Italian burials from the Upper Palaeolithic. Inventory and anthropological observations

The Upper Paleolithic burials currently known in Italy represent a rich and important group which constitutes the major part of the European sample. Among these burials, those attributed to the Gravettian are concentrated in two regions, Liguria and Puglia. Epigravettian burials were found in most parts of the peninsula and in Sicily. Grave goods are often very rich, especially in Gravettian burials. With regard to the anthropological characteristics of the buried, research has focused mainly on postcranial skeleton and on the information it can give us about weight, stature and somatic proportions. Among the Gravettians, Ligurian males reach the highest stature. The average height decreases from Gravettian to Epigravettian, as already observed in the European sample

SARS-CoV-2 infection in cancer patients on active therapy after the booster dose of mRNA vaccines

The protective role against SARS-CoV-2 infection by the third booster dose of mRNA vaccines in cancer patients with solid malignancies is presently un- known. We prospectively investigated the occurrence of COVID-19 in cancer patients on active therapy after the booster vaccine dose. Methods: Cancer patients on treatment at the Center for Immuno-Oncology (CIO) of the University Hospital of Siena, Italy, and health care workers at CIO who had received a booster third dose of mRNA vaccine entered a systematic follow-up monitoring period to prospectively assess their potential risk of SARS-CoV-2 infection. Serological and microneu- tralization assay were utilized to assess levels of anti-spike IgG, and of neutralizing antibodies to the SARS-CoV-2 Wild Type, Delta and Omicron variants, respectively, after the booster dose and after negativization of the nasopharyngeal swab for those who had developed COV- ID-19. Results: Ninety cancer patients with solid tumors on active treatment (Cohort 1) and 30 health care workers (Cohort 2) underwent a booster third dose of mRNA vaccine. After the booster dose, the median value of anti-spike IgG was higher (p Z 0.009) in patients than in healthy subjects. Remarkably, 11/90 (12%) patients and 11/30 (37%) healthy subjects tested positive to SARS-CoV-2 infection during the monitoring period. Similar levels of anti-spike IgG and of neutralizing antibodies against all the investigated variants, with geometric mean titers of neutralizing antibodies against the Omicron being the lowest were detected after the booster dose and after COVID-19 in both Cohorts. Conclusions: The occurrence of SARS-CoV-2 infection we observed in a sizable proportion of booster-dosed cancer patients and in healthy subjects during the Omicron outbreak indicates that highly specific vaccines against SARS-CoV-2 variants are urgently required

Taxon ordering in phylogenetic trees by means of evolutionary algorithms

<p>Abstract</p> <p>Background</p> <p>In in a typical "left-to-right" phylogenetic tree, the vertical order of taxa is meaningless, as only the branch path between them reflects their degree of similarity. To make unresolved trees more informative, here we propose an innovative Evolutionary Algorithm (EA) method to search the best graphical representation of unresolved trees, in order to give a biological meaning to the vertical order of taxa.</p> <p>Methods</p> <p>Starting from a West Nile virus phylogenetic tree, in a (1 + 1)-EA we evolved it by randomly rotating the internal nodes and selecting the tree with better fitness every generation. The fitness is a sum of genetic distances between the considered taxon and the <it>r </it>(radius) next taxa. After having set the radius to the best performance, we evolved the trees with (<it>λ </it>+ <it>μ</it>)-EAs to study the influence of population on the algorithm.</p> <p>Results</p> <p>The (1 + 1)-EA consistently outperformed a random search, and better results were obtained setting the radius to 8. The (<it>λ </it>+ <it>μ</it>)-EAs performed as well as the (1 + 1), except the larger population (1000 + 1000).</p> <p>Conclusions</p> <p>The trees after the evolution showed an improvement both of the fitness (based on a genetic distance matrix, then close taxa are actually genetically close), and of the biological interpretation. Samples collected in the same state or year moved close each other, making the tree easier to interpret. Biological relationships between samples are also easier to observe.</p

A comparison of machine learning techniques for survival prediction in breast cancer

<p>Abstract</p> <p>Background</p> <p>The ability to accurately classify cancer patients into risk classes, i.e. to predict the outcome of the pathology on an individual basis, is a key ingredient in making therapeutic decisions. In recent years gene expression data have been successfully used to complement the clinical and histological criteria traditionally used in such prediction. Many "gene expression signatures" have been developed, i.e. sets of genes whose expression values in a tumor can be used to predict the outcome of the pathology. Here we investigate the use of several machine learning techniques to classify breast cancer patients using one of such signatures, the well established <it>70-gene signature</it>.</p> <p>Results</p> <p>We show that Genetic Programming performs significantly better than Support Vector Machines, Multilayered Perceptrons and Random Forests in classifying patients from the NKI breast cancer dataset, and comparably to the scoring-based method originally proposed by the authors of the 70-gene signature. Furthermore, Genetic Programming is able to perform an automatic feature selection.</p> <p>Conclusions</p> <p>Since the performance of Genetic Programming is likely to be improvable compared to the out-of-the-box approach used here, and given the biological insight potentially provided by the Genetic Programming solutions, we conclude that Genetic Programming methods are worth further investigation as a tool for cancer patient classification based on gene expression data.</p

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death

BACKGROUND: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. METHODS: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. FINDINGS: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. INTERPRETATION: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. FUNDING: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR)

Non-Agonistic Bivalent Antibodies That Promote c-MET Degradation and Inhibit Tumor Growth and Others Specific for Tumor Related c-MET

The c-MET receptor has a function in many human cancers and is a proven therapeutic target. Generating antagonistic or therapeutic monoclonal antibodies (mAbs) targeting c-MET has been difficult because bivalent, intact anti-Met antibodies frequently display agonistic activity, necessitating the use of monovalent antibody fragments for therapy. By using a novel strategy that included immunizing with cells expressing c-MET, we obtained a range of mAbs. These c-MET mAbs were tested for binding specificity and anti-tumor activity using a range of cell-based techniques and in silico modeling. The LMH 80 antibody bound an epitope, contained in the small cysteine-rich domain of c-MET (amino acids 519–561), that was preferentially exposed on the c-MET precursor. Since the c-MET precursor is only expressed on the surface of cancer cells and not normal cells, this antibody is potentially tumor specific. An interesting subset of our antibodies displayed profound activities on c-MET internalization and degradation. LMH 87, an antibody binding the loop connecting strands 3d and 4a of the 7-bladed β-propeller domain of c-MET, displayed no intrinsic agonistic activity but promoted receptor internalization and degradation. LMH 87 inhibited HGF/SF-induced migration of SK-OV-3 ovarian carcinoma cells, the proliferation of A549 lung cancer cells and the growth of human U87MG glioma cells in a mouse xenograft model. These results indicate that c-MET antibodies targeting epitopes controlling receptor internalization and degradation provide new ways of controlling c-MET expression and activity and may enable the therapeutic targeting of c-MET by intact, bivalent antibodies

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.</p> <p>Rationale</p> <p>We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.</p> <p>Conclusion</p> <p>Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.</p

LKR/SDH Plays Important Roles throughout the Tick Life Cycle Including a Long Starvation Period

BACKGROUND:Lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH) is a bifunctional enzyme catalyzing the first two steps of lysine catabolism in plants and mammals. However, to date, the properties of the lysine degradation pathway and biological functions of LKR/SDH have been very little described in arthropods such as ticks. METHODOLOGY/PRINCIPAL FINDINGS:We isolated and characterized the gene encoding lysine-ketoglutarate reductase (LKR, EC 1.5.1.8) and saccharopine dehydrogenase (SDH, EC 1.5.1.9) from a tick, Haemaphysalis longicornis, cDNA library that encodes a bifunctional polypeptide bearing domains similar to the plant and mammalian LKR/SDH enzymes. Expression of LKR/SDH was detected in all developmental stages, indicating an important role throughout the tick life cycle, including a long period of starvation after detachment from the host. The LKR/SDH mRNA transcripts were more abundant in unfed and starved ticks than in fed and engorged ticks, suggesting that tick LKR/SDH are important for the starved tick. Gene silencing of LKR/SDH by RNAi indicated that the tick LKR/SDH plays an integral role in the osmotic regulation of water balance and development of eggs in ovary of engorged females. CONCLUSIONS/SIGNIFICANCE:Transcription analysis and gene silencing of LKR/SDH indicated that tick LKR/SDH enzyme plays not only important roles in egg production, reproduction and development of the tick, but also in carbon, nitrogen and water balance, crucial physiological processes for the survival of ticks. This is the first report on the role of LKR/SDH in osmotic regulation in animals including vertebrate and arthropods