On 30 October 2017, selected faculty and administrators from Research Centers in Minority Institutions (RCMI) grantee institutions gathered to share first-hand accounts of the devastating impact of Hurricanes Harvey, Irma, and Maria, which had interrupted academic activities, including research, education, and training in Puerto Rico, Florida, and Texas. The presenters reviewed emergency response measures taken by their institutions to maintain community health care access and delivery, the storm-related impact on clinical and research infrastructure, and strategies to retain locally grown clinical expertise and translational science research talent in the aftermath of natural disasters. A longer-term perspective was provided through a comparative review of lessons learned by one New Orleans-based institution (now more than a decade post-storm) in the aftermath of Hurricane Katrina. Caring for the internal and external communities associated with each institution and addressing the health disparities exacerbated by storm-related events is one key strategy that will pay long-term dividends in the survival of the academic institutions and the communities they serve. There are limited recent reports that describe the recovery of academic institutions from storm-related natural disasters, which impact the lives of institutional personnel and their families, compromise associated physical infrastructure, and impair academic operations. The ability of these institutions and affiliated employees to fulfill service obligations to their local community, contribute to the local economy, and continue academic  missions is a product of storm-related harm to the institution and surrounding community. Such harm can be mitigated by appropriate anticipation of potential storm-related damage and a coordinated response. Smaller academic institutions may be particularly vulnerable to such storms, given limited resources to mount a coordinated response. To share valuable lessons associated with institutional responses from recent devastating storms impacting Research Centers in Minority Institutions (RCMI) grantee institutions, an observational report was prepared.On 30 October 2017, selected faculty and administrators from RCMI grantee institutions gathered in Washington DC to discuss their recent first-hand institutional accounts of the devastating impact of Hurricanes Harvey, Irma, and Maria, which had interrupted academic activities in Puerto Rico, Florida, and Texas. The presenters addressed emergency measures taken at their institutions to maintain community health care access and delivery, address clinical and research infrastructure challenges, and retain locally grown clinical expertise and translational science research talent in the aftermath of these storm-related disasters.Following a brief historical overview of the three storms to set the environmental context, relevant institutional experiences and lessons learned are summarized. A longer-term perspective was provided by the review of lessons learned and perspectives gained at one New Orleans-based institution (now more than a decade post-storm) in the aftermath of Hurricane Katrina. These summaries and lessons learned are presented in the historical order of storm occurrence beginning with Hurricane Katrina. On 29 August 2005, Hurricane Katrina struck the Gulf Coast of the United States (U.S.). It is believed to be the largest—and the third strongest—hurricane to make U.S. continental landfall. The major damage was due to storm surge and rainfall-associated levee breaching in New Orleans and surrounding counties with massive flooding ,2,3. HunOn 25 August 2017, Hurricane Harvey made landfall in southwest Texas, causing rainfall-triggered flooding in the Houston metropolitan area on 28 August 2017 and an estimated $125 billion in damages . Over foIn early September 2017, Hurricane Irma became the strongest storm known to exist in the open Atlantic region. It was the first Category 5 hurricane of the 2017 Atlantic hurricane season and caused widespread damage in the northeastern Caribbean and the Florida Keys [On 20 September 2017, Hurricane Maria, a Category 4 hurricane, made direct landfall on the south side of Puerto Rico, traveling northwest across the entire island as a 50-mile-wide tornado . For weeHurricane Maria took off-line 85% of the 1360 cell phone towers on the island, and nearly a month later only 43% had been repaired. Many communities were isolated from the outside world for weeks. The extent of the infrastructure damage remains to be determined. One estimate by Moody’s Analytics, a financial services firm, estimated the storm could cost Puerto Rico $45 billion to $95 billion , while tProlonged flooding and structural damage, a breakdown in communication, and massive displacement of the population complicated the recovery from Hurricane Katrina. The Xavier University of Louisiana worked with FEMA and local businesses to attain operational support and temporary housing  for employees and students. When the immediate flooding threat had passed, faculty/staff/students assisted with neighborhood assessments and support of survivors (including the rescue of those who were isolated by flooding).Political influence was needed to gain the attention and support of FEMA leadership to move forward with recovery activities. Alumni and friends provided financial aid and assistance. Other sources of support for long-term rebuilding efforts included religious organizations, concerts and other benefit events, foundations, and corporate donors. Agencies such as the National Science Foundation (NSF) and National Institutes of Health (NIH) also provided supplements to their grants to move the research forward. At Texas Southern University, widespread flooding resulted in the displacement of faculty and staff members from their homes and loss of their vehicles from extensive water damage.Delays in academic recovery occurred due to disrupted infrastructure and loss of data. Graduate students experienced similar personal losses and family burdens as well as additional challenges, including a two-week delay in the start of classes coupled with associated delays in registration and other administrative activities. Specific infrastructure challenges included an inability to access the university facilities for two weeks, major instrument damage, loss of paper/electronic data, and damage to the animal care facility with subsequent challenges meeting environmental standards.Nonetheless, the response and recovery were less than what would be anticipated with such extensive flooding. Some proactive mitigating actions included the protection of freezers full of valuable samples using backup generators and the implementation of emergency response plans for the facilities housing research animals using lessons learned from prior events .Some ongoing help has been required for unanticipated major instrument replacement or repair as well as recalibration. Some building improvements, including flood wall installation, will be needed to mitigate damage from future floods.The experience of Puerto Rico in the aftermath of these hurricanes can be viewed from the perspective of social determinants of health. Puerto Rico is an archipelago located in the Caribbean, 1000 miles south-east of Florida. Puerto Rico is an organized but unincorporated U.S. territory. As evidenced by a recent poll, nearly half of the adults in mainland U.S. do not know Puerto Ricans are fellow citizens , yet PueCertain U.S. policies are relevant to the economic crisis in Puerto Rico. The Jones Act affects shipping of goods to and from the island . In effePuerto Rico is still treated as a colony. In the aftermath of Hurricane Maria, issues of governance were evident as was the limited ability to implement emergency preparedness plans . The expDespite these challenges, within two weeks of the direct impact of Hurricane Maria, the University of Puerto Rico—Medical Sciences Campus (UPR-MSC) was able to resume most of its academic, research, and service activities. This was possible in part due to its privileged location within the Puerto Rico Medical Center. This area was prioritized for re-establishment of services. Moreover, despite personal challenges experienced in the aftermath of the hurricanes, the UPR-MSC personnel and the administration were able to sustain services at a minimal level; however, the global financial situation in Puerto Rico has compromised the overall recovery toward achievement of normal robust operations.Inadequate systematic health and humanitarian disaster relief following Hurricane Irma and Maria led to outbreaks and exacerbation of infectious diseases , limitedIf anything has been evidenced in the aftermath of the hurricanes besides the sociopolitical crisis in Puerto Rico, it is the ability of the people of Puerto Rico to overcome adversity. In this process, we have witnessed solidarity and commitment to the restoration of our communities. Academic institutions and health centers and networks are working in solidarity for the restoration of our communities.This experience must inform how we conduct translational research to address the social determinants of health inequities. Research initiatives and interventions should be aimed not only at the individual but, importantly, at the community and structural levels to improve and sustain healthy environments. Puerto Rico has the capacity to develop and respond with grassroots initiatives that might be more culturally relevant than poorly adapted “evidence-based” interventions developed elsewhere. Academic institutions in Puerto Rico can use existing resource networks and collaborations from other institutions to support capacity building and a research agenda for sustainable public health interventions in Puerto Rico.The Ponce Health Sciences University made a number of pre-storm preparations, including installation of storm windows, back-up of critical data, physical protection of scientific equipment, removal of items that could be water damaged from the floor, provision of maintenance to backup power generators, full diesel tanks for backup generators, storage of multiple days of food and water for animals in the vivarium, assessment of all patients in clinical trials prior to storm arrival, and advance processing of pending fiscal requisitions, orders, and payroll payments. The post-storm response to Hurricane Maria occurred in several phases.Phase 1 represented a survival mode and assessment. Activities included an initial assessment of the facilities; movement of animals from the vivarium to a safe building; coordination of diesel delivery for subsequent indefinite operation of generators; assessment of the status and location of all staff ; assessment of the status and location of all students ; coordination with local hospitals, airport, Department of Health, and local municipality for needs assessment and capacity; implementation of counseling with mental health services for staff and students; and undertaking an inventory of facility and equipment damages. Phase 2 was the process of undertaking campus and facility cleanup and sustaining operations, thus resulting in successful continuity of operations. This included coordination with the H.Lee Moffitt Cancer Center in Tampa, FL, a long-time collaborator institution, to transport over 3,500 tumor tissue samples from PR to Tampa, for safekeeping due to power fluctuations on the island. Phase 3 was Ponce Health Sciences University faculty, staff, students, and other learners’ efforts to engage and lead in local relief efforts and supplemental outreach to the community. Overall, over 6,500 patient visits were completed in the 90 days following the storm, and over 100,000 of supplies were received and distributed by a network of over 300 volunteers. Analog telephone lines are invincible when the digital system is down.Non-network photocopiers can help print hardcopy materials.A satellite phone and Satellite Internet service can help when local phone services are lost.Redundant power sources  are critical.Confirmation of diesel/gas delivery prior to the event and advanced payment arrangements can support fuel delivery, even if communications go down.A list of physical addresses and other contact information for all key personnel expected for an on-campus recovery is critical.The stability of the workforce must be maintained, i.e., ice, water, and temporary accommodations must be provided for all.Mental health support should be available—stressing that everyone should take one day at a time—every day—hoping for a better tomorrow.Some key lessons learned regarding emergency response equipment and preparation include the following:The impact on the University of Puerto Rico from Hurricanes Irma and Maria has been significant. In the aggregate, buildings were damaged, students and residents were displaced, and already distressed budgets were further strained. At the Cayo Santiago Field Station—home to more than 1000 rhesus monkeys with DNA samples since the 1950s—the infrastructure compromise that occurred may lead to loss of animals and research materials, which are all irreplaceable. Efforts to fortify the facility are needed .There is also a need to train faculty members, residents, and students in terms of local disaster response with respect to preparation, disaster mitigation, and recovery. Areas of focus should include maintaining electricity by using back-up generators and fuel supplies, providing access to water, and ensuring options for transportation. Issues related to specific research challenges include controlling and permitting access of staff to research facilities, ensuring adequate personnel availability, transportation for research participants to continue their clinical trial involvement, and sample collection and transportation to active laboratory facilities. Communication challenges include access to the internet, cell phones, and alternative methods for clinical trial patients to participate in research .Other thoughts regarding infrastructure preparation include the use of cement buildings rather than wooden structures to mitigate structural damage, providing alternatives for electricity , and maintaining communication diversification options . Specific clinical services that warrant additional consideration include mental health support for anxiety and depression related to loss of life/property and mitigating the risk of mosquito-borne viral infections and disease in the tropical climate  and water-borne infectious diseases . The coordination of public and private resources to support communities and satisfy basic needs is always a challenge, given the competing demands, more limited personnel, and communication challenges.Two weeks after Hurricane Maria, only 25 (less than 50%) hospitals were operational, only 9.2% of people had electrical power, only 54% had potable water, and only 45% had cell phone service. Thus, redeveloping a functional infrastructure will take considerable time. Helping students re-engage in their studies and scientists re-engage in their research is a challenge and will take time.During natural disasters, the elderly are particularly at risk. Nursing homes, community centers, and other resources needed for social interaction and activities of daily living by elders were destroyed or rendered inoperative by Hurricane Maria. The care of elders with chronic diseases, such as cancer, cardiovascular diseases, diabetes, dementia, and stroke, was disrupted and at times became impossible. Access to medicines, preventive and primary care, and acute interventions were also often disrupted.Efforts to restore health care and support services remains a priority but depends upon migration of the frail and vulnerable population to sites with intact infrastructure that is culturally relevant and fosters community engagement. Clinical research has been compromised by the loss of electricity and technology and due to the pressing urgency of basic care for the vulnerable.Lessons learned from prior storm-related disasters are transportable to other vulnerable academic institutions, especially those situated in flood plains and coastal regions. Preparations should be made in advance of storms, both in the short-term  and further in advance . Although there are some limits to the planning and development of contingencies, academic institutions have shown great resiliency and accommodation to a variety of contingencies that arise during the aftermath of a storm-related disaster. Caring for the internal and external communities associated with each institution will pay long-term dividends in the survival of academic institutions and the communities they serve.


Decades of study have shown that epigenetic regulation plays an important role in neural development and function. Several layers of epigenetic mechanisms control functions of the eukaryotic cell nucleus, a well-organized subcellular organelle with distinct compartments: chromatin, its related architectural proteins, and nuclear bodies. As these components function together in the epigenetic regulation of cellular development and functions, they are collectively termed nuclear architecture. In the nervous system, dynamic rearrangement of nuclear architecture correlates with alteration of transcription programs. During maturation and upon depolarization, neurons undergo a reorganization of nuclear architecture that alters gene expression programs. As such changes allow for specialized functions, including learning and memory, nuclear architecture is distinct among cell types. Studying nuclear architecture of neurons may uncover cell-division-independent mechanisms of global and local changes to nuclear architecture. We herein review recent research concerning nuclear architecture in the nervous system and will discuss its importance to the development, maturation, function, and diseases of the nervous system. Eukaryotic nuclei stably retain large genomic DNA in a compact space without compromising its ability to read necessary information from genomic DNA to create diverse cell types in the right place at the right time. Uncovering how a cell selects and expresses appropriate genes to acquire its identity is central to understanding the mechanisms underlying the physiological functions of a cell.Epigenetic alterations play pivotal roles in gene expression and cellar functions in the nervous system . Major eNeurons, the principal cell type of the nervous system, are distinct in their ability to change their morphology, gene expression programs, and functions by adapting to their environment . This fuWe herein review a series of studies that demonstrate the functions and significance of nuclear architecture in the nervous system and discuss its relevance to brain function. The findings on post-mitotic neurons are especially intriguing, and therefore, understanding the underlying mechanisms of cell-division-independent rearrangement of nuclear architecture provides insight into the basic mechanisms of nuclear architecture.N-methyl-D-aspartate (NMDA) receptor activation dramatically increases the number of infolded nuclei. This observation is reversed when extrasynaptic NMDA receptors are activated by the bath-application of NMDA to the culture. Infolding increases the surface area of the nucleus, as well as the number of nuclear pore complexes. This further leads to an enhancement of nuclear calcium signaling especially in the smaller compartments of nuclei. Intriguingly, similar invaginations of the nuclear envelope (NE) have been observed in many types of mammalian cells .Along with the architecture inside the nucleus, the morphology of the organelle itself changes during neural differentiation and post-mitotic maturation. By analyzing three-dimensional reconstruction images of rat hippocampal neurons, an cells . An addiFigure 2a; The arrangement of nuclear bodies is related to the functions of post-mitotic neurons. Nucleoli are found adjacent to the nuclear periphery in immature Purkinje neurons but converge into one or two larger nucleoli while relocating toward the center of the nucleus during maturation . This binding further modulates the number of nucleoli and global protein synthesis.Cajal bodies, which are speculated to act as sites of assembly for small nuclear ribonucleoproteins, are often found adjacent to nucleoli in mature neurons , which change according to cell differentiation and functions . SeveralFigure 2a; The repositioning of specific regions of a chromosome in post-mitotic neurons has also been reported. In mouse Purkinje neurons, the number of centromeric domains changes during maturation, along with their shift from the nuclear periphery to the nucleolus .Global structures of chromatin also change during neural differentiation and maturation. One of the structural features of global chromatin organization is the spacing between two adjacent nucleosomes, termed the nucleosome repeat length (NRL), which has been shown to change in rat cortical neurons during neuronal differentiation and maturation . In addiin vivo via a sequencing assay (ATAC-seq). Changes elicited by the procedure were observed by comparing the neurons before and after the activation  in post-mitotic neurons. Chromatin accessibility is an indicator of global chromatin change. An investigation studied this property in adult mouse dentate granule neurons by subjecting them to synchronous neuronal activation using transposase-accessible chromatin tivation . This stArc and brain-derived neurotrophic factor (Bdnf), are downregulated in CTCF CKO hippocampi. A chromosome confirmation-capture-based (3C-based) analysis showed that this transcriptional abnormality is attributed to the loss of CTCF-dependent chromatin interaction within these genes loci. Further research has supported such findings: CTCF is mutated in a subset of individuals with intellectual disabilities  features important roles in neuronal development . This migration is concurrent with the changes in chromatin structure and transcriptional upregulation upon neural induction from ES cells . Though LADs overlapped by 73–87% among the examined cell types, many gene loci that determine cellular identity relocate from the lamina. Several such genes that move away from the lamina are concurrently activated, while others become activated in the next phase of differentiation. Furthermore, most gene loci apparently relocate separately, not as clusters, and many gene loci migrate according to cell type, differentiation stage, and the expression levels of the genes. This mechanism may compose another layer of spatial-gene-positioning-related transcriptional regulation during neuronal differentiation. Studies using rat hippocampal dentate gyrus neurons have further found that intranuclear positions of Bdnf move away from the nuclear lamina upon neuronal activation following kainite-induced seizures  is expressed in the early stage NPCs and is both necessary and sufficient to specify early-born neuronal identity. Interestingly, gene loci of Hb move toward the nuclear periphery when competence to specify early-born fates is lost  is repositioned toward the nuclear center during astrocyte differentiation . Clustering of Osmr with Gfap enhances the transcription of both genes and requires the presence of both brahma-related gene 1 (BRG1), an ATP-dependent chromatin remodeling factor, and STAT3 . However, it is not observed in brain samples derived from patients with AS, Rett syndrome, autism, or other conditions (Gene clustering between homologous gene loci has further been reported to contribute to gene regulation . Homolognditions . The finnditions . HoweverEpigenetic changes are accompanied by the reconstruction of nuclear architecture. The proteins that participate in the construction of nuclear architecture, such as cohesin, NIPBL, MeCP2, CTCF, SATB2, and LMNB1, have been shown to be pivotal for a healthy nervous system. The dysfunction of these molecules reportedly causes neurodevelopmental disorders (see excellent review in vivo studies are increasingly performed to characterize the natural states of nuclear architecture and avoid the limitations of in vitro approaches (in vivo investigations, the CRISPR/Cas9 system and its derivative technologies have been applied to studies of epigenetic states, such as DNA methylation and chromatin conformation (in vivo poses difficulties, overcoming these experimental challenges will open a new avenue for uncovering the importance of nuclear architecture and its significance to brain function in diseased and healthy states.Neurons consist of many subtypes of cells, and this diversity underlies the intricate functions of the nervous system. Nuclear architecture is presumably distinct among such subtypes. To elucidate the differences in their nuclear architecture at a single-cell level and to characterize their components, such as genome-nuclear lamina interaction and chromatin conformation, novel methods have been developed . In addiproaches . At the ormation . AlthougAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Creativity is a multifaceted phenomenon which entails generation of new ideas to solve problems and produce innovation. It is also conceived as a means to improve the quality of life, and promote general health in both normal and clinical populations. This has progressively lead the scientific community to investigate creativity, and its inherent components , in terms of cognitive processes . In this vein, in children and adolescents, drama pedagogy training was related to divergent thinking and problem-solving if based on storytelling, pretend-play and playfulness, and to risk or perspective taking if based on improvisation and role-play . Interestingly, multiple sessions of improvisational theater improved both teenagers' flexibility and originality of verbal divergent thinking . These studies showed the potential of creativity in educational settings in a wide range of domains, suggesting the need to operate in different types of problem space. Other studies highlighted the key role of mediating factors. Children (6 to 10-years old) practicing dances showed higher ability in representing the topological map of the body, which mediated their divergent thinking ability in motor domain . Adolescents' (16 to 19-years old) cognitive self-regulation mediated the relationships between mind wondering and verbal divergent thinking . In people aged 12–88 years, gender, age, and composite intelligence quotient predicted creative achievement, whereas interpersonal emotional competence predicted creative style .Regarding the role of creativity in educational settings, an enriching program for gifted children (6 to 10-years old) in the areas of language and science showed positive effects only on intelligence operating in well-defined problem space . This means that the understanding of the pathological mechanisms underlying these disorders provides not only an opportunity to clarify visual art, but also gives the possibility to use visual artistic creativity to improve the spatial distortions after brain damages. Moreover, verbal divergent thinking, which positively correlated to the integration of the default mode network and cerebellum, was suggested for treating depression , which is characterized by a reduced functional connectivity between the cerebellum and the default mode network . Finally, the relationships between different proxies of cognitive reserve and verbal divergent thinking were also showed, in light of the creative jobs rather than of the job complexity , confirming that creativity, and its components, might be aimed at fostering active aging.Regarding the role of creativity in rehabilitation settings, spatial distortions in patients' drawings after right brain damage  was related to the space representation in art .In conclusion, the variety of approaches and insights gained certainly offer a new and encouraging window to continue to work in this fascinating field.MP: planned the topic and edited the most of papers included in the topic. LaP: planned the topic. RN, LiP, CS, and CG: edited some papers included in the topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Bioactive peptides (BP) are specific protein fragments that are physiologically important for most living organisms. It is proven that in humans they are involved in a wide range of therapeutic activities as antihypertensive, antioxidant, anti-tumoral, anti-proliferative, hypocholesterolemic, and anti-inflammatory. In plants, BP are involved in the defense response, as well as in the cellular signaling and the development regulation. Most of the peptides used as ingredients in health-promoting foods, dietary supplements, pharmaceutical, and cosmeceutical preparations are obtained by chemical synthesis or by partial digestion of animal proteins. This makes them not fully accepted by the consumers because of the risks associated with solvent contamination or the use of animal derived substances. On the other hand, plant and microalgae derived peptides are known to be selective, effective, safe, and well tolerated once consumed, thus they have got a great potential for use in functional foods, drugs, and cosmetic products. In fact, the interest in the plant and microalgae derived BP is rapidly increasing and in this review, we highlight and discuss the current knowledge about their studies and applications in the cosmetic field. Peptides are short amino acid chains, usually ranging from 2 to 20 units, with a molecular weight under 3 kDa. As most of them possess a wide range of biological activities in living organisms, they are generally defined as bioactive peptides (BP). Due to their specific amino acid sequence and 3D conformation, BP are capable of interacting with a huge number of biological macromolecules and biochemical compounds, modulating several functions and conditions in living organisms . Their mAnalogously, in plants the role of endogenous BP has been extensively studied and linked to defense response mechanisms, as well as cellular signaling during plant development stages . A classSignaling peptides, as plant natriuretic peptides (PNP), phytosulfokines (PSK), and rapid alkalinization factor (RAF) were purified from different plant species and it has been established their involvement in homeostatic functions . AnotherNevertheless in both animals and plants many BP exist as free forms, the vast majority of known BP are produced and released following a chemical hydrolysis or enzymatic intervention, since they are encrypted in the structure of a parent protein. Thus, several classes of proteins from plant and animal origins hide active portions in their structure with specific amino acid sequences, making them potential sources of encrypted BP . The chaThe BP that are employed in cosmetic applications come from different sources. Two of the most used methods to obtain peptides are the chemical synthesis and the partial digestion of animal proteins. Chemical synthesis involves the use of amino acid mixtures as starting material, allowing to obtain peptides with different amino acid sequence and combinations. The advantage is mostly related to the almost infinite sequences that can be intentionally assembled, giving rise to a huge range of desired functional structures.in vitro and in clinical tests for its capacity to reduce facial wrinkles  formation and oxidation when used at higher doses  proteins in the skin, such as collagen I, thanks to its capacity to penetrate through the stratum corneum and reach the dermis layer . A seconwrinkles . The teter doses . A Palmi placebo . In addi placebo .stratum corneum. The biomimetic tetrapeptide PEGP, due to the presence of the amino acids glycine and proline, was identified as a potent candidate to delay early-onset skin aging by the loss of ECM mass. Once tested, both in vitro and in vivo, it induced collagen I, elastin and fibronectin, resulting into a significant sharpening of the facial contours and wrinkle depth reduction , derived from porcine type I collagen hydrolysis, significantly reduced the wrinkles volume after 4 and 8 weeks of intake. Additionally, after 8 weeks the content of procollagen type I and elastin was higher by 65 and 18%, respectively, in the BCP-treated volunteers compared to the placebo-treated patients .The described examples of BP for cosmetic use, nevertheless still requested by the market, present certain drawbacks and are not fully accepted by all the consumers, mostly due to the risks associated with the presence of contaminating chemicals used in the process  or the use of animal derived substances (for digested products). The use of chemical reactions to synthesize peptides implies the use of toxic solvents and reagents in the cycle and, although the last step of the process involves the elimination of most chemicals, the final product can still carry contaminating solvent residues or impurities . Even thOn the other hand, the use of animal proteins in enzymatic digestions implies very strict veterinary controls in the animal source in order to exclude infections from any kind of pathogenic virus, or even the presence of dysfunctional protein aggregates, that can cause very serious diseases in human as well, such as the case of the Bovine Spongiform Encephalopathy (BSE) in cattle. Nevertheless of the several check points during the whole production process, certain risks associated with the presence of animal derived harmful substances cannot be completely abolished . Besidesin vitro or in vivo, for their capacity to activate significant biological functions in skin cells, acquiring promising potentialities to be developed as cosmetic active ingredients.All plant and microalgae-derived peptides used in Cosmetics today, in particular in the skin care market, are formulated as mixtures of many different protein fragments, obtained from hydrolysis of bigger proteins, using either the chemical or enzymatic methods . By chooAvena sativa (oat) peptide-rich preparation, obtained from oat bran by enzymatic hydrolysis, was tested in vitro on H2O2-stressed dermal human fibroblasts and the results demonstrated that the preparation was effective to reduce oxidative stress-induced cell injury, through an enhanced activity of the enzymes SODs and an inhibition of the malondialdehyde (MDA) levels. Although further exploration about the skin care potential in vivo might be necessary, the oat BP preparation was proposed as functional ingredient in anti-aging skin creams to help preventing damages induced by oxidative stress and UV (An s and UV .Glycine max (soy) lysate, containing BP with amino acid sequences similar to those of ECM proteins present in the human skin, was explored  have also been produced and proposed as skin and hair-conditioning ingredients in personal care products , Interleukin 6 (IL-6), Tumor Necrosis Factor (TNF) -alpha, and ProstaGlandin E2 (PGE-2) (Protein hydrolysates from products . The BP  (PGE-2) . To prev (PGE-2) , other a (PGE-2) .Solanum tuberosum (potato) protein hydro-lysate provided an additional example of how BP, generated by a hydrolytic process, activated response mechanisms in skin cells and could be advantageously applied to skin care Cosmetics. The potato hydrolysate stimulated the lipid metabolism in skin keratinocytes when added to the culture medium  and the longevity markers, Sirtuins  certainly represent the most established and well known sources of compounds in the skin care market. The freshwater grown unicellular alga Chlorella was already known for the different biological effects on human cells, such as boosting immune functions (Chlorella derived peptide (CDP) fraction, with molecular distribution of 430–1350 Da, diminished UVB-induced matrix metalloproteinase-1 (MMP-1) and cysteine-rich 61 (CYR61) gene expression and monocyte chemoattractant protein-1 (MCP-1) production in UV-B irradiated fibroblasts , belonging to the group of blue-green Cyanobacteria, is a consistent source of protein, being approximately 60% of its entire weight , that was responsible for an increased uptake of osmolytes (Analogously, the microalga e weight . A BP-ene weight . More ree weight . SDS–PAGsmolytes .As reported in An additional limitation could be associated with the risk of potential allergens, since most of the peptide preparations are produced as unpurified mixtures of several components . Plant aAs described through the reported examples, BP, deriving from plant and microalgae sources, possess a broad spectrum of biological activities and their uses as ingredients in skin care and cosmetic products are acquiring more and more opportunities.Moreover, once derived from plants or microalgae, BP can be used as combinations and mixture with other metabolites in cosmetic formulas, and can exert their biological effects with very low risk of inducing allergenic reaction or undesired side effects.Despite of the significant progress in the isolation and the characterization of BP from natural sources, as well as the assessment of their biological activities, there are still some aspects, as their production at large scale and the activity maintenance in formulas, which would need further studies in order to extend the range of applications and fulfill the requirements of the continuously growing cosmetic market.As future development, the plant and microalgae can provide even more innovative opportunities to develop new products for the cosmetic market, thanks to their enormous versatility: for example, new species may represent a valuable source of unexplored BP with novel chemical features and unexpected biological properties. In addition, many plant and microalgae species can be employed as natural bio-factories of recombinant protein and peptides with specific sequences and structures, whose production by chemical synthesis may present some limitations. Indeed, thanks to the recent progresses of Molecular Biology, the expression of proteins and peptides in plant and microalgae by using genetic transformation has become a common practice. Although the employment of genetically modified organisms to produce recombinant compounds has been adopted in Medicine for years, in Cosmetics the feedback of the consumers about this topic has not been totally positive so far, probably because of their limited understanding and unfamiliarity about this issue, and certainly the unclearness of the current legislation is not helping either. Nevertheless, proteins and BP produced in plant and microalgae systems can be considered even safer than those produced through conventional methods, thus they have got all the right credentials to be adopted as ingredients in different human health care products.All authors conceived and designed the manuscript, and revised, read, and approved the final version of the manuscript.AB was employed by the company Arterra Bioscience srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The valorization of lignocellulosic biomass, in the form of forest and agricultural wastes, industrial processing side-streams, and dedicated energy crops, toward chemicals, fuels and added-value products has become a major research area with increasing exploitation potential Lange, . The effThe most important reactions in biomass conversion include hydrolysis, isomerization, dehydration, hydrogenation, hydrodeoxygenation, hydrogenolysis, oxidation, esterification, ketonization, condensation, and others. Different types of homogeneous and heterogeneous catalysts, as well as biocatalysts (enzymes), with single or dual functionalities  have been reported so far in the literature, ranging from fundamental catalyst design, to combined optimization of catalyst properties and reaction conditions, to pilot scale validation catalysis in lignocellulosic biomass valorization” aims to further contribute to the momentum of research and development in the (bio)catalytic conversion of biomass, by featuring original research papers as well as two review papers, authored and reviewed by experts in the field.Based on these premises, the present Special Issue in Den et al.). The mechanisms of reaction pathways, selectivity and efficiency of end-products obtained using greener processes such as ozonolysis, photocatalysis, oxidative catalysis, electrochemical oxidation, and Fenton or Fenton-like reactions, as applied to depolymerization of lignocellulosic biomass were summarized with deliberation on future prospects of biorefineries with greener pretreatment processes in the context of the life cycle assessment.The first review paper provided a comprehensive overview of the recent research on chemical oxidative techniques for the pretreatment of lignocellulosics with the explicit aim to rationalize the objectives of the biomass pretreatment step and the problems associated with the conventional processes . More specifically, the review discussed advances obtained in major production pathways recently explored, splitting them in the following categories: (i) non-catalytic routes, like use of critical solvents or hot water pretreatment, (ii) use of various homogeneous catalysts like mineral or organic acids, metal salts, or ionic liquids, (iii) feedstock dehydration making use of various solid acid catalysts; (iv) feedstock dehydration making use of supported catalysts, (v) other heterogeneous catalytic routes. The paper also briefly overviewed current understanding of furfural chemical synthesis and its underpinning mechanism.The second review paper discussed the hydrolysis of hemicellulose and the recent advances in the production of furfural . Very high yields of water soluble sugars (90–97%), mostly as oligosaccharides with a degree of polymerization (DP) up to 11, were obtained under optimized conditions using Aquivion PW98 and PW66, respectively, as solid acid catalysts.The topic of efficient and controlled cellulose hydrolysis, not using enzymes or strong inorganic acids, has attracted considerable interest. To this end, one of the original research papers of this Special Issue focused on the mechanocatalytic depolymerization of cellulose with perfluorinated sulfonic acid ionomers . In this work, the heterologous expression and characterization of two Cellobiohydrolases (CBHs) from the filamentous fungus Thermothelomyces thermophila, and their synergism with endoglucanases (EGs) for cellobiose release from organosolv pretreated spruce and birch, was systematically studied and discussed.Although, homogeneous and heterogeneous chemo-catalysis can offer high reaction rates as well as other benefits, enzymatic catalysis provides exceptionally high selectivities to the desired products. In a related paper of this issue, it was shown how the enzymatic hydrolysis of organosolv pretreated forest materials can be fine-tuned toward the efficient production of cellobiose, a non-digestible oligosaccharide (NDO), which together with other cello-oligosacharides (COS), are considered as prebiotic candidates that have been related to the prevention of intestinal infections and other disorders for both humans and animals . It was shown that by the use of trichlorosilanes as silylating agents, the hydrothermal stability of zeolite Y can be improved significantly, although an inhibition in the yield of GVL was observed due to blockage of the pores by the silane. The second relevant paper presents a study of nickel modified zeolite optimization as bi-functional catalyst (Ni/HZSM-5) for the vapor-phase hydrogenation of levulinic acid to GVL . The content and state of nickel and its interaction with the zeolite were critical parameters affecting both the acidity of the zeolite as well as the reducibility of Ni. At the best case, the authors reported 99% conversion of levulinic acid and 100% selectivity to GVL at 320°C.Levulinic acid, being produced from HMF, has been recognized as a very important platform chemical that can be catalytically converted further to a series of functional chemicals. In the present special issue, two papers have focused on the hydrogenation of levulinic acid toward γ-Valerolactone, another very important chemical with a wide range of uses. The first paper deals with the development of silylated zeolitic catalysts (3 wt.% Pt on zeolite Y) with enhanced hydrothermal stability for the aqueous-phase hydrogenation of levulinic acid to γ-Valerolactone (GVL) . It was shown that the basicity and the textural properties of the MgGa materials determined their catalytic activity and selectivity while their properties resembled those of MgAl hydrotalcite-based materials.Aldol condensation and C-C coupling reactions in general are also very important in biomass valorization, especially when the targeted products are hydrocarbon based transportation fuels, such as gasoline and diesel. In a relevant paper of this issue, the physico-chemical properties of MgGa mixed oxides derived from the corresponding Layered Double Hydroxides (LDHs), as well as of their reconstructed layered analogs, were studied and correlated to their performance in aldol condensation of furfural and acetone  on the deoxygenation activity .Fast pyrolysis is one of the most promising thermochemical processes for the direct conversion of biomass into a liquid product, the so called pyrolysis oil or biooil, with gases and char being formed to a lesser extent. Biooil contains water and its organic fraction consists of phenolics, ketones, aldehydes, acids, sugars, and other compounds in minor amounts. It is relatively acidic, unstable and not miscible with petroleum fractions, and needs to be upgraded, usually via (hydro)deoxygenation. One of the papers in this issue, describes the continuous hydrodeoxygenation (HDO) of biooil with an Lazaridis et al.). The effect of ZSM-5's acidity and hierarchical porosity on product yields, selectivity of various compounds and resistance to coking was studied and discussed. In another paper of this issue, monolignols such as sinapyl (SA) and coniferyl (CA) alcohols were linked together with caffeic acid (CafAc) via enzymatic catalysis affording a polymeric network similar with natural lignin . The production of the valuable compound vanillin from isoeugenol under mild conditions was investigated in another paper included in this special issue, using bifunctional nanocatalysts (iron on sulphonated SBA-15) which were prepared by an alternative mechanochemical method .Lignin has gained increased interest within the biorefinery concept as it can act as source of high added value phenolics and aromatics. It can be depolymerized via various types of hydrothermal processes, such as reductive or oxidative hydrogenolysis, or by fast pyrolysis which produces a biooil that contains essentially various alkoxy-phenols. In a relevant paper, the fast pyrolysis of a kraft lignin (byproduct of the production of cellulose pulp from biomass via the Kraft processes) was compared to the catalytic fast pyrolysis using conventional, mesoporous, and nanosized ZSM-5 zeolite, aiming at the production of a partially deoxygenated biooil, enriched in alkyl-phenols and aromatics  catalysts with tailored properties according to the nature of the reactant/feedstock and the targeted products.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Apo J is involved in several important pathological processes in thetransport of lipids, and in the differentiation of vascular smooth muscle cells (VSMC),including cell death by apoptosis, cell cycle regulation, cell adhesion, tissueremodeling, regulation of the immune system and oxidative stress, playing a role in thedevelopment of clinical atherosclerosis.5,6 In theprocess of attenuating atherosclerosis, Apo J can promote the export of cholesterol andphospholipids from foam cells of macrophages,7 and show cytoprotective and anti-inflammatory actionsinteracting with many known inflammatory proteins that may act in the initial phase ofclinical cardiovascular events, and may play an important role in mediatingatherosclerotic disease, such as C-reactive protein, paraoxonase and leptin.8 There are studies reporting that Apo Jcan stimulate the proliferation and migration of VSMC, and promote restenosis,9,10 and there have been studies showing thatoverexpression of CLUs can inhibit migration and proliferation of VSMC, and inhibitcellular apoptosis.11 In view of thesecontroversial results, the authors sought to elucidate the role of Apo J in neointimalhyperplasia, using the rat carotid artery in vivo, with or without rosuvastatin.The study by Yang et al.The results of the study published here suggest that rosuvastatin can inhibit intimalhyperplasia due to the high expression of Apo J in the active proliferation andmigration phase of VSMC, after balloon injury in rats. In the present study, the authorsevidenced an increase in the intimal/media (I/M) area rate after the balloon injury thatreached the maximum value in the fourth week in the model group; in addition, I/M wasincreased at week 2, and such increase ceased after the administration of rosuvastatin.These results suggest that rosuvastatin can significantly reduce the degree of intimalhyperplasia in the balloon-injured carotid arteries in rats. The levels of MessengerRibonucleic Acid (mRNA) and Apo J were increased in the carotid arteries in the groupusing rosuvastatin, when compared to the model group, reaching the maximum in the secondweek, earlier than in the model group, suggesting that rosuvastatin can inhibit intimalhyperplasia by increasing Apo J after balloon injury in rats. Therefore, Apo J has beenidentified as having a central role in the migration, adhesion and vascularproliferation process, and that it can contribute significantly to restenosis aftervascular injury.The results of this study showed that Apo J can be an acute phase reagent after ballooninjury in the carotid arteries of rats; therefore, it plays a favorable role, decreasingthe development of restenosis, which in spite of all existing interventions remains as achallenge to be overcome. Rosuvastatin, a potent inhibitor of the HMG-CoA(hydroxymethylglutaryl-CoA) reductase enzyme, seems to reduce neointimal thickeningafter vascular endothelial injury in rats.This study opens new perspectives by highlighting possible mechanisms involved in thegenesis of restenosis after percutaneous interventions, opening the way for clinicalstudies researching the action of Apo J as a new predictor and a therapeutic target forthe protection of the vessel after PTCA.


Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in the ischemic condition is also presented. Hedgehog (Hh) signaling was first described in 1980 by Nusslein-Volhard and Wieschaus and was initially addressed as a key mediator of cellular proliferation, differentiation, and migration during organogenesis in invertebrates . In the It was 2001 when we first reported that the Hh signaling pathway has a role in angiogenesis . Before It is well established that ischemia induces strong upregulation of many components of the Hh pathway, including the Shh ligand, the Ptch receptor, and the transcription factors Gli1, Gli2, and Gli3, in the skeletal muscle ,15,16,17Once the Hh pathway is upregulated, it exerts important regulatory effects on angiogenesis in the ischemic muscle. There is strong evidence that such regulatory effects mainly occur in an indirect manner, with the production of angiogenic growth factors by Shh-responding cells, i.e., interstitial fibroblasts/mesenchymal cells. This has been demonstrated in vivo in a murine model of hindlimb ischemia, in which fibronectin-positive interstitial mesenchymal cells within the ischemic area produce vascular endothelial growth factor (VEGF) through an Hh-dependent mechanism . The facSome controversies exist on the identity of the Hh ligand that plays the most important role during ischemia-induced angiogenesis in the skeletal muscle. We have found that hindlimb ischemia results in upregulation of Shh expression, without a detectable effect on Ihh and Dhh . We haveRegarding potential therapeutic implications, it has been demonstrated that Shh recombinant protein, injected intraperitoneally in aged mice, augments blood-flow recovery and limb salvage following operatively induced hindlimb ischemia . Also, iA summary of the results of the studies conducted on the ischemic skeletal muscle is presented in Ischemia results in the upregulation of Hh signaling in the heart, with strong overexpression of Shh and Ptch in the adult mouse during myocardial ischemia ,39,40. AThere is evidence that the endogenous Hh pathway has a homeostatic role in the ischemic myocardium. In particular, there is a seminal paper by Levine and coll. that demonstrates that myocardial Hh signaling is required for proper cardiac anatomy and function even in the absence of ischemia, as it is responsible for the integrity and maintenance of coronary vessels . Xiao anSeveral experimental studies have tested the possibility of enhancing angiogenesis and improving heart function after myocardial ischemia by acting on the Hh pathway. Our group has used intramyocardial gene transfer of naked DNA encoding human Shh (phShh) to enhance neovascularization, reduce fibrosis, and preserve left ventricular function in rabbit and pig models of acute and chronic myocardial ischemia . Ahmed aThe results of the studies conducted on the ischemic heart are summarized in A number of data support the concept that Hh signaling is an important regulator of neurogenesis and angiogenesis in the adult brain. For instance, it is known that Shh is required for the maintenance of neural progenitor cells (NPCs) in the adult hippocampus and regulates the proliferation of NPCs after ischemia/hypoxia . Middle 2O2-induced apoptosis and increases cell viability [The importance of endogenous Shh upregulation in the ischemic brain is demonstrated by the fact that, upon induction of experimental cerebral ischemia, inhibition of the Shh pathway results in increased infarct volume, brain water content, and behavioral deficits . The endiability . Regardiiability .2O2-treated neurons, exogenous Shh increases the activity of Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) and decreases the production of Malondialdehyde (MDA). It also promotes the expression of the anti-apoptotic gene Bcl-2 and inhibits expression of pro-apoptotic gene Bax. Activation of the Shh signal also leads to an upregulated expression of both neurotrophic and vascular factors, such as VEGF and brain-derived neurotrophic factor (BDNF) [In Hr (BDNF) ,58. Intrr (BDNF) . These br (BDNF) . Stimular (BDNF) . Furtherr (BDNF) . Huang ar (BDNF) . They foThe results of the studies conducted on the ischemic brain are summarized in In addition to the skeletal muscle, heart, and brain, there are some organs, such as liver, lung, and kidney, in which it has been brought to evidence that the activation of the Hh pathway may be involved in pathologic angiogenesis, with an effect on fibrogenesis and whole diseased organs fibrotic degeneration .HSP90 gene, involved in the stabilization of HIF-1α in an oxygen-independent manner. This study brings to evidence that Shh-induced angiogenesis in liver hypoxia may be more associated with hepatic fibrosis than to liver regeneration [The contribution of Shh signaling to fibrogenesis has been particularly studied in the liver. Hypoxia-induced pathological angiogenesis is an important phenomenon closely correlated to the disruption of the hepatic architecture occurring in chronic liver diseases. Feng and coll. elegantly demonstrated the pro-angiogenic and pro-fibrinogenic role of the canonical Hh pathway in a model of liver fibrosis in rats. First, they observed high expression of Shh and other hypoxia-associated proteins, such as VEGF and HIF-1α, in the setting of hepatic fibrosis, consistent with the existence of a hypoxic micro-environment. Then, they found that treatment with Gli1 antagonist (GANT)-58 results in reduced the expression of VEGF and Ang-1 and inhibits hepatic stellate cell (HSC)-mediated tubulogenesis. These actions appear to be mediated by the interaction of Gli1 with the neration . Pratap neration . Conversneration . Shh signaling in the embryonic respiratory epithelium appears to have a crucial role in the branching morphogenesis of the lung, and the expression of Ptch by lung mesenchymal cells is vital for normal lung formation . In the Polygonum Cuspidatum Sieb., exhibits beneficial effects in ischemic organs such as heart, brain, lungs, and kidneys, demonstrated that blocking the Shh pathway (through cyclopamine or the Shh antibody 5E1) markedly suppressed the positive effects of polydatin both in ischemic kidneys in unilateral renal IRI mice in vivo and in renal tubular cells under OGD in vitro [Few studies analyzed the effect of Shh on the ischemic kidney. Some attention has been paid to the pro- or anti-fibrotic activity of Shh in renal IRI. Ozturk et al. studied the expression of Shh in murine models of IRI after treatment with L-Arg, a precursor of NO . They shin vitro . Metabolin vitro . Moreovein vitro . Canonically, Hh signaling occurs through the binding of Hh proteins to the twelve-transmembrane domain receptor Ptch. Binding of a Hh ligand to Ptch results in Ptch internalization and abolishment of its inhibitory activity on the seven-transmembrane protein Smoothened (Smo). Smo is subsequently phosphorylated at its intracellular C-terminus and undergoes reciprocal translocation to the plasma membrane of non-motile cilia. Through an unknown mechanism, ciliary Smo inhibits the downstream proteolytic processing of GLI2 and GLI3, leading to the production of full-length activated Gli proteins (GliA). GliA enter the nucleus and stimulate transcription of the ubiquitous Hh target genes, GLI1, PTCH, and HHIP (Hh interacting protein). When the pathway is off, Gli2 and Gli3 proteins are converted into truncated repressor forms, named GliR (Gli repressors), which inhibit target gene transcription. When the pathway is on, GliR production is blocked, and Gli2 and Gli3 proteins are converted into GliA . The balA limitation of the vast majority of the studies listed in this review is that they have not evaluated which pathway is acting in what situations. One exception is the study published by Renault and coll. in 2009, in which it is shown that Gli3-deficient mice have reduced capillary density after induction of hindlimb ischemia . They alOnce believed to be important only during embryonic development, the Hh signaling pathway is now recognized as a crucial player in many physiological and pathological conditions in post-natal life. Its role during ischemia-induced angiogenesis and tissue repair has been extensively investigated in the last two decades and seems to be particularly important in organs such as the heart, the brain, and the skeletal muscle. Although the precise molecular and cellular mechanisms underlying Hh-mediated angiogenesis still require full elucidation, there is substantial evidence supporting the concept that the endogenous Hh signaling pathway has the ability to orchestrate multiple aspects of the angiogenic response to ischemia, mainly through the production of angiogenic growth factors from interstitial cells and fibroblasts and the regulation of EPC activity. Nevertheless, there is evidence that many activities of Hh proteins in the ischemic heart and brain occur through direct stimulation of cardiomyocytes and neural cells. Based on the concept that the endogenous Hh pathway is important for efficient angiogenic response to ischemia, several studies have focused on the use of agonists of the Hh pathway to stimulate therapeutic angiogenesis. Successful results have been achieved in experimental models of myocardial infarction, ischemic stroke, and peripheral limb ischemia. However, at the moment, there is a complete lack of data on human subjects, and doubts remain on the actual possibility of manipulating the Hh pathway in a safe manner in humans. In this context, it is worth pointing out that Shh has been implicated in the pathogenesis of several types of cancer and that anti-Hh strategies are currently used, or are under investigation, for the treatment of many neoplastic diseases, including basal cell carcinoma, acute promyelocytic leukemia, medulloblastoma, small cell lung cancer, pancreatic cancer, intracranial meningioma, recurrent glioblastoma, prostate cancer, renal cell carcinoma, and colon cancer. Based on this, it is unseemly that none of the experimental studies performed so far made an effort to evaluate whether stimulation of angiogenesis by Shh agonists in the ischemic heart, brain, and skeletal muscle is safe or may have dismal consequences. Studies testing the safety of exogenous administration of Hh agonists are therefore mandatory in order to understand whether the large amount of experimental data produced so far has translational significance and potential clinical implications.


This paper is a review of recent (≤10 years) information on litterfall, standing stock of benthic organic matter, breakdown rates, and fungal colonization of organic matter in streams. In some cases, recent research reinforces the findings of classic reference papers. In other cases, the additional knowledge provided by recent research introduces a higher variation in the processes analyzed. In many aspects, especially those concerning stream organic matter, the review is biased towards the temperate North American streams, reflecting the fact that most research was carried out there. However, during the 1990s European studies increased enormously, especially those related with instream processes, such as leaf litter decomposition. The first part of this review analyzes the origin of allochthonous organic matter to streams , and it provides data on the amounts estimated in different streams and on the methodology used in the studies. The second part analyzes the fate of detritus in streams: mechanisms of leaf breakdown, relative importance of fungi and bacteria, factors affecting the activity of microbial decomposers, and chemical changes of leaf litter during decomposition. A list of breakdown rates of several different leaf species is given, together with the methodology used, and the main characteristics of the incubation streams.


The observation of a close concordance between perivascular fibrin(ogen) deposition and the occurrence of clinical signs in EAE has led to numerous studies to investigate the role of thrombin and fibrin(ogen). Most findings supported that blood-brain barrier (BBB) breakdown, presence of active plaques, and disease exacerbation in both humans and animal models are conditions characterized by an increased coagulation activity.Ziliotto et al. pointed out that increased BBB permeability leads to the irruption into the CNS of blood components including coagulation factors. Their cytotoxic deposition with the activation of microglia, resident innate immune cells, already in pre-demyelinating lesion stage in EAE and MS, cause inflammatory response and immune activation sustaining neurodegenerative events in MS. In particular, among the coagulation factors, FXII could act as an autoimmunity mediator due to its deposition near dentritic cells positive for CD87.Furthermore, Ziliotto et al. investigated multiple FXII-related variables, including either its circulating levels, pro-coagulant function, ratio values or variation over time, in 74 MS patients and 49 healthy subjects. They found in MS patients an increased FXII plasma level, a significant difference over time for FXII procoagulant activity and reduced function within the intrinsic coagulation pathway, which supports investigation of FXII contribution to disease phenotype and progression.In their research, La Starza et al.. Moreover, genes coding for cluster of differentiation 40 (CD40), especially operative in B lymphocytes, and plasminogen activator urokinase (PLAU) shared both networks, pointing to an integral interplay between coagulation cascade and one of main pathogenic immune effectors.Interestingly, the role of the coagulation process entangled with other pathogenic pathways in MS , was reinforced by over-connectivity between genome-wide associations MS data and a network of coagulation pathways studied by Göbel et al. who highlighted the molecular mechanisms underlying the balance between haemostasis and thrombosis, and between protection from infection and extensive inflammation.The involvement of coagulation factors, especially factor XII, fibrinogen and thrombin, beyond their traditional roles in haemostasis, in the development of inflammatory diseases like MS, rheumatoid arthritis and colitis was again the focus of the systematic review by Fleetwood et al.. APS is an autoimmune antibody-mediated condition characterized by thrombotic events and/or pregnancy morbidity in association with persistent positivity to antiphospholipid antibodies. The CNS is frequently affected, as intracranial vessels are the most frequent site of arterial pathology. Nevertheless, ischemic injury is not always sufficient to explain clinical features of the syndrome and immune-mediated damage has been advocated.The double nature, thrombotic and immunologic, is also evident in other specific neurologic condition such as the antiphospholipid syndrome (APS) and in the therapeutic strategy adopted for this disorder as discussed in the review by Festoff and Citron reviewed available evidence on the role of coagulation cascade activation, in particular of thrombin signaling, in neurodegeneration and in the potential development of effective therapeutic approaches for ALS and traumatic brain injury. Different elements and regulators of the coagulation pathway have significant impact in these conditions and each of these molecules are entangled in choices dependent upon specific signaling pathways in play. For example, the particular cleavage of protease activated receptor 1 (PAR1) by thrombin versus activated protein C will have downstream effects through coupled factors to result in toxicity or neuroprotection.Shavit-Stein et al. who studied the role of these factors in rat experimental autoimmune neuritis (EAN), a model of the human Guillain-Barre syndrome. The authors showed that thrombin activity in the sciatic nerve was elevated in EAN compared to control sham rats. Furthermore, treatment with non-selective thrombin inhibitors significantly inhibited specific thrombin activity in EAN rats' sciatic and improved clinical scores compared to the untreated EAN rats with normalization of proximal amplitude observed in nerve conduction studies.Thrombin and its PAR1 are potentially important also in peripheral nerve inflammatory diseases as it has been addressed by Di Domenico et al.. In fact, invasive forms of B. burgdorferi are known to expresses multiple plasminogen-binding surface proteins that likely assist pathogen dissemination through host tissues. During the course of the infection, bacteria migrate through the host tissues altering the coagulation and fibrinolysis pathways and the immune response, reaching the CNS within 2 weeks after the bite of an infected tick.The emerging role of coagulation in infectious diseases such as Lyme neuroborreliosis (LB), the most common tick-borne disease involving nervous system caused by the spirochete Borrelia, has been investigated by Galgani et al. who found that there are only few case reports describing such interactions and, therefore, limited evidence is available.The importance of coagulation system in the management of neurological diseases, particularly in elderly, is also evident by the potential risk associated with the increasing prescription of the new direct oral anticoagulants (DOACs), namely apixaban, dabigatran, edoxaban, and rivaroxaban, in patients with epilepsy taking concomitant antiepileptic drugs (AEDs). As a result, potential interactions may cause an increased risk of DOAC-related bleeding or a reduced antithrombotic efficacy. This issue was evaluated by Alisi et al. who reviewed recent evidence on the emerging involvement of vitamin K, whose biological activity in blood coagulation has been thoroughly explored, even in brain cells development and survival and, hence, in brain functions. In particular, vitamin K seems to have an antiapoptotic and anti-inflammatory effect mediated by the activation of Growth Arrest Specific Gene 6 and Protein S and to be involved in sphingolipids metabolism, a class of lipids that participate in the proliferation, differentiation and survival of brain cells. Vitamin K antagonists, used worldwide as oral anticoagulants, may have a negative influence on cognitive domains such as visual memory, verbal fluency and brain volume.An indirect role of the coagulation system in neurocognitive disorders has been assessed by All these contributions indicate that the study of coagulation pathways in neurological diseases would lead to a greater understanding of their pathophysiology and a more appropriate therapeutic approach. We hope that this Research Topic will help the reader to find a useful reference for the state of the art in this emerging research field and, in particular, both researchers and clinicians to face their challenges with a more complete pathogenic approach since the role of innate immunity and of its effector coagulation factors is very relevant in both health and pathology.SL, MI, and TK all contributed equally to the literature research and writing.MI has received research grants from NIH, NMSS, FISM, and Teva Neuroscience; TK has received research grant from the Italian Ministry of Health. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Depression is a mental disorder characterized by low mood and anhedonia that involves abnormalities in multiple brain regions and networks. Epidemiological studies demonstrated that depression has become one of the most important diseases affecting human health and longevity. The pathogenesis of the disease has not been fully elucidated. The clinical effect of treatment is not satisfactory in many cases. Neuroimaging studies have provided rich and valuable evidence that psychological symptoms and behavioral deficits in patients with depression are closely related to structural and functional abnormalities in specific areas of the brain. There were morphological differences in several brain regions, including the frontal lobe, temporal lobe, and limbic system, in people with depression compared to healthy people. In addition, people with depression also had abnormal functional connectivity to the default mode network, the central executive network, and the salience network. These findings provide an opportunity to re-understand the biological mechanisms of depression. In the future, magnetic resonance imaging (MRI) may serve as an important auxiliary tool for psychiatrists in the process of early and accurate diagnosis of depression and finding the appropriate treatment target for each patient to optimize clinical response. Major depressive disorder (MDD) is a mental illness characterized by significant persistent low mood and emotional changes. Its clinical manifestations include depression, sorrow, anhedonia, rumination. Patients with severe depression may have suicidal will or behavior. According to statistics, depression has become the most widely distributed mental disorder in the globe , and it On the other hand, neuroimaging can compensate for the defect of EEG, providing more spatial information and locating abnormal brain areas in patients with depression . For nowGray matter is a significant component of the central nervous system, and the volume of gray matter in the brain is associated with many physiological senses and higher functions, including muscle control, vision and hearing, memory, emotion, language, decision-making and self-control . Volume The primary function of white matter is to transmit information efficiently and accurately between different gray matter areas of the central nervous system. Reduced white matter connectivity and volume can lead to impaired information delivery, which may cause deficits in attention, declarative memory, executive function, and intelligence . DiffusiOn the other hand, the resting and active status of brain regions can be observed by detecting fluctuations in blood oxygen levels. Blood oxygenation level-dependent (BOLD) functional MRI (fMRI) can contribute to the assessment of brain abnormalities by showing changes in brain activity of subjects in resting-state or task-state. Especially, resting-state functional magnetic resonance has become an essential basis for brain functional analysis . The comThis article reviews recent advances in neuroimaging studies related to depression and summarizes the imaging changes of the disease from the structural and functional aspects.Article searching was performed in PubMed , BioMed and PsycINFO between earliest record and September 1, 2019, using  AND  as search terms in title and abstract. Two authors jointly established inclusion and exclusion criteria and applied them to literature screening and quality assessment. These criteria were: (1) DSM-III, DSM-IV, DSM-V, ICD-10 or ICD-11 was used as criteria for diagnosing depression; (2) The experimental group and the control group matched at the age and gender level; (3) Clearly grouped medicated and unmedicated patients instead of mixing them into one group; (4) Subjects in the experimental group were not accompanied by bipolar disorder or other mental or organic diseases; (5) Studies with fewer than 10 people in the experimental group were excluded; (6) Studies on postpartum depression was excluded; (7) Animal experiments were excluded. The process of literature selection is shown in the flowchart . ParticiVBM is widely used in the study of abnormal brain anatomy. This technique uses the statistical parameter map method to measure the volume and density of each voxel corresponding to gray matter and white matter. Changes were quantitatively calculated to assess changes in gray matter and white matter.Meta-analyses indicate that hippocampal volume reduction is the most common brain anatomical change in patients with depression , and, esFrontal atrophy is also one of the critical changes in depression . StudiesIn addition to the frontal lobe, the volume of the bilateral putamen and left thalamus in patients with depression is also smaller in contrast to healthy controls . These gAbnormal white matter is also widespread in patients with depression . DTI shoMeta-analysis  indicateOn the other hand, compared with the healthy control group, elderly patients with depression have more severe cerebral vascular lesions such as white matter hyperintensities (WMH), subcortical lacunar, microinfarction, and microangiopathy . As earlfMRI is widely used in the study of abnormal brain activity. When the neuronal activity is enhanced, the local blood flow in the cortex of the functional brain area is significantly increased, and the oxygen consumption is relatively insignificant, resulting in the proportion of deoxygenated hemoglobin/oxyhemoglobin is reduced. Due to deoxygenated hemoglobin is a paramagnetic substance, the functional region shows a different BOLD signal compared with the inactive brain region. Neuronal activity in a resting state or giving emotional stimuli and cognitive tasks can be indirectly reflected by a BOLD signal representing the local neuron activity of the brain.Depending on the purpose and the experimental design of the study, the fMRI study can be divided into two types: resting-state and task-based. The former mainly examines the spontaneous nerve activity of the subject in a calm and awake state, while the latter mainly explores the activity state of the brain when the individual is subjected to emotional stimulation or completing specific tasks.A study  indicateOn the other hand, due to the differences in experimental task design and sample selection methods, although many task-based fMRI experiments have studied the abnormalities of brain activity patterns in patients with depression during cognitive and emotional processing, consistent conclusions are still lacking . A meta-Young et al.’s small sample studies  found thFunctional connectivity is defined as the temporal correlation of multiple brain regions. Each brain region, defined as a node, is connected, eventually forming a brain network with highly complex and concentration. These brain networks play an important role in cognitive and emotional processing . In 2011The most common methods for studying brain function connectivity include seed-based correlation analysis (SCA) and independent component analysis (ICA). SCA predetermines “seed” (a region of interest) based on previous assumptions, and calculates the correlation with the other voxels or specific other regions of the brain by their BOLD signal fluctuations. In contrast, ICA uses all available data in the fMRI image and decomposes it several independent components. An increase in functional connectivity represents increased synchronization between the two regions.The DMN consists mainly of the medial prefrontal cortex, posterior cingulate cortex/precuneus, and inferior parietal lobule . Also, tThe default mode network is currently the most commonly studied brain network for depression. So far, one of the most consistent conclusions is that the connectivity of multiple nodes in the default mode network of depression patients is abnormally increased , and is The CEN, also known as the executive control network, consists mainly of the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, the posterior parietal cortex, and the frontal eye field and plays a role in working memory, problem-solving, goal-oriented behavior and decision-making.Compared with the control group, the functional connectivity between the central executive network and the default mode network of MDD patients is decreased, while the functional connectivity with the salience network is increased, which might be related to the rumination . In addiThe SN consists of the insular cortex, dorsal anterior cingulate cortex, temporal pole and amygdala and is responsible for detecting and filtering stimuli, as well as in recruiting relevant functional networks . CompletAbnormal salience network connectivity is considered to be one of the crucial links in the pathogenesis of depression, especially in the insula and amygdala. Salience network, especially the right anterior insula, is thought to be critical in the transition from the central execution network’s dominant “execution state”. to the default state-preferred “default state” . A studyAnother important anomaly node in the salience network is the amygdala. In adults and adolescents with depression and children at high risk of depression, the functional connectivity between the amygdala and the hippocampus is found to be decreased , while hIn summary, neuroimaging studies have shown that depression involves multiple brain regions with structural and functional abnormalities, most of which are related to the limbic system, the default mode network, the central execution network, and the salience network. Together, they caused a variety of clinical symptoms of depression. Among them, atrophy and abnormal activity of parahippocampal gyrus and hippocampus led to patients’ positive memory recall disorder, which may further lead to anhedonia. Negative emotions and exaggerated responses to negative stimuli and degrading life events were mainly related to amygdala activity abnormality. While the decrease in the performance of cognitive processing and working memory is mainly related to the decrease in CEN functional connection, the abnormality of SN is mainly due to the abnormal adjustment of functional balance between DMN and CEN. However, due to the low consistency and reproducibility of the study results and the lack of clinical specificity at the individual level, the above examination methods have not been widely used in clinical diagnosis. Future research needs to enhance the homogeneity of the sample and obtain more data from patients of different age groups, different symptoms and related diseases to obtain highly specific results. It is also worthwhile to look for the commonality of the brain structure and/or brain function of patients in various subgroups and to find the best treatment.10.7717/peerj.8170/supp-1Table S1* prospective studyClick here for additional data file.


Anomalies in primary teeth are comparatively fewer than in the permanent teeth. The presence of a primary canine with two roots is very rare. An unusual anomaly like this may lead to problems during extraction or exfoliation. Emphasis on the importance of anomalies is required for proper diagnosis and to facilitate a better treatment outcome.The present case report describes a case of a bilateral bi-rooted primary maxillary canines diagnosed during a radiographic examination in a 9-year-old Saudi boy. To the best of our knowledge, this is the first case of bi-rooted primary maxillary canine reported from the region of Saudi Arabia.This case report aims to increase awareness of the morphological alterations in primary canines and to emphasize the importance of diagnosis and radiographic examination using different angles. Clinicians should consider all the possible tooth variations during routine intra-oral and radiographic examinations to facilitate a better treatment outcome and to avoid unwanted complications. The primary and the permanent teeth are subject to considerable variation in their form, size, number, and structure of the dental tissues. Abnormalities in tooth morphology in primary teeth are comparatively fewer than in the permanent teeth . The preOn 3 April 2017, a 9-year-old Saudi boy with a complaint of missing teeth in maxillary anterior region visited the Department of Preventive Dental Science, Faculty of Dentistry, Najran University, Saudi Arabia. On 15 April 2017, he underwent a clinical examination which revealed: unerupted permanent maxillary lateral incisors; decay in tooth numbers 54, 55, 62, 64, 65, 26, 84, 74, 75, and 85 ; and anterior crossbite between tooth numbers 53 and 83. Radiographic examination revealed bi-rooted bilateral maxillary canines (53 and 63)  of the crown. It has been explained that during normal root formation, at the dental organ’s cervical loop, the outer and the inner enamel epithelia multiply in the form of a double layer of cells called Hertwig’s epithelial root sheath. The inner and outer epithelia of enamel turn at the future cementoenamel junction, producing the epithelial diaphragm. The primary apical foramen is enclosed by the rim of this sheath. An unknown aspect in multi-rooted teeth stimulates continued morphodifferentiation. Tongue-like extensions of the horizontal diaphragm grow and extend toward each other, and fuse by differential growth. For every new secondary apical foramen, a root will be developed .Although trauma and other disturbances may affect morphodifferentiation, improved expression of the gene starting the differential growth of Hertwig’s epithelial root sheath or a defect in the dental lamina through the initial stage of formation of the root is thought to develop double roots . In the In conclusion, clinicians should consider all the possible tooth variations during routine intra-oral and radiographic examinations to facilitate a better treatment outcome and to avoid unwanted complications. Also, the presence of two roots in primary canines bilaterally cannot be attributed to a specific cause in the present report and further studies are needed for the proper treatment of this anomaly.


The aim of this review is to revise the current knowledge on basal ganglia circuits, highlighting similarities and differences across species, in order to widen the current perspective on the intricate model of the basal ganglia system. This will allow us to explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum recently described in animals and humans.Much of our present understanding of the function and operation of the basal ganglia rests on models of anatomical connectivity derived from tract-tracing approaches in rodents and primates. However, the last years have been characterized by promising step forwards in the  Identifying anatomical physical pathways between the various structures of the brain has always been a major challenge in neuroscience. Neuronal connectivity patterns can be investigated at different levels of scale: (i) the microscale allows to study single synaptic connections linking two or more individual neuronal cells, providing a detailed anatomical description of the basic substrates of the cerebral microcircuits; (ii) at the mesoscale level, where brain connectivity is investigated at the level of columns and mini-columns; and (iii) at macroscale level that explore large-scale anatomical connectivity patterns focusing on the inter-regional white matter pathways connecting distinct neuronal populations  . In this treatise, Ferrier writes that “the basal ganglia—the corpora striata and optic thalami—are ganglionic masses, intercalated in the course of the projection system of fibers which connect the cortex with the crura cerebri, and through these with the periphery. The corpora striata are the “ganglia of interruption” of the projection system of the foot or basis of the crus, an anatomical indication of their motor signification”  has allowed the development of neuroimaging approaches as an alternative modality to assess morphological neuronal connectivity patterns in living humans. Diffusion-weighted magnetic resonance imaging (DWI) and tractography have been successfully employed to model and infer white matter bundles’ trajectory of white matter bundles together with their microstructural properties  being constrained to the main axonal direction; therefore DWI indirectly evaluates white matter microstructure  gross anatomy between rodents and primates. Both in human and non-human primates, the internal (GPi) and external (GPe) segments of the GP are structurally divided by the internal lamina and are placed close to each other. On the other hand, in rodents, the GPi functional homologous, termed entopeduncular nucleus, is mostly embedded in the internal capsule  has been considered for many decades one of the relevant nodes of the “indirect” pathway, it also receives direct signals from the cerebral cortex  via GABAergic inhibitory projections thus selectively reducing GPi/SNr activity and releasing firing from thalamocortical neurons.When a given motor pattern is computed by cortical motor areas, it is first conveyed to the basal ganglia Along with the initial signal to the striatum, the cerebral cortex suppresses surrounding or competing motor patterns. This activity is known to be mediated by the “indirect” and “hyperdirect” pathways. When excited by the glutamatergic inputs of the cerebral cortex, striatal D2 receptors allow the cells of the striatal matrix to send inhibitory signals to the GPe which normally exerts a tonic GABAergic inhibition on the STN. Therefore, the glutamatergic neurons of the STN can then excite the GPi/SNr thus suppressing thalamic activity on the cerebral cortex and increasing inhibitory influences on the upper motor neurons , a slow negative electroencephalographic (EEG) activity that usually precedes self-paced movements . These fibers (demonstrated both by anatomic dissection and by neuronography), originate from area 6” . On the other hand, the computational role of the subthalamic-ponto-cerebellar pathway is not clear at all; nevertheless, considering the involvement of the subthalamic nucleus in the indirect pathway and aversive learning phenomena, it is tempting to speculate that it would prevent the new forward models to be conveyed to the striatum  found made the hypothesis of rapidly funneling stimuli from cerebellum to basal ganglia neglectable (Ratchetson and Li, via the superior cerebellar peduncles and bypassing the red nucleus, thalamus and striatum (Milardi et al., In addition to the dento-thalamo-striatal and subthalamo-ponto-cerebellar pathways, Milardi et al.  reconstrvia tract-tracing in cats and rats (Snider et al., Although its physiological meaning is still unknown, the dento-nigral pathway, reconstructed in human by means of dMRI and tractography, could represent the phylogenetical equivalent of the pathway observed Recent evidences of a direct route connecting dentate nucleus to globus pallidus, on human side, comes from a MEG-LFP study (Neumann et al., These direct connections between the dentate nucleus and GPi and SNr are very intriguing considering the presence of a direct cortico-pallidal and cortico-SN pathways bypassing the striatum in humans (Milardi et al., The basal ganglia and the cerebellum have been often conceived separately as structures involved in different neurological syndromes. However, evidences concerning the co-operation of cerebellum and basal ganglia in movement disorders are currently growing. Thus, the above-described scenario could open an entirely new perspective into the pathophysiology of basal ganglia and cerebellum disorders (Coenen et al., Different aspects of movement disorders could be gathered by cerebellum-basal ganglia interface. Cerebellum and basal ganglia have been involved in time computation: the former should be accounted for millisecond-range intervals whilst the latter would work mainly on the second-ranges Ivry, . FunctioAlthough the involvement of basal ganglia in the pathophysiology of dystonia is indisputable, the mechanisms producing dystonia are incompletely understood, with recent evidence pointing to the involvement of a variety of brain areas including the cerebellum (Quartarone and Hallett, Anomalies in the cerebellum and basal ganglia have been widely investigated in both animal and human studies of dystonia (Filip et al., Moreover, also primary dystonia, such as cervical dystonia has also been conceptualized as deriving from alterations in neural integration for head and eye movements, involving cerebellum and basal ganglia in association with oculomotor structures (Shaikh et al., The pathway linking the STN to cerebellum could be involved in motor symptoms of PD. In particular, STN pathological activity, characterized by burst activity and higher firing rates, may in turn be responsible for hyperactivity of cerebellar cortex leading to alterations in the cerebello-thalamo-cortical circuits (Bostan et al., In conclusion, further experimental and challenging studies should be fostered to characterize the full extent of the interplay between the cerebral cortex, the basal ganglia and the cerebellum. However, several evidences have already suggested that the system is more intricated than initially assumed. In the present review, we discussed the invasive and non-invasive techniques to investigate the anatomy and the extrinsic and intrinsic connections of the basal ganglia network. We illustrated the neuroanatomical findings obtained in non-human species that have inspired a paradigmatic shift in this scenario, providing evidences that the cortico-basal ganglia circuits constitute a complex system. Finally, we provide further support coming from neuroimaging studies that these pathways may exist in humans and may exert a meaningful role in basal ganglia disorders. Taken together, these observations suggest that the cerebral cortex, the basal ganglia and the cerebellum form an integrated and segregated network acting on multiple motor and non-motor functions. Although such complex interplay has not yet been explored in detail, we hope it will be a focus of new-generation optogenetic, physiologic, behavioral and neuroimaging studies.The proposed scenario, with the presence of parallel direct and indirect projections running between the cortex, basal ganglia and cerebellum, complements new ideas that view movement disorders as disorders of a complex motor network rather than a limited disruption of individual nuclei in the basal ganglia.DM: writing of the first draft of the manuscript, conception, organization, and execution of the research project, data analysis and interpretation, literature research, and critically revised the manuscript. AQ: writing of the first draft of the manuscript, conception, organization, and execution of the research project, data analysis and interpretation, literature research, critically revised the manuscript, and Guarantor and supervisor of the research project. GA: conception, organization, and execution of the research project, data interpretation, critically revised the manuscript, Guarantor and supervisor of the research project. AC: conception, organization, and execution of the research project, data analysis and interpretation, writing of the first draft and revision of the final version of the manuscript, and Guarantor and supervisor of the research project. AB, SB, GB, PB and GP: data analysis and interpretation, writing of the first draft and literature research. GC: data analysis and interpretation, revised the manuscript and literature research. GR and DB: data analysis and interpretation and literature research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.