Optimal control of the spatial allocation of COVID-19 vaccines: Italy as a case study

While campaigns of vaccination against SARS-CoV-2 are underway across the world, communities face the challenge of a fair and effective distribution of a limited supply of doses. Current vaccine allocation strategies are based on criteria such as age or risk. In the light of strong spatial heterogeneities in disease history and transmission, we explore spatial allocation strategies as a complement to existing approaches. Given the practical constraints and complex epidemiological dynamics, designing effective vaccination strategies at a country scale is an intricate task. We propose a novel optimal control framework to derive the best possible vaccine allocation for given disease transmission projections and constraints on vaccine supply and distribution logistics. As a proof-of-concept, we couple our framework with an existing spatially explicit compartmental COVID-19 model tailored to the Italian geographic and epidemiological context. We optimize the vaccine allocation on scenarios of unfolding disease transmission across the 107 provinces of Italy, from January to April 2021. For each scenario, the optimal solution significantly outperforms alternative strategies that prioritize provinces based on incidence, population distribution, or prevalence of susceptibles. Our results suggest that the complex interplay between the mobility network and the spatial heterogeneities implies highly non-trivial prioritization strategies for effective vaccination campaigns. Our work demonstrates the potential of optimal control for complex and heterogeneous epidemiological landscapes at country, and possibly global, scales.     

Social stress shortens lifespan in mice

Stress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.     

Construction of a medium-density horse gene map

A medium-density map of the horse genome (Equus caballus) was constructed using genes evenly distributed over the human genome. Three hundred and twenty-three exonic primer pairs were used to screen the INRA and the CHORI-241 equine BAC libraries by polymerase chain reaction and by filter hybridization respectively. Two hundred and thirty-seven BACs containing equine gene orthologues, confirmed by sequencing, were isolated. The BACs were localized to horse chromosomes by fluorescent in situ hybridization (FISH). Overall, 165 genes were assigned to the equine genomic map by radiation hybrid (RH) (using an equine RH(5000) panel) and/or by FISH mapping. A comparison of localizations of 713 genes mapped on the horse genome and on the human genome revealed 59 homologous segments and 131 conserved segments. Two of these homologies (ECA27/HSA8 and ECA12p/HSA11p) had not been previously identified. An enhanced resolution of conserved and rearranged chromosomal segments presented in this study provides clarification of chromosome evolution history.     

The importance of molecular histology to study glial influence on neurodegenerative disorders. Focus on recent developed single cell laser microdissection

Neuron-glia interaction is involved in physiological function of neurons, however recent evidences have suggested glial cells as participants in neurotoxic and neurotrophic mechanisms of neurodegenerative/neuroregenerative processes. Histological techniques employing immunolabeling, historadiography and in situ hybridization have been useful to localize at cell levels molecules in normal and pathological situations. The intercellular accomplishment leading to neuronal injury in central nervous system disorders implies the performance of quantitative assays to better interpret the role of related molecules or signal pathways, however one limitation employing the whole tissue is the loss of cellular resolution. The laser capture microdissection was developed recently and allows the selection of specific cell types from their original environment after freezing and sectioning the tissue sampling, leading to the quantification of gene expression in individual cells, thus providing a unique opportunity to get new informations on cell signaling related to neurodegeneration. Here we reviewed the role of glial cell signaling on neurodegenerative disorders like ischemia, Parkinson and Alzheimer diseases, and also amyotrophic lateral sclerosis and what has been published with regards to single cell laser capture microdissection technique in the molecular biology investigation on these issues.     

Caenorhabditis elegans APN-1 plays a vital role in maintaining genome stability

We previously showed that Caenorhabditis elegans APN-1, the only metazoan apurinic/apyrimidinc (AP) endonuclease belonging to the endonuclease IV family, can functionally rescue the DNA repair defects of Saccharomyces cerevisiae mutants completely lacking AP endonuclease/3′-diesterase activities. While this complementation study provided the first evidence that APN-1 possesses the ability to act on DNA lesions that are processed by AP endonucleases/3′-diesterase activities, no former studies were conducted to examine its biological importance in vivo. Herein, we show that C. elegans knockdown for apn-1 by RNAi displayed phenotypes that are directly linked with a defect in maintaining the integrity of the genome. apn-1(RNAi) animals exhibited a 5-fold increase in the frequency of mutations at a gfp-lacZ reporter and showed sensitivities to DNA damaging agents such as methyl methane sulfonate and hydrogen peroxide that produce AP site lesions and strand breaks with blocked 3′-ends. The apn-1(RNAi) worms also displayed a delay in the division of the P1 blastomere, a defect that is consistent with the accumulation of unrepaired lesions. Longevity was only compromised, if the apn-1(RNAi) animals were challenged with the DNA damaging agents. We showed that apn-1(RNAi) knockdown suppressed formation of apoptotic corpses in the germline caused by an overburden of AP sites generated from uracil DNA glycosylase mediated removal of misincorporated uracil. Finally, we showed that depletion of APN-1 by RNAi partially rescued the lethality resulting from uracil misincorporation, suggesting that APN-1 is an important AP endonuclease for repair of misincorporated uracil.     

Early Gene Expression Changes in Skeletal Muscle from SOD1G93A Amyotrophic Lateral Sclerosis Animal Model

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons. Familial ALS is strongly associated to dominant mutations in the gene for Cu/Zn superoxide dismutase (SOD1). Recent evidences point to skeletal muscle as a primary target in the ALS mouse model. Wnt/PI3 K signaling pathways and epithelial–mesenchymal transition (EMT) have important roles in maintenance and repair of skeletal muscle. Wnt/PI3 K pathways and EMT gene expression profile were investigated in gastrocnemius muscle from SOD1^G93A mouse model and age-paired wild-type control in the presymptomatic ages of 40 and 80 days aiming the early neuromuscular abnormalities that precede motor neuron death in ALS. A customized cDNA microarray platform containing 326 genes of Wnt/PI3 K and EMT was used and results revealed eight up-regulated (Loxl2, Pik4ca, Fzd9, Cul1, Ctnnd1, Snf1lk, Prkx, Dner) and nine down-regulated (Pik3c2a, Ripk4, Id2, C1qdc1, Eif2ak2, Rac3, Cds1, Inppl1, Tbl1x) genes at 40 days, and also one up-regulated (Pik3ca) and five down-regulated (Cd44, Eef2 k, Fzd2, Crebbp, Piki3r1) genes at 80 days. Also, protein–protein interaction networks grown from the differentially expressed genes of 40 and 80 days old mice have identified Grb2 and Src genes in both presymptomatic ages, thus playing a potential central role in the disease mechanisms. mRNA and protein levels for Grb2 and Src were found to be increased in 80 days old ALS mice. Gene expression changes in the skeletal muscle of transgenic ALS mice at presymptomatic periods of disease gave further evidence of early neuromuscular abnormalities that precede motor neuron death. The results were discussed in terms of initial triggering for neuronal degeneration and muscle adaptation to keep function before the onset of symptoms.     

Advances in the Non-culture Based Laboratory Diagnosis of <Emphasis Type="Italic">Cryptococcus</Emphasis> and the Endemic Molds

Given the widespread availability of non-culture based diagnostic techniques, the approach to diagnosis of Cryptococcus spp. and the endemic molds has become increasingly complex. These techniques include: histopathology, cytopathology, fungal serology, antigen detection, and molecular methods such as polymerase chain reaction (PCR). This paper reviews the approach to diagnosis of Cryptococcus spp. and the endemic molds focusing on non-culture based diagnostic techniques.     

Construction of a cytogenetically anchored microsatellite map in rabbit

Rabbit (Oryctolagus cuniculus) represents a valuable source of biomedical models and corresponds to a small but active economic sector in Europe for meat and fur. The rabbit genome has not been thoroughly studied until recently, and high-resolution maps necessary for identification of genes and quantitative trait loci (QTL) are not yet available. Our aim was to isolate over 300 new and regularly distributed (TG)n or (TC)n rabbit microsatellites. To achieve this purpose, 164 microsatellite sequences were isolated from gene-containing bacterial artificial chromosome (BAC) clones previously localized by fluorescence in situ hybridization (FISH) on all the rabbit chromosomes. In addition, 141 microsatellite sequences were subcloned from a plasmid genomic library, and for 41 of these sequences, BAC clones were identified and FISH-mapped. TC repeats were present in 62% of the microsatellites derived from gene-containing BAC clones and in 22% of those from the plasmid genomic library, with an average of 42.9% irrespective of the microsatellite origin. These results suggest a higher proportion of (TC)n repeats and a nonhomogeneous distribution of (TG)n and (TC)n repeats in the rabbit genome compared to those in man. Among the 305 isolated microsatellites, 177 were assigned to 139 different cytogenetic positions on all the chromosomes except rabbit Chromosome 21. Sequence similarity searches provided hit locations on the Human Build 35a and hypothetical assignments on rabbit chromosomes for ten additional microsatellites. Taken together, these results report a reservoir of 305 new rabbit microsatellites of which 60% have a cytogenetic position. This is the first step toward the construction of an integrated cytogenetic and genetic map based on microsatellites homogeneously anchored to the rabbit genome.