Frataxin is a kinetic activator of the mitochondrial supercomplex for iron‐sulfur cluster assembly. Low frataxin expression or a decrease in its functionality results in Friedreich's Ataxia (FRDA). ...With the aim of creating new molecular tools to study this metabolic pathway, and ultimately, to explore new therapeutic strategies, we have investigated the possibility of obtaining small proteins exhibiting a high affinity for frataxin. In this study, we applied the ribosome display approach, using human frataxin as the target. We focused on Affi_224, one of the proteins that we were able to select after five rounds of selection. We have studied the interaction between both proteins and discussed some applications of this specific molecular tutor, concerning the modulation of the supercomplex activity. Affi_224 and frataxin showed a KD value in the nanomolar range, as judged by surface plasmon resonance analysis. Most likely, it binds to the frataxin acidic ridge, as suggested by the analysis of chemical shift perturbations (nuclear magnetic resonance) and computational simulations. Affi_224 was able to increase Cys NFS1 desulfurase activation exerted by the FRDA frataxin variant G130V. Importantly, Affi_224 interacts with frataxin in a human cellular model. Our results suggest quaternary addition may be a new tool to modulate frataxin function in vivo. Nevertheless, more functional experiments under physiological conditions should be carried out to evaluate Affi_224 effectiveness in FRDA cell models.
Frataxin is a kinetic activator for iron‐sulfur cluster assembly. Low frataxin expression or a decrease in its functionality results in Friedreich's Ataxia (FRDA). We applied the ribosome display approach, using human frataxin as the target to select affitins as tutor proteins. Affi_224 showed a nanomolar KD, it binds to the frataxin acidic ridge, and it was able to increase the activation exerted by the FRDA frataxin variant G130V. Moreover, Affi_224 interacts with frataxin in a cellular environment.
Oncogenic mutations in the KRAS/PI3K/AKT pathway are one of the most frequent alterations in cancer. Although PI3K or AKT inhibitors show promising results in clinical trials, drug resistance ...frequently emerges. We previously revealed Wnt/β-catenin signaling hyperactivation as responsible for such resistance in colorectal cancer. Here we investigate Wnt-mediated resistance in patients treated with PI3K or AKT inhibitors in clinical trials and evaluate the efficacy of a new Wnt/tankyrase inhibitor, NVP-TNKS656, to overcome such resistance.
Colorectal cancer patient-derived sphere cultures and mouse tumor xenografts were treated with NVP-TNKS656, in combination with PI3K or AKT inhibitors.We analyzed progression-free survival of patients treated with different PI3K/AKT/mTOR inhibitors in correlation with Wnt/β-catenin pathway activation, oncogenic mutations, clinicopathological traits, and gene expression patterns in 40 colorectal cancer baseline tumors.
Combination with NVP-TNKS656 promoted apoptosis in PI3K or AKT inhibitor-resistant cells with high nuclear β-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear β-catenin content and progressed earlier upon PI3K/AKT/mTOR inhibition. Nuclear β-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not.
High nuclear β-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear β-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/β-catenin inhibition and together with β-catenin may be predictive biomarkers of drug response providing a rationale to stratify colorectal cancer patients to be treated with PI3K/AKT/mTOR and Wnt/β-catenin inhibitors.
Congenital amusia in its most common form is a disorder characterized by a musical pitch processing deficit. Although pitch is involved in conveying emotion in music, the implications for pitch ...deficits on musical emotion judgements is still under debate. Relatedly, both limited and spared musical emotion recognition was reported in amusia in conditions where emotion cues were not determined by musical mode or dissonance. Additionally, assumed links between musical abilities and visuo-spatial attention processes need further investigation in congenital amusics. Hence, we here test to what extent musical emotions can influence attentional performance. Fifteen congenital amusic adults and fifteen healthy controls matched for age and education were assessed in three attentional conditions: executive control (distractor inhibition), alerting, and orienting (spatial shift) while music expressing either joy, tenderness, sadness, or tension was presented. Visual target detection was in the normal range for both accuracy and response times in the amusic relative to the control participants. Moreover, in both groups, music exposure produced facilitating effects on selective attention that appeared to be driven by the arousal dimension of musical emotional content, with faster correct target detection during joyful compared to sad music. These findings corroborate the idea that pitch processing deficits related to congenital amusia do not impede other cognitive domains, particularly visual attention. Furthermore, our study uncovers an intact influence of music and its emotional content on the attentional abilities of amusic individuals. The results highlight the domain-selectivity of the pitch disorder in congenital amusia, which largely spares the development of visual attention and affective systems.
Habitat loss is one of the main threats to species survival and, in the case of parasites, it is their hosts that provide their habitat. Therefore, extinction even at local scale of host taxa also ...implies the extinction of their parasites in a process known as co-extinction. This is the case of the bearded vulture (Gypaetus barbatus), which almost became extinct at the beginning of the twentieth century. After several attempts, this species was successfully reintroduced into the Alps at the end of the twentieth century. We collected 25 lice specimens from an electrocuted bearded vulture from Susa (Italian Alps) that were morphologically identified as Degeeriella punctifer. Six individuals were studied by scanning electron microscopy, with particular emphasis on their cephalic sensorial structures, while four further specimens were characterized at molecular level by amplifying partial regions of the 12SrRNA, COX1 and elongation factor 1 alpha (EF-1) genes. From a morphological perspective, the number, type and arrangement of the sensillae on the two distal antennal segments is quite similar to that of other species of the family Philopteridae (Phthiraptera: Ischnocera). The mandibles and tarsal claws allow lice to cling firmly to their host's feathers. Phylogenetic analyses help unravel the paraphyletic nature of the genus Degeeriella and demonstrate the clear differentiation between lice parasitizing Accipitriformes and Falconiformes, as well as the close relationship between D. punctifer, D. fulva, D. nisus and Capraiella sp. that, along with other genera, parasitize rollers (Aves: Coraciiformes).
The ability to map an unknown environment is a fundamental milestone for autonomous robotic vehicles. Solutions in this field must combine efficiency, accuracy, and precision. We propose a novel ...methodology for map feature extraction in indoor environments. The mathematical model and its implementation are designed to operate with 2-D light detection and ranging (LiDAR) measurements. Map parameters and associated uncertainty levels are determined through bivariate linear regression. The final step is experimental validation, using a low-cost commercial LiDAR sensor. The main contributions of the proposed methodology lie in the domains of computational efficiency and uncertainty. In addition, the results prove the ability of our methodology to handle large volumes of data while maintaining restrained growth in computational time. This outcome suggests considerable potential for real-time applications with limited hardware resources. A second methodology, extracted from the current state of the art, is used in parallel for benchmarking purposes.
In adults with COPD basic mobility scores on the AM-PAC "6-clicks" measure completed at discharge had the best sensitivity and specificity for predicting discharge to home and need for rehab services.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
A commonly stated critique of Solution Focused Brief Therapy (SFBT) is a lack of attention to the client's emotional experience and the use of emotion as a mechanism for producing meaningful change. ...We review and define the current research regarding emotion, feeling, and affect and its value and relevance to the clinical application of SFBT. We also provide a brief history of the SFBT model and its documented emphasis on cognitive and behavioral change versus emotional change. In embodying the spirit of this approach for examining what works and doing more of it, we propose a next step of SFBT to more overtly attend to the emotional language of clients and to purposefully create emotional experiences with our clients. We demonstrate this by providing clinical examples for how SFBT practitioners can incorporate and build upon clients' emotional language to create emotionally‐changing experiences to more broadly and effectively co‐create long‐lasting change.
Ceefourin-1 is a specific MRP4/ABCC4 inhibitor with potential antileukemic activity. In this study, we evaluate the ability of ceefourin-1 alone or in combination with histamine, an approved ...antileukemic agent, to induce cell differentiation or apoptosis in human acute myeloid leukemic cells. We also examine ceefourin-1 toxicity in mice.
U937, HL-60, and KG1a cells were used as models for human acute myeloid leukemia. Cyclic AMP efflux was estimated by measuring intracellular and extracellular cAMP levels. Cell differentiation was assessed by levels of CD14 and CD11b by FACS, and CD88 by western blot, and by cell morphology. Apoptosis was evaluated by cleavage of caspase-3 and PARP by western blot, and by annexin V binding assay. Subacute toxicity study of ceefourin-1 was carried out in BALB/c mice.
Ceefourin-1 inhibits cAMP exclusion in AML cells and promotes intracellular signaling via CREB. Ceefourin-1 leads AML cells to apoptosis and histamine potentiates this effect, without evidence of cell differentiation. Intraperitoneal administration of ceefourin-1 shows no important alterations in mice blood parameters, hepatic, and renal functions, nor signs of histologic damage.
These results show that ceefourin-1 promotes apoptosis in AML cells that is enhanced by histamine.
General significance:
This work indicates that ceefourin-1 represents a promising molecule that could be used alone or in combination with histamine for in vivo evaluation in acute myeloid leukemia malignancies.
•Ceefourin-1, a specific MRP4 inhibitor, blocks cAMP extrusion in AML cells.•Ceefourin-1 induces apoptosis in AML cells, and not differentiation.•Histamine enhances ceefourin-1 proapoptotic capacity.•Ceefourin-1 can be administered intraperitoneally to mice without apparent toxicity.
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•Mitogenomes and nuclear rDNA resolve diphyllobothriidean evolutionary relationships.•Host and habitat diversity studied from a phylogenetic perspective.•Freshwater inferred as ...diphyllobothriidean ancestral habitat.•Confirmed Schistocephalus solidus and S. pungitii as distinct species.•Demonstrated conspecificity of Ligula cf. intestinalis in ringed seal subspecies.
Broad tapeworms (Diphyllobothriidea) are parasites whose adults are capable of infecting a wide range of freshwater, marine and terrestrial tetrapods including humans. Previous works examining the evolution of habitat and host use in this group have been hampered by the lack of a well-resolved phylogeny. In order to produce a robust phylogenetic framework for diphyllobothriideans, we sequenced the complete mitochondrial genome of 13 representatives, carefully chosen to cover the major clades, and two outgroup species representing the Spathebothriidea and Haplobothriidea. In addition, complementary data from the nuclear ribosomal operon was sequenced for 10 representative taxa. Mitogenomes and ssrDNA and lsrDNA were used towards elucidating the phylogenetic framework for the Diphyllobothriidea. The Cephalochlamydidae is confirmed as the earliest diverging diphyllobothriidean lineage, and Solenophoridae and Diphyllobothriidae are sister groups. We infer a probable freshwater origin of the diphyllobothriideans. The ancestral condition for life cycle complexity could not be unambiguously resolved. However, we infer exclusive use of a three-host life cycle following the origin of the Solenophoridae + Diphyllobothriidae. Regarding definitive host use, although we infer reptiles as the most likely ancestral condition, this result should be revisited with a more densely sampled phylogeny in future studies. Freshwater habitat is used by the early diverging lineages within the Solenophoridae + Diphyllobothriidae clade. For the latter, habitat use shifts between freshwater and marine environments, and definitive host use includes marine and terrestrial mammals and birds. We use mitochondrial genomes to distinguish Schistocephalus species occurring in different species of sticklebacks and demonstrate conspecificity of Ligula cf. intestinalis specimens collected from two Fennoscandian ringed seal subspecies.
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