response, and safety outcomes in the ITT population and in pts with and without sRCC will be reported with additional follow-up based on a September 10, 2020 database lock. Conclusions: NIVO+CABO demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability of outcomes in this trial. Clinical trial information: NCT03141177 . [Table: see text]
Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice
2021-02-20

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.
Zoomorphic Gestures for Communicating Cobot States
2021-02-20

Communicating the robot state is vital to creating an efficient and\\ntrustworthy collaboration between humans and collaborative robots (cobots).\\nStandard approaches for Robot-to-human communication face difficulties in\\nindustry settings, e.g., because of high noise levels or certain visibility\\nrequirements. Therefore, this paper presents zoomorphic gestures based on dog\\nbody language as a possible alternative for communicating the state of\\nappearance-constrained cobots. For this purpose, we conduct a visual\\ncommunication benchmark comparing zoomorphic gestures, abstract gestures, and\\nlight displays. We investigate the modalities regarding intuitive\\nunderstanding, user experience, and user preference. In a first user study (n =\\n93), we evaluate our proposed design guidelines for all visual modalities. A\\nsecond user study (n = 214) constituting the benchmark indicates that intuitive\\nunderstanding and user experience are highest for both gesture-based\\nmodalities. Furthermore, zoomorphic gestures are considerably preferred over\\nother modalities. These findings indicate that zoomorphic gestures with their\\nplayful nature are especially suitable for novel users and may decrease initial\\ninhibitions.\\n
Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study.
2021-02-20

327 Background: In the randomized, open-label, phase III KEYNOTE-426 study (NCT02853331), pembrolizumab + axitinib significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus sunitinib as first-line therapy for advanced RCC. Per protocol, patients could discontinue pembrolizumab or axitinib and continue the other agent. Pembrolizumab was stopped for all patients at 2 years. Axitinib could be continued until progression or toxicity. This exploratory subgroup analysis of KEYNOTE-426 describes outcomes of patients who completed 2 years of pembrolizumab. Methods: Patients included in KEYNOTE-426 were treatment naive, with clear cell RCC, KPS ≥70%, and measurable disease (RECIST v1.1). Patients were randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 35 doses + axitinib 5 mg orally twice daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off) until progression, toxicity, or withdrawal. Primary end points of the original analysis were OS and PFS. Key secondary end points were ORR and safety. Results: Of 432 patients treated with pembrolizumab + axitinib, 129 (29.9%) completed 2 years of study therapy. Median (range) age of these patients was 61 (36-82) years, and 72.1% were male; 42 (32.6%) and 87 (67.4%) patients had International mRCC Database Consortium favorable and intermediate/poor risk, respectively, consistent with the intention-to-treat population (31.9% vs 68.1%). Median (range) follow-up (time from randomization to data cutoff) was 31.1 (24.0-37.7) months. For patients who completed 2 years of study therapy, the OS rates at 36 months was 93.8% (95% CI, 85.5%-97.4%). The PFS rates at 24 and 36 months were 72.7% (95% CI, 64.0%-79.7%) and 57.7% (95% CI, 46.3%-67.5%), respectively. The ORR was 85.3%, and the CR rate was 14.0%. 59.7% of patients experienced grade 3-5 treatment-related adverse events and 8.5% experienced grade 3-5 immune-mediated adverse events. Conclusions: In this exploratory analysis, a significant proportion of patients in the pembrolizumab + axitinib arm completed 2 years of pembrolizumab with ongoing clinical benefit. Clinical trial information: NCT02853331 .
Efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) in men with de novo (M1) metastatic hormone-sensitive prostate cancer (mHSPC) versus progression to mHSPC (M0): Post hoc analysis of the phase III ARCHES trial.
2021-02-20

102 Background: In ARCHES (NCT02677896) ENZA + ADT reduced the risk of radiographic progression-free survival (rPFS) events, primary endpoint, and improved key secondary endpoints vs PBO + ADT in men with mHSPC (also known as metastatic castration-sensitive PC). Given the progressive nature of PC, this exploratory analysis evaluated efficacy of ENZA + ADT in patients (pts) who progressed to M1 HSPC following initial diagnosis (M0) vs pts who presented with de novo mHSPC at diagnosis (M1). Methods: mHSPC pts (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. In this post hoc analysis, pts previously centrally categorized as MX/unknown metastasis at initial diagnosis (n=213) were adjudicated as either M0 or M1 disease following review of their medical profiles; efficacy outcomes were compared according to M0 vs M1 disease at initial diagnosis. Results: In this analysis, 246 pts (ENZA n=117; PBO n=129) had M0 and 890 pts (ENZA n=448; PBO n=442) had M1 disease at initial diagnosis; metastatic status of 14 pts (ENZA n=9; PBO n=5) were unknown (data not shown). Baseline characteristics were generally comparable between treatment arms; however, a greater proportion of M1 pts had high disease volume (n=606; 68.1% vs n=116; 47.2% [M0]) and prior docetaxel (n=173, 19.4% vs n=29, 11.8% [M0]). ENZA + ADT improved rPFS vs PBO + ADT irrespective of M0 or M1 disease at diagnosis; similar improvements were observed for secondary endpoints including prostate-specific antigen (PSA) and objective responses, time to PSA progression, time to new antineoplastic therapy (Table). Safety profiles were generally similar between subgroups and the overall population; exceptions include higher fatigue in M0 ENZA and PBO treatment arms. Conclusions: This post hoc analysis demonstrates clinical benefit of ENZA + ADT vs PBO + ADT based on rPFS and secondary endpoints in men who progressed from M0 to M1 HSPC and those with de novo M1 HSPC. Clinical trial information: NCT02677896. [Table: see text]
Paradigmatic and syntagmatic effects in Estonian spontaneous speech
2021-02-20

Recent evidence indicates that a word’s paradigmatic neighbors affect production. However, thesefindings have mostly been obtained in careful laboratory settings using words in isolation, and thusignoring potential effects that may arise from the syntagmatic context, which is typically present inspontaneous speech. The current corpus analysis investigates paradigmatic and syntagmatic effectsin Estonian spontaneous speech. Following work on English, we focus on the duration of inflectedand uninflected word-final /-s/ in content words, while simultaneously investigating whole words.Our analyses reveal three points. First, we find an effect of realized inflectional paradigm size,such that smaller paradigms actively used by the speakers lead to longer durations. Second, higherconditional probability is associated with shorter word forms and shorter segments. Finally, wedo not directly replicate previous work on effects of inflectional status as in English word-final/-s/. Instead, we find that inflectional status interacts with conditional probability. We discussthe results in light of models of speech production and how they account for morphologicallycomplex words and their paradigmatic neighbors.