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Osteoporosis is a disease characterized by low bone mass and alterations of bone microarchitecture, with an increased risk of fractures. It is a multifactorial disorder that is more frequent in postmenopausal women but can be associated to other diseases (inflammatory and metabolic diseases). At present, several options are available to treat osteoporosis trying to block bone reabsorption and reduce the risk of fracture. Anyway, these drugs have safety and tolerance problems in long-term treatment. Recently, gut microbiota has been highlighted to have strong influence on bone metabolism, becoming a potential new target to modify bone mineral density. Such evidences are mainly based on mouse models, showing an involvement in modulating the interaction between the immune system and bone cells. Germ-free mice represent a basic model to understand the interaction between microbiota, immune system, and bone cells, even though data are controversial. Anyway, such models have unequivocally demonstrated a connection between such systems, even if the mechanism is unclear. Gut microbiota is a complex system that influences calcium and vitamin D absorption and modulates gut permeability, hormonal secretion, and immune response. A key role is played by the T helper 17 lymphocytes, TNF, interleukin 17, and RANK ligand system. Other important pathways include NOD1, NOD2, and Toll-like receptor 5. Prebiotics and probiotics are a wide range of substances and germs that can influence and modify microbiota. Several studies demonstrated actions by different prebiotics and probiotics in different animals, differing according to sex, age, and hormonal status. Data on the effects on humans are poor and controversial. Gut microbiota manipulation appears a possible strategy to prevent and treat osteopenia and/or osteoporosis as well as other possible bone alterations, even though further clinical studies are necessary to identify correct procedures in humans.

Background and purpose The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Introduction: About one third of patients affected with thyroid cancer present with recurrent disease. Unresectability, advanced disease and radioiodine refractoriness are considered poor prognostic factors. Treatment with small molecules inhibiting molecular signaling can be considered for patients with progressive disease, when other therapeutic strategies cannot be applied. Lenvatinib is a tyrosine kinase inhibitor targeting multiple molecular factors involved in angiogenesis and tumor progression. Preclinical studies have demonstrated the utility of lenvatinib as a targeted therapy for different tumors, including both differentiated and anaplastic thyroid cancer.Areas covered: The authors provide an overview of the preclinical development of lenvatinib in the treatment of thyroid cancer and review its clinical application. They also provide their expert opinion on its development.Expert opinion: Preclinical studies have helped in the understanding of the mechanisms of thyroid carcinogenesis and in the development of a targeted therapy. These findings have represented the rationale for the use of lenvatinib in clinical trials, which have confirmed its utility but yet failed to prove a clear benefit in overall survival. The decision to start a systemic treatment with lenvatinib must be personalized for each patient evaluating the risk/benefits ratio. Treatment emergent adverse events must be considered and reasonably managed by a multidisciplinary approach.

A study on submonomer solid-phase synthesis of S-glycopeptoids has been carried out by screening different parameters. Dimeric species, featuring glycosylated bridging amino monomers, were found under suitable conditions. These dimers arise from an on-resin cross-linking reaction occurring with the incorporation of a glycoamino submonomer into the growing chain and subsequent nucleophilic attack of the resulting secondary amine to a still unreacted bromoacetylated unit. The arising byproduct can be regarded as a novel dimeric peptoid type.

The mesenchymal sub-type of triple negative breast cancer (MES-TNBC) has a highly aggressive behavior and worse prognosis, due to its invasive and stem-like features, that correlate with metastatic dissemination and resistance to therapies. Furthermore, MES-TNBC is characterized by the expression of molecular markers related to the epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs). The altered expression of &alpha, v&beta, 3 integrin has been well established as a driver of cancer progression, stemness, and metastasis. Here, we showed that the high levels of &alpha, 3 are associated with MES-TNBC and therefore exploited the possibility to target this integrin to reduce the aggressiveness of this carcinoma. To this aim, MES-TNBC cells were treated with a novel peptide, named &psi, RGDechi, that we recently developed and characterized for its ability to selectively bind and inhibit &alpha, 3 integrin. Notably, &psi, RGDechi was able to hamper adhesion, migration, and invasion of MES-TNBC cells, as well as the capability of these cells to form vascular-like structures and mammospheres. In addition, this peptide reversed EMT program inhibits mesenchymal markers. These findings show that targeting &alpha, 3 integrin by &psi, RGDechi, it is possible to inhibit some of the malignant properties of MES-TNBC phenotype.

Due to strict reliance on competitive labor markets, standard approaches which measure skill biased technical change (SBTC) conflate labor market distortions which prevent firms from choosing the efficient ratio between skilled and unskilled labor and `true' SBTC. This contrasts with recent evidence on decoupling between wages and productivity. To overcome this limitation, we present a unified framework to estimate SBTC which accounts for factor accumulation (FA) effects, and quantifies the discrepancy (i.e., relative misallocation) between the wage ratio (skilled to unskilled) and the marginal rate of technical substitution (MRTS). The suggested methodology takes advantage of recent developments in nonparametric estimation methods (i.e., discrete smoothing) that allow us to estimate the marginal productivity of inputs at the country-sector level directly from data. Over the 1995-2005 period, we find a 3\% yearly growth rate for the MRTS between skilled and unskilled labor and show such change to be almost entirely driven by SBTC, rather than FA, on average. In most cases, SBTC and MRTS growth do not come with increasing skill premia; this fosters the decoupling and results in relative misallocation patterns (across countries and sectors) which are quite heterogeneous, for which we report a 6\% overall increase. Finally, we show evidence that relative misallocation increased less in country-sectors in which it was larger at the beginning of the period and grew more in country-sectors characterized by: (a) higher skill-intensity; (b) lower bargaining power of skilled over unskilled workers; and (c) lower FA effects.

Purpose This study forms part of a larger project funded by Cariplo Foundation. The purpose of this paper is to focus on the scope to exploit the full potential and upgrade the functions of abandoned or under-utilized typical highland Alpine pasture systems (made by a complex of grazing fields, buildings for temporal animal and human recovery and dairy production, identified as Malga system or Alpeggio), by adopting the property investor’s point of view. Design/methodology/approach This study has adapted the traditional property development processes to rural buildings, thus generating an analysis model that proves able to define a new destination of use whenever the project considers the reuse of existing facilities. Findings The proposed model analyzes the technological, functional and territory features of the building to be upgraded, to assess the technical feasibility of the changeover project and identify the highest and best use of Malga-systems. The model has been applied to all the Malga-systems in the Orobie Bergamasche Park; it performed a comprehensive assessment of the development potential of the Malga-systems in the same Park. Research limitations/implications The design of the model took into consideration the specificities of the Orobie Bergamasche Park; nevertheless, the method can be taken as an example to be applied to any grazing land in the Alps. Originality/value This research provides the real estate market with a new analysis tool that is specific for the rural buildings, and suitable to streamline the procedures designed to upgrade these properties and to infuse new life into the territories that are experiencing a period of hardship and/or decay.

We use a panel of European firms to investigate the relationship between intangible assets and productivity. We distinguish between total factor productivity (tfp) and technology adoption, whereas standard estimations consider only a notion of productivity that conflates the two effects. Although we are unable to address simultaneity, we allow for the existence of multiple technologies within sectors through a mixture model approach. We find that intangible assets have nonnegligible effects that both push firms toward better technologies (technology adoption effects) and allow for more efficient exploitation of a given technology (tfp effects).

A RGD motif was identified in the N-terminal region of cE5, a potent salivary thrombin inhibitor from the African malaria vector Anopheles gambiae. A peptide (APQ30) encompassing the first 30 amino acids residues of the protein and including the RGD tripeptide was tested in cell adhesion assays and found to inhibit ?? and ?? mediated adhesion. A shorter peptide (APQ16), strongly conserved among members of the A. gambiae species complex and including only the first 16 residues, retained adhesion inhibitory properties, however with enhanced specificity toward ??. In addition, migration and invasion assays showed its capacity to inhibit the invasiveness of the malignant cell lines HepG2 and MDA-MB231. Altogether our data point to APQ16 as a new promising candidate as theranostic agent.

Integrins are a large family of heterodimeric receptors critically engaged in pathological processes such as tumor progression and metastasis. Although they are validated therapeutic targets, the molecular determinants governing integrin-ligand interactions are not yet fully understood, leading to a scarcity of integrin sub-type exclusive antagonists. In the past decade, we have investigated the biological behavior of the RGDechi, a chimeric peptide able to specifically bind avb3 integrin without cross reacting with avb5 and aIIbb3 integrins. Here we have investigated the capability of the peptide to bind a5b1 integrin and characterized the molecular determinants governing this interaction through a combined experimental and computational approach. The detailed comparison of RGDechi-a5b1 structural model with that previously determined of RGDechi in complex with avb3 shows how the bifunctional nature of the peptide renders the molecule an important tool to recognize integrins with different recognition modalities, providing novel insight on the structural requirements needed to their specific recognition.

Streamlined access to S-glycosylated Fmoc-amino acids was developed. The process provides diverse glycosylated modified amino acids in high yield and stereoselectivity taking advantage of the in situ generation of a glycosylthiolate obtained from carbohydrate acetates in a few steps. Mild basic conditions make the conjugation reaction compatible with Fmoc-iodo-amino acids. To validate the strategy the glycosylated building blocks were used for SPPS and the unprecedented incorporation of a long thio-oligosaccharide to the peptide chain was demonstrated.

Productivity has recently slowed down in many economies around the world. A crucial challenge in understanding what lies behind this “productivity puzzle” is the still short time span for which data can be analysed. An exception is Italy where productivity growth started to stagnate 25 years ago. Italy therefore offers an interesting case to investigate in search of broader lessons that may hold beyond local specific cities. We find that resource misallocation has played a sizeable role in slowing down Italian productivity growth. If misallocation had remained at its 1995 level, in 2013 Italy's aggregate productivity would have been 18% higher than its actual level. Misallocation has mainly risen within sectors than between them, increasing more in sectors where the world technological frontier has expanded faster. Relative specialization in those sectors explains the patterns of misallocation across geographical areas and firm size classes. The broader message is that an important part of the explanation of the productivity puzzle may lie in the rising difficulty of reallocating resources between firms in sectors where technology is changing faster rather than between sectors with different speeds of technological change

Herein, we report the synthesis and biological characterization of the new peptide ψRGDechi as the first step toward novel-targeted theranostics in melanoma. This pseudopeptide is designed from our previously reported RGDechi peptide, known to bind selectively α

Crossmodal correspondences have often been demonstrated using congruency effects between pairs of stimuli in different sensory modalities that vary along separate dimensions. To date, however, it is still unclear the extent to which these correspondences are relative versus absolute in nature: that is, whether they result from pre-defined values that rigidly link the two dimensions or rather result from flexible values related to the previous occurrence of the crossmodal stimuli. Here, we investigated this issue in a speeded classification task featuring the correspondence between auditory pitch and visual size (e.g., congruent correspondence between high pitch/small disc and low pitch/large disc). Participants classified the size of the visual stimuli (large vs. small) while hearing concurrent high- or low-pitched task-irrelevant sounds. On some trials, visual stimuli were paired instead with “intermediate” pitch, that could be interpreted differently according to the auditory stimulus on the preceding trial (i.e., as “lower” following the presentation of a high pitch tone, but as “higher” following the presentation of a low pitch tone). Performance on sequence-congruent trials (e.g., when a small disc paired with the intermediate-pitched tone was preceded by a low pitch tone) was compared to sequence-incongruent trials (e.g., when a small disc paired with the intermediate-pitch tone was by a high-pitched tone). The results revealed faster classification responses on sequence-congruent than on sequence-incongruent trials. This demonstrates that the effect of the pitch/size correspondence is relative in nature, and subjected to trial-by-trial interpretation of the stimulus pair.

Summary Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6′-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy.

Purpose– The paper aims at describing a supporting model for the decision-making process that may steer the location decisions of international businesses. This is made possible by a measurement system where the characteristics of a territory are assessed with reference to some key factors that are internationally known to investors, to the aim of spotting the best location to implement a property investment.Design/methodology/approach– The surveys analysed when producing this paper highlighted the presence of internationally renowned and shared factors that the enterprises generally take into consideration in their decision-making process, and which strongly influence the decision to locate a business in a territory to the detriment of another. By adopting and organizing these “key factors” in a systemic way, the model introduced in this paper supports enterprises in their location choice. It analyses and measures some territorial contexts (with no limits regarding their size) based on the scores assigned to these contexts after the analysis of the 12 key factors.Findings– The analysis had two outputs: on the one hand, its results allowed to check whether the areas are actually in line with the expectations and with the requirements of a potential investor, with reference to the activity that such investor is willing to promote; on the other, the identification of the characteristics of the area provides the basis to define the vocation of the areas under examination, thus helping the drawing of future development scenarios.Originality/value– The surveys analysed when producing this paper highlighted the presence of internationally renowned and shared factors that the enterprises generally take into consideration in their decision-making process, and which strongly influence the decision to locate a business in a territory to the detriment of another.