Tackling Alzheimer's Disease with Existing Drugs:A Promising Strategy for Bypassing Obstacles

The unmet need for the development of effective drugs to treat Alzheimer's disease has been steadily growing, representing a major challenge in drug discovery. In this con-text, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them, preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer’s disease, considering not only the finding of new uses for existing drugs but also the new hypotheses on disease pathogenesis that could promote previ-ously unconsidered therapeutic regimens. Moreover, some examples of structural modifica-tions performed on existing drugs in order to obtain multifunctional compounds will also be described

Integrated 3D information for custom-made bone grafts: focus on biphasic calcium phosphate bone substitute biomaterials

none5Purpose: Several studies showed that the sintering temperature of 1250 °C could affect the formation of α-Ca3(PO4)2, which is responsible for the reduction of the hardness value of biphasic calcium phosphate biocomposites, but they did not evaluate the inference of the sintering time at peak temperature on transition of β-Ca3(PO4)2 to α-Ca3(PO4)2. This analysis explored, in an innovative way, inferences and correlations between volumetric microstructure, mechanical properties, sintering temperature, and time at peak temperature in order to find the best sintering conditions for biphasic calcium phosphate composites grafted in severe alveolar bone defects. Methods: Sintered biphasic calcium phosphates (30%-hydroxyapatite/70%-tricalcium phosphate) were tested by microCT imaging for the 3D morphometric analysis, by compressive loading to find their mechanical parameters, and by X-ray diffraction to quantify the phases via Rietveld refinement for different sintering temperatures and times at the peak temperature. Data were analysed in terms of statistical inference using Pearson’s correlation coefficients. Results: All the studied scaffolds closely mimicked the alveolar organization of the jawbone, independently on the sintering temperatures and times; however, mechanical testing revealed that the group with peak temperature, which lasted for 2 hours at 1250 °C, showed the highest strength both at the ultimate point and at fracture point. Conclusion: The good mechanical performances of the group with peak temperature, which lasted for 2 hours at 1250 °C, is most likely due to the absence of the α-Ca3(PO4)2 phase, as revealed by X-ray diffraction. However, we detected its presence after sintering at the same peak temperature for longer times, showing the time-dependence, combined with the temperature-dependence, of the β-Ca3(PO4)2 to α-Ca3(PO4)2 transition.openAlessandra Giuliani; Maria Laura Gatto; Luigi Gobbi; Francesco Guido Mangano; Carlo ManganoGiuliani, Alessandra; Gatto, MARIA LAURA; Gobbi, Luigi; Guido Mangano, Francesco; Mangano, Carl

Solid-State Fermentation of Trichoderma spp.: A New Way to Valorize the Agricultural Digestate and Produce Value-Added Bioproducts

In this study, the agricultural digestate from anaerobic biogas production mixed with food wastes was used as a substrate to grow Trichoderma reesei RUT-C30 and Trichoderma atroviride Ta13 in solid-state fermentation (SSF) and produce high-value bioproducts, such as bioactive molecules to be used as ingredients for biostimulants. The Trichoderma spp. reached their maximum growth after 6 and 3 SSF days, respectively. Both Trichoderma species were able to produce cellulase, esterase, and citric and malic acids, while T. atroviride also produced gibberellins and oxylipins as shown by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) profiling. Experimental evaluation of germination parameters highlighted a significant promotion of tomato seed germination and root elongation induced by T. atroviride crude extracts from SSF. This study suggests an innovative sustainable use of the whole digestate mixed with agro-food waste as a valuable substrate in fungal biorefineries. Here, it has been applied to produce plant growth-promoting fungi and bioactive molecules for sustainable agriculture

Reemergence of Strongyloidiasis, Northern Italy

Strongyloidiasis is a helminth infection caused by Strongyloides stercoralis, a nematode ubiquitous in tropical and subtropical countries and occasionally reported in temperate countries, including Italy (1). Sources of infection are filariform strongyloid larvae present in soil contaminated by infected feces; the larvae penetrate through the skin of a human host. After the first life cycle, a process of autoinfection begins, which persists indefinitely in the host if the infection is not effectively treated. The infection can remain totally asymptomatic for many years or forever or cause cutaneous (itching and rash), abdominal (epigastric pain, pseudoappendicitis, diarrhea), respiratory (cough, recurrent asthma), and systemic (weight loss, cachexia) symptoms that can be enervating. More importantly, when host immunity is impaired because of a concurrent disease or immunosuppressive therapy (including corticosteroids, sometimes used to treat symptoms of the unrecognized infection or the concurrent eosinophilia), disseminated strongyloidiasis may occur (2\u20134), causing a massive and almost invariably fatal invasion of virtually all organs and tissues by filariform larvae and even adult worms (Figure), often combined with bacterial superinfection. This complication is believed to be rare but is probably underestimated because of the extreme variability of the clinical presentation. Although strongyloidiasis can be suspected in the presence of symptoms or eosinophilia (which is frequent but not mandatory), the low sensitivity of direct diagnostic methods often lets the disease go unrecognized (5\u20137). By far the most sensitive diagnostic tools are serologic tests: sensitivity and specificity of indirect fluorescent antibody test (IFAT) (in-house produced IFAT) are 97.4% and 97.9%, respectively, at a dilution >1/20, and 70.5% and 99.8% at a dilution >1/80 (6). A suspected case is defined by a positive antibody titer >20 (IFAT); a case is confirmed by a positive direct test result (culture in agar being the most sensitive direct technique) or by a positive antibody titer >80 (6). Despite some anecdotal reports on the presence of strongyloidiasis in Italy (1,6), reliable information about the real prevalence of the infection is lacking. After seeing several patients affected by the disease, 1 of whom died because of dissemination (Z. Bisoffi, unpub. data), we decided to carry out a preliminary rapid assessment of the extent of the problem in elderly patients with eosinophilia. During a 4-month period, from February through May 2008, every patient born in 1940 or earlier who came to the clinical laboratories of 2 contiguous health districts in northern Italy (Mantova, Lombardy Region, and Legnago, Veneto Region) for a diagnostic blood test (hematocrit and leukocyte count/formula) for whatever reason and having a eosinophil count >500 cells/\u3bcL was asked to join the study. This study was the pilot phase of a larger, multicentered study, which obtained formal approval from the Ethical Committee of Sacro Cuore Hospital of Negrar, Verona. Informed consent was required of each patient. Of the 132 patients eligible for inclusion (mean age 76.4 years, range 68\u201390 years, male:female ratio 1.6), none refused to give informed consent. Serum specimens were subjected to the IFAT for S. stercoralis at the Sacro Cuore Hospital Centre for Tropical Diseases. Unexpectedly, we found that 37 (28%) of 132 patients were positive, with titers ranging between 20 and >320 (and >80 in most cases). However, caution should be exercised in interpreting the results because the patients may not be representative of the general population. Moreover, our results are based on an indirect (although highly sensitive and specific) test. Because the reported cases involve only a few patients every year (of whom some are anecdotally reported as dying from the infection, usually unpublished), we suspect that most strongyloidiasis cases remain undetected. If relevant transmission still exists in the area, it is unknown but is unlikely because of the improvement of hygienic conditions in the past 5 decades. Reports of the infection in children or young adults with no travel history outside Italy are lacking. Strongyloidiasis in the elderly is therefore most likely to result from an infection that occurred much earlier in life, either in infancy or at a young age, while walking or working barefoot in agricultural fields. The long persistence is the consequence of the autoinfection cycle typical of this parasite as described above. The result is an important and unrecognized public health problem affecting the geriatric population of northern Italy. These preliminary results confirm the need for the already planned, multicentered study involving a larger sample and a wider geographic area

Pruning wound protection products induce alterations in the wood mycobiome profile of Grapevines

Fungal pathogens involved in grapevine trunk diseases (GTDs) may infect grapevines throughout their lifetime, from nursery to vineyard, via open wounds in stems, canes or roots. In vineyards, pruning wound protection products (PWPPs) offer the best means to reduce the chance of infection by GTD fungi. However, PWPPs may affect non-target microorganisms that comprise the natural endophytic mycobiome residing in treated canes, disrupting microbial homeostasis and indirectly influencing grapevine health. Using DNA metabarcoding, we characterized the endophytic mycobiome of one-year-old canes of cultivars Cabernet Sauvignon and Syrah in two vineyards in Portugal and Italy and assessed the impact of established and novel PWPPs on the fungal communities of treated canes. Our results reveal a large fungal diversity (176 taxa), and we report multiple genera never detected before in grapevine wood (e.g., Symmetrospora and Akenomyces). We found differences in mycobiome beta diversity when comparing vineyards (p = 0.01) but not cultivars (p > 0.05). When examining PWPP-treated canes, we detected cultivar- and vineyard-dependent alterations in both alpha and beta diversity. In addition, numerous fungal taxa were over- or under-represented when compared to control canes. Among them, Epicoccum sp., a beneficial genus with biological control potential, was negatively affected by selected PWPPs. This study demonstrates that PWPPs induce alterations in the fungal communities of grapevines, requiring an urgent evaluation of their direct and indirect effects on plants health with consideration of factors such as climatic conditions and yearly variations, in order to better advise viticulturists and policy makers.info:eu-repo/semantics/publishedVersio

Social Parasite Ants in the Alps: a New Site of the Vulnerable Myrmica myrmicoxena and New Uppermost Altitudinal Limit for M. microrubra

We conducted a survey on the Alpine fauna of one of the largest Natural Park of the Italian Alps (Stelvio National Park) in the framework of a broad ecological monitoring of Alpine biodiversity. A two-years standardized sampling employing pitfall traps along a 1200 m altitudinal gradient led to the discovery of two interesting inquiline social parasite ants of the genus Myrmica: M. myrmicoxena Forel, 1895 and M. microrubra Seifert, 1993. Myrmica myrmicoxena, which is classified as Vulnerable according to the IUCN Red List, was so far known from only three sites across a narrow geographic range between Italy and Switzerland. Our data support the previous hypothesis over its ecology and host association. Myrmica microrubra is considered an incipient species of high evolutionary interest, sometimes regarded as an intraspecific form of M. rubra. While having a wide distribution in Europe, its presence in Italy was hitherto known only from a single site, and our record extends its altitudinal distribution limit in Europe upwards by about 600 m

Sacrificial Adhesive Bonding: A Powerful Method For Fabrication Of Glass Microchips.

A new protocol for fabrication of glass microchips is addressed in this research paper. Initially, the method involves the use of an uncured SU-8 intermediate to seal two glass slides irreversibly as in conventional adhesive bonding-based approaches. Subsequently, an additional step removes the adhesive layer from the channels. This step relies on a selective development to remove the SU-8 only inside the microchannel, generating glass-like surface properties as demonstrated by specific tests. Named sacrificial adhesive layer (SAB), the protocol meets the requirements of an ideal microfabrication technique such as throughput, relatively low cost, feasibility for ultra large-scale integration (ULSI), and high adhesion strength, supporting pressures on the order of 5 MPa. Furthermore, SAB eliminates the use of high temperature, pressure, or potential, enabling the deposition of thin films for electrical or electrochemical experiments. Finally, the SAB protocol is an improvement on SU-8-based bondings described in the literature. Aspects such as substrate/resist adherence, formation of bubbles, and thermal stress were effectively solved by using simple and inexpensive alternatives.51327

The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions

: Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy