Rational modification of estrogen receptor by combination of computational and experimental analysis

In this manuscript, we modulate the binding properties of estrogen receptor protein by rationally modifying the amino acid composition of its ligand binding domain. By combining sequence alignment and structural analysis of known ER-ligand complexes with computational analysis, we were able to predict ER mutants with altered binding properties. These predictions were experimentally confirmed by producing single point variants with up to an order of magnitude increased binding affinity towards some estrogen disrupting chemicals and reaching an IC50 value of 2 nM for the 17α−Ethinylestradiol ligand. Due to increased affinity and stability, utilizing such mutated ERs instead of the wild type ER as bio-recognition element would be beneficial in an assay or biosensor.JRC.I-Institute for Health and Consumer Protection (Ispra

A neuronal network of mitochondrial dynamics regulates metastasis.

The role of mitochondria in cancer is controversial. Using a genome-wide shRNA screen, we now show that tumours reprogram a network of mitochondrial dynamics operative in neurons, including syntaphilin (SNPH), kinesin KIF5B and GTPase Miro1/2 to localize mitochondria to the cortical cytoskeleton and power the membrane machinery of cell movements. When expressed in tumours, SNPH inhibits the speed and distance travelled by individual mitochondria, suppresses organelle dynamics, and blocks chemotaxis and metastasis, in vivo. Tumour progression in humans is associated with downregulation or loss of SNPH, which correlates with shortened patient survival, increased mitochondrial trafficking to the cortical cytoskeleton, greater membrane dynamics and heightened cell invasion. Therefore, a SNPH network regulates metastatic competence and may provide a therapeutic target in cancer

Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the stemness marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease

Vrātya and vrātīna in Sanskrit Grammatical Sources

The present research aims at studying the derivation of vrātya- on the basis of the Aṣṭādhyāyī [A] of Pāṇini and on the relevant commentaries, to understand the Vedic usage of this lexeme and to investigate the origin of the notion of violence linked by default with the Vrātya identity. After a general overview of vrata- and vrāta- lexemes, rule A 5.2.21 vrātena jīvati is used to derive vrātīna-, and the relevant commentaries Mahābhāṣya [M], Kāśikāvṛttī [KV], and Siddhāntakaumudī [SK], turn out to be useful in understanding the many nuances of vrāta-. The derivation of vrātya- appears more complicated; the proposal advanced here resorts to A 5.3.113 vrātacphañor astriyām to explain both vrātyaḥ (nom. sg.), i.e., the outstanding ascetic mentioned in Śaunaka Atharvaveda-Saṃhitā and in Jaiminīya-Upaniṣad-Brāhmaṇa, and the more widespread vrātyāḥ (nom. pl.). Instead, other authoritative etymologies advanced over this last century interpret vrātya- as deriving from vrāta- based on vrata- (‘ritual vow’) or are influenced by the late association of Vrātyas with a violent behaviour

The taddhita affixes prescribed for pronominal stems: Analysis of pre-Pāṇinian ātI (A 5.3.34) occurrences

The present article can be inserted in a broader line of research, where specific pre-Pāṇinian occurrences of sarvanāmans + taddhita affixes are analysed to show how Pāṇini explains what in appearance was anomie and immediately transforms it into a strict norm. A previous analysis focused on several instances of the affix aka̲C (A 5.3.71), which all the translators of Ṛgveda and Śaunakīya Saṁhitā interpret as ka (A 5.3.70), with a generic diminutive meaning; even though the affix aka̲C can be understood as a pure device created by Pāṇini to deal with an internal sandhi problem in a systematic way, that is, it can be considered equivalent to ka, it is important to also consider what the several meanings aka̲C can bring (see Ferrero 2023). This regulatory process can be found also in the prescription of other taddhita affixes; for this reason, the affixes ātI / enaP / āC (A 5.3.34 – A 5.3.36) have been generally examined in this article. Moreover, some examples of the application of the affix ātI to pronominal stems have been specifically studied in the Vedic saṃhitās. The aim is to understand why Pāṇini needs to introduce these further rules in an already standardised grammatical system

Model-Based Fitting of EEG Signals With Uncertainty Quantification for Robust Alpha Wave Identification

Electroencephalography (EEG) is a noninvasive technique widely used to assess the brain's electrical activity, suitable for a variety of applications in clinical and nonclinical environments. However, the reliable identification of specific EEG features still remains a challenge, especially if the signals are recorded from wearable devices, notably less accurate than their hospital counterparts. The uncertainty analysis can help to address this challenge, by providing a robust and rigorous tool to assess the validity of the information extracted from the signals. This is particularly important in automated processes, such as brain-machine interfaces (BMIs), to avoid misclassifications and misinterpretation. This article proposes the use of a model-based fitting of prefiltered EEG signals, combined with uncertainty quantification, to extract the alpha amplitude oscillation with an optimal trade-off between accuracy and time resolution and, importantly, to allow the identification of those parts of the signal that do not follow the expected alpha dynamics, e.g., because affected by artifacts. This is achieved through a metrology-sound analysis of compatibility between measurement and model, taking their respective uncertainties into consideration. The proposed method has been successfully tested on real EEG signals and shown to have significant advantages in terms of time resolution and interpretability, compared with more traditional techniques, such as the independent component analysis (ICA) by temporal decorrelation, especially when applied to single-channel signals

Anemia in the Elderly: not Always what it Seems.

Anemia in the elderly is a common but challenging clinical scenario. Here we the described the case of an elderly women who presented with anemia and elevated inflammation markers. After a complete diagnostic workup a clear etiology of the anemia could not be found and eventually a bone marrow biopsy was performed: she was diagnosed with myelodysplastic syndrome. She responded well to erythropoietin treatment but her inflammation markers remained elevated and a positron emission tomography was eventually performed. It turned out that the patient suffered from giant cell artheritis, and after steroid treatment her anemia completely resolved. Our case outlines that it is necessary to pay particular attention to anemia of chronic inflammation, which could be due to several and often masked conditions. Myelodysplatic syndromes should be considered when other causes have been ruled out, but their diagnosis can be difficult and requires expertise in the field