Miracle-dz/UniFAR-FTUs huggingface dataset:
FGFR3 activating mutations induce luminal-like papillary bladder tumor formation and favor a male gender bias

Background FGFR3 mutations are among the most frequent genetic alterations in bladder cancer and are enriched in the luminal papillary subtype of muscle-invasive tumors (MIBC) and luminal-like classes 1 and 3 of non-MIBC. To study their oncogenic properties in vivo, we developed here a genetically engineered mouse (GEM) model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Methods Bladder tumorigenesis was monitored in FGFR3-S249C mice. FGFR3 expression was assessed by RT-qPCR in the transgenic mice urothelium and in various human epithelia. Transcriptomic data were obtained from mouse bladder tumors and crossspecies comparisons were performed. Sex bias in FGFR3-mutated tumors was evaluated in our GEM model and in the TCGA and UROMOL cohorts of patients including 408 MIBC and 419 NMIBC, respectively. The association of androgen receptor (AR) activity, based on the expression of its target genes, with FGFR3 mutations was examined in these two cohorts. Binding of AR to its response element and AR phosphorylation in FGFR3-dependent cell lines were evaluated. Results FGFR3-S249C expression in the urothelium of mice induced spontaneous low-grade papillary bladder tumors resembling the human counterpart at the histological and transcriptomic levels. Mutant-FGFR3 expression levels impacted tumor formation incidence in mice and mutant-FGFR3-driven human tumors were restricted to epithelia presenting high normal expression levels of FGFR3. The known bladder cancer male gender bias, also found in our model, was even higher in human FGFR3-mutated compared to wild-type tumors and associated with a higher AR regulon activity considering gender adjustment. AR phosphorylation and regulon activity were modulated by FGFR3 in FGFR3-dependent models. Conclusions Mutant-FGFR3 is an oncogene per se, inducing bladder tumorigenesis. Patients with early stage bladder lesions could thus potentially benefit from FGFR3 targeting. Our results also reinforce the interest in elucidating the role of AR in bladder carcinogenesis, specifically in FGFR3-mutated driven tumors. Finally, our results suggest FGFR3 expression level in epithelium as a determinant for the FGFR3-driven tumors tissue specificity.
Wheat EARLY FLOWERING3 is a dawn-expressed circadian oscillator component that regulates heading date

Using an eight-parent Multiparent Advanced Generation Inter-Cross (MAGIC) population we investigated how variation at circadian clock-associated genes contributes to the regulation of heading date in UK and European winter wheat varieties. We identified homoeologues of EARLY FLOWERING 3 (ELF3) as candidates for the Earliness per se (Eps) D1 and B1 loci in field conditions. We confirmed that a SNP within the coding region of TaELF3-B1 is a candidate polymorphism underlying the Eps-B1 locus. We found that a reported deletion at the Eps-D1 locus encompassing TaELF3-D1, is instead a novel allele that lies within an introgression region containing an inversion relative to the Chinese Spring D genome. Using T. turgidum cv. Kronos carrying loss of function alleles of TtELF3 we show that ELF3 does regulate heading by demonstrating that the loss of a single ELF3 homoeologue was sufficient to alter heading date. These studies demonstrated that ELF3 forms part of the circadian oscillator but loss of all homoeologues was required to affect circadian rhythms. Similarly, loss of functional LUX ARRHYTHMO (LUX) in T. aestivum, an orthologue of a protein partner of Arabidopsis ELF3, severely disrupted circadian rhythms. ELF3 and LUX transcripts are not co-expressed at dusk suggesting the structure of the wheat circadian oscillator might differ to that of Arabidopsis. Our demonstration that alteration to ELF3 homoeologues can affect heading date separate from effects on the circadian oscillator suggests a role for ELF3 in cereal photoperiodic responses that could be selected for, without pleiotropic deleterious alterations to circadian rhythms.
An Extended Coatomer Binding Motif in the SARS-CoV-2 Spike Protein

β-Coronaviruses such as SARS-CoV-2 hijack coatomer protein-I (COPI) for spike protein retrograde trafficking to the progeny assembly site in endoplasmic reticulum-Golgi intermediate compartment (ERGIC). However, limited residue-level details are available into how the spike interacts with COPI. Here we identify a novel extended COPI binding motif in the spike that encompasses the canonical K-x-H dibasic sequence. This motif demonstrates selectivity for αCOPI subunit. Guided by an in silico analysis of dibasic motifs in the human proteome, we employ mutagenesis and binding assays to show that the spike motif terminal residues are critical modulators of complex dissociation, which is essential for spike release in ERGIC. αCOPI residues critical for spike motif binding are elucidated by mutagenesis and crystallography and found to be conserved in the zoonotic reservoirs, bats, pangolins, camels, and in humans. Collectively, our investigation on the spike motif identifies key COPI binding determinants with implications for retrograde trafficking.
The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. We have previously demonstrated that a subset of spinal V3 neurons contributes to stable locomotion by mediating mutual excitation between left and right lumbar rhythm generators (RGs). Here, we expanded our investigation to the V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used lateral-sequence walk. To understand the functional roles of V3 aLPNs, we adapted our previous model of spinal circuitry controlling quadrupedal locomotion (Danner et al., 2017), by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The updated model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left–right interactions within lumbar and cervical cords, promote left–right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.
Production of Offspring from Azoospermic Mice with Meiotic Failure: Precise Biparental Meiosis within Halved Oocytes

While the large volume of mammalian oocytes is necessary for embryo development, it can lead to error-prone chromosomal segregation during meiosis. Consequently, a smaller ooplasm might assure better chromosomal integrity of oocytes and embryos, but there is no evidence to support this hypothesis. Here, we show that reducing the ooplasm is beneficial for assisted fertilization using primary spermatocytes, involving synchronous biparental meiosis within oocytes. High-resolution live-imaging analysis revealed that erroneous chromosome segregation occurred in most (90%) spermatocyte-injected oocytes of normal size, but could be ameliorated to 40% in halved oocytes. The birth rate improved remarkably from 1% to 19% (P < 0.0001). Importantly, this technique enabled the production of offspring from azoospermic mice with spermatocyte arrest caused by STX2 deficiency, an azoospermia factor also found in humans. Thus, reduced ooplasmic volume can indeed correct the lethal meiotic errors and might help rescue cases of untreatable human azoospermia with spermatocyte arrest.
How to hash onto G 2 and not to hash onto G 1 for pairing-friendly curves

Let E 1 be an ordinary pairing-friendly elliptic curve of embedding degree k > 1 over a ﬁnite ﬁeld F q . Besides, let E 2 be a twist of E 1 of degree d := #Aut( E 1 ) over the ﬁeld F q e , where e := k/d ∈ N . As is customary, for a common prime divisor r of the orders N 1 := # E 1 ( F q ) and N 2 := # E 2 ( F q e ) denote by G 1 ⊂ E 1 ( F q ) and G 2 (cid:44) → E 2 ( F q e ) the eigenspaces of the Frobenius endomorphism on E 1 [ r ] ⊂ E 1 ( F q k ), associated with the eigenvalues 1, q respectively. This short note explains how to hash onto G 2 more eﬃciently and why we do not need to hash directly onto G 1 . In the ﬁrst case, we signiﬁcantly exploit the presence of clearing the cofactor c 2 := N 2 /r . In the second one, on the contrary, clearing the cofactor c 1 := N 1 /r can be fully avoided. The fact is that optimal ate pairings a : G 2 × G 1 → µ r ⊂ F ∗ q k can be painlessly (unlike E 2 ( F q e ) × G 1 ) extended to G 2 × E 1 ( F q ), at least in main pairing-based protocols. Throughout the text we mean hashing indiﬀerentiable from a random oracle. At the moment, the curve BLS12-381 (with e = 2) is the most popular in practice. Earlier for this curve (and a number of others) the author constructed encodings F 2 q → E 1 ( F q ) and F q → E 2 ( F q 2 ) computable in constant time of one exponentiation in F q . Combining the new ideas with these encodings, we obtain hash functions { 0 , 1 } ∗ → E 1 ( F q ) and { 0 , 1 } ∗ → G 2 , which seem to be diﬃcult to speed up even more. We also discuss how much performance gain they provide over hash functions that are actively applied in the industry.
Adoption of Robots for Disasters: Lessons from the Response to COVID-19

This article describes how robot innovations are adopted during a disaster using the COVID-19 response both as a natural experiment and a case study. The article is based on an analysis of the R4ID dataset of 203 instances of ground and aerial robots in 34 countries explicitly reported in the press, social media, and scientific literature from January 24, 2020, to July 4, 2020, as being used due to the COVID-19 pandemic. While the reports do not provide sufficient detail to ascertain gaps in specific algorithms or specific subsystems, such as perception, manipulation, or autonomy, the size and the pervasiveness of the data permits examination of three questions: 1) how the need for a robot arises during a disaster, 2) whether those needs are met with existing technically mature robots, adapting existing robots, or in-novating new robots, and 3) what are the major barriers to
Early Life-History Dynamics of Caribbean Octocorals: The Critical Role of Larval Supply and Partial Mortality

Recruitment is a key demographic process for maintenance of local populations and recovery following disturbance. For marine invertebrates, distribution and abundances of recruits are impacted by spatiotemporal variation in larval supply, settlement rates and post-settlement survival. However, for colonial and modular organisms, differences in survival and growth between settlers and colonial recruits may also affect recruitment patterns. In the Caribbean, shifts in the benthic community structure favoring octocoral’s have been detected, and recruitment has been suggested as key for octocoral’s resilience. Hence, we studied octocoral recruitment dynamics, and evaluated the role of pre-settlement, settlement and post-settlement processes in recruit’s densities. We performed the study at two sites with different octocoral densities, on the south coast of St. John, United States Virgin Islands, and distinguished between processes occurring to recently settled polyps and to colonial recruits. At both sites, we monitored P. homomalla settlers on settlement tiles for 3 months, and colonial recruits of two of the most abundant genera (Eunicea and Pseudoplexaura) for 3 years. In addition, we assessed whether recruits morphological traits affected recruitment and divided recruits of the genus Eunicea based on the presence of large calyces. The major contributor to both, single-polyps and colonial recruit densities was larval supply. Single-polyp densities were not limited by the availability of space, settlement cues, or early post-settlement survival. Height was the only predictor of survival and growth of colonial recruits, with potential growth rates increasing with height. However, large recruits suffered partial mortality often, distorting the relationship between recruit age and size, and causing most recruits to remain in the recruit size class (≤5 cm) longer than a year. Octocorals have been resilient to the conditions that have driven the decline of scleractinian corals throughout the Caribbean, and recruitment has been key to that success. Our results are crucial to understand early life history dynamics of Caribbean octocorals, and highlights the need to standardize the definition of recruit among colonial and modular taxa to facilitate inter-specific comparisons, and to understand future changes in coral reef community assemblages.
Longitudinal Characterization of Cytokine Overproduction: A Case Report in Critically Ill COVID-19 Patients With Hyperinflammation in Bronchoalveolar Lavage

Objectives: The longitudinal characterization and risk of poor outcomes related to cytokine overproduction in critical coronavirus disease 2019 (COVID-19) patients with hyperinflammation in bronchoalveolar lavage requires further investigation. Methods: We enrolled two critically ill patients with comorbidities diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detected by RT-PCR during hospitalization. Clinical characteristics, longitudinal immunological, and biochemical parameters of each critical COVID-19 case were collected. Main Results: The clinical characteristics and laboratory results of each case demonstrated critical symptoms of COVID-19 with poor outcomes. Both nasopharyngeal swabs and bronchoalveolar lavage fluid (BALF) samples tested positive for SARS-CoV-2. Two patients received targeted treatments against pathogen infection and inflammation in addition to interventional therapies, except for Patient 2, who received an additional artificial liver system treatment. Hyperinflammation with a dominantly high level of IL-6 was observed in BALF samples from both critical cases with decreased T cell populations. High levels of cytokines and pathological parameters were successively maintained in Patient 1, but rapidly reduced at the late treatment stage in Patient 2. The outcome of Patient 1 is death, whereas the outcome of Patient 2 is recovery. Conclusions: This case report suggests that a high risk of poor outcomes was related to a heavily hyperinflammatory milieu in both the blood and lungs of critical COVID-19 patients. The artificial liver intervention on cytokines overproduction might be beneficial for the recovery of critical COVID-19 patients as a reliable therapy that can be coordinated with targeted treatments, which ought to be further tested in adequately designed and powered clinical trials.
Xiaoyaosan Exerts Antidepressant Effect by Downregulating RAGE Expression in Cingulate Gyrus of Depressive-Like Mice

Xiaoyaosan (XYS), as a classic Chinese medicine compound, has been proven to have antidepressant effect in many studies, but its mechanism has not been clarified. In our previous studies, we found that chronic stress can induce depressive-like behavior and lead to emotion-related cingulate gyrus (Cg) dysfunction, as well as the decrease of neurotrophic factors and the increase of inflammatory-related proteins. Therefore, we speculated that XYS may play an antidepressant role by regulating the inflammation-related receptor of advanced glycation protein end product (RAGE) to affect the functional connectivity (FC) signal of the Cg and improve the depressive-like behavior. In order to verify this hypothesis, we analyzed the FC and RAGE expression in the Cg of depressive-like mice induced by chronic unpredictable mild stress (CUMS) and verified it with RAGE knockout mice. At the same time, we detected the effect of XYS on the depressive-like behavior, expression of RAGE, and the FC of the Cg of mice. The results showed that the FC of the Cg of depressive-like mice induced by CUMS was weakened, and the expression of RAGE was upregulated. The antidepressant effect of XYS is similar to that of fluoxetine hydrochloride, which can significantly reduce the depressive-like behavior of mice and inhibit the expression of the RAGE protein and mRNA in the Cg, and increase the FC of the Cg in mice. In conclusion, XYS may play an antidepressant role by downregulating the expression of RAGE in the Cg of depressive-like mice induced by CUMS, thereby affecting the functional signal and improving the depressive-like behavior.
Decreased Autonomic Reactivity and Psychiatric Comorbidities in Neurological Patients With Medically Unexplained Sensory Symptoms: A Case-Control Study

Up to 48% of patients with medically unexplained symptoms seen in neurological practice suffer from sensory symptoms, which could be of functional nature or secondary to psychiatric disorders. These patients show high medical care utilization causing elevated healthcare costs. Despite the high prevalence, little is known about clinical characteristics and pathophysiological mechanisms. For functional disorders such as irritable bowel syndrome, a reduction of heart rate variability (HRV) has been shown, suggesting a dysfunction of the autonomic nervous system (ANS). The aim of this study was to investigate psychological data and functional changes of the ANS in patients with medically unexplained sensory symptoms (MUSS). In this exploratory pilot study, 16 patients (11 females, 31.6 ± 11.9 years) with MUSS, who were recruited at a single tertiary neurological center, underwent a structured clinical interview (SCID) to evaluate psychiatric comorbidities. Patients and age- and sex-matched healthy volunteers filled in questionnaires, and individual sensory thresholds (perception, pain) were detected by quantitative sensory testing (QST). HRV was assessed at baseline and under three different experimental conditions (tonic pain stimulus, placebo application, cold-face test). All tests were repeated after 6–8 weeks. SCID interviews revealed clinical or subclinical diagnoses of psychiatric comorbidities for 12 patients. Questionnaires assessing somatization, depression, anxiety, and perceived stress significantly discriminated between patients with MUSS and healthy controls. While there was no difference in QST, reduced ANS reactivity was found in patients during experimental conditions, particularly with regard to vagally mediated HRV. Our pilot study of neurological patients with MUSS reveals a high prevalence of psychiatric comorbidities and provides evidence for altered ANS function. Our data thus give insight in possible underlying mechanisms for these symptoms and may open the door for a better diagnostic and therapeutic approach for these patients in the future.
Emotion Differentiation in Current and Remitted Major Depressive Disorder

People with current major depressive disorder (MDD) experience diminished emotion differentiation. We tested the hypothesis that this emotional disturbance is chronic and also characterizes those whose MDD has remitted. As our main aim, we examined emotion differentiation in conjunction with elevated negative and diminished positive emotional intensity, which are both cardinal symptoms of MDD. As an exploratory aim, we examined the predominant theoretical conceptualization that people low in emotion differentiation use more general state terms (e.g., bad) and fewer emotion terms (e.g., anger) to describe their emotional experience. Participants (assessed via diagnostic interview) included individuals who had current MDD (current depressed; n = 48), individuals whose MDD was in full remission (remitted depressed; n = 80), and healthy controls (n = 87). Participants also completed two self-report measures of depressive symptoms and reported momentary emotion repeatedly for 14 days via experience sampling, from which we computed emotion differentiation (i.e., intraclass correlation coefficient) and emotional intensity (i.e., average of the mean emotion ratings across surveys). Finally, participants described a momentary emotional experience via an open-response format, which was coded for the use of general state and emotion terms. Compared to the healthy control group, the current and remitted depressed groups showed similarly low levels of negative and positive emotion differentiation. These findings suggest that diminished emotion differentiation may be a stable characteristic of depressive disorders and a possible target for future prevention efforts. Diminished negative emotion differentiation was significantly associated with higher depressive symptoms as assessed by only one of the depression measures, though this finding did not hold after adjusting for negative emotional intensity. Finally, participants’ emotion differentiation was not associated with use of general state and emotion terms, and groups did not use general state and emotion terms in ways that were consistent with the predominant theoretical conceptualization of emotion differentiation, suggesting the need for clarification in this research domain.
Extracellular Vesicles as Natural Delivery Carriers Regulate Oxidative Stress Under Pathological Conditions

Extracellular vesicles are cellular secretory particles that can be used as natural drug delivery carriers. They have successfully delivered drugs including chemotherapeutics, proteins, and genes to treat various diseases. Oxidative stress is an abnormal physiological phenomenon, and it is associated with nearly all diseases. In this short review, we summarize the regulation of EVs on oxidative stress. There are direct effects and indirect effects on the regulation of oxidative stress through EVs. On the one hand, they can deliver antioxidant substances or oxides to recipient cells, directly relieving or aggravating oxidative stress. On the other hand, regulate factors of oxidative stress-related signaling pathways can be delivered to recipient cells by the mediation of EVs, realizing the indirect regulation of oxidative stress. To the best of our knowledge, however, only endogenous drugs have been delivered by EVs to regulate oxidative stress till now. And the heterogeneity of EVs may complicate the regulation of oxidative stress. Therefore, this short review aims to draw more attention to the EVs-based regulation of oxidative stress, and we hope excellent EVs-based delivery carriers that can deliver exogenous drugs to regulate oxidative stress can be exploited.
Management of Large Cell Neuroendocrine Carcinoma

Background Large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive cancer with a dismal prognosis. The majority of cases occur in the lung and the gastrointestinal tract; however, it can occur throughout the body. Recently advances in the understanding of the molecular underpinnings of this disease have paved the way for additional novel promising therapies. This review will discuss the current best evidence for management of LCNEC and new directions in the classification and treatment of this rare disease. Methods We performed a PubMed search for “Large cell neuroendocrine carcinoma” and “High grade neuroendocrine carcinoma. ” All titles were screened for relevance to the management of LCNEC. Papers were included based on relevance to the management of LCNEC. Results Papers were included reviewing both pulmonary and extra pulmonary LCNEC. We summarized the data driven best practices for the management of both early and advanced stage LCNEC. We describe emerging therapies with promising potential. Discussion LCNEC are rare and aggressive neoplasms. In advanced disease, the historical regimen of platinum based therapy in combination with etoposide or irinotecan remains among the commonly used first line therapies, however for extra thoracic LCNEC regimens like FOLFOX, FOLFOIRI and CAPTEM can also be used. Further effective and safe treatment options are desperately needed. Recently, new advances including a new understanding of the genetic subcategories of LCNEC and immunotherapy agents may guide further treatments.