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Background: Malnutrition among inpatients is highly prevalent, and has a negative impact on their clinical outcome. The Working Group for the Study of Malnutrition in Hospitals in Catalonia was created to generate consensus guidelines for the prevention and/or treatment of malnutrition in hospitals in Catalonia, Spain. Aims: The objectives of the study were to determine the prevalence of malnutrition on admission to hospital in Catalonia and to assess relationships between malnutrition, social and demographic data, overall costs, and mortality. Methods: Prospective and multicenter study conducted with 796 patients from 11 hospitals representative of the hospitalized population in Catalonia. Nutritional status was evaluated using the Nutritional Risk Screening 2002 method. Results: Overall, 28.9% of the patients are malnourished or at nutritional risk. Elderly patients, non-manual workers, those admitted to hospital as emergencies and with higher co-morbidities had higher risk of malnutrition. The type of hospital (second level vs. tertiary or University referral) to which they were admitted was also a factor predisposing to malnutrition. Length of hospital stay was longer in malnourished patients (10.5 vs. 7.7 days, p < 0.0001). The need for a convalescent home on leaving hospital was higher as well as the risk of mortality (8.6% malnourished vs. 1.3% nonmalnourished, p < 0.0001). Conclusions: The prevalence of malnutrition is high in patients on admission to hospital in our community, resulting in elevated overall costs and higher risk of mortality. Age, social class and characteristics of the Unit and the Hospital are the main factors involved in hospital malnutrition. [ABSTRACT FROM AUTHOR]

For successful regeneration, the identity of the missing tissue must be specified according to the pre-existing tissue. Planarians are ideal for the study of the mechanisms underlying this process; the same field of cells can regrow a head or a tail according to the missing body part. After amputation, the differential activation of the Wnt/β-catenin signal specifies anterior versus posterior identity. Initially, both wnt1 and notum (Wnt inhibitor) are expressed in all wounds, but 48 hours later they are restricted to posterior or anterior facing wounds, respectively, by an unknown mechanism. Here we show that 12 hours after amputation, the chromatin accessibility of cells in the wound region changes according to the polarity of the pre-existing tissue in a Wnt/β-catenin-dependent manner. Genomic analyses suggest that homeobox transcription factors and chromatin-remodeling proteins are direct Wnt/β-catenin targets, which trigger the expression of posterior effectors. Finally, we identify FoxG as a wnt1 up-stream regulator, probably via binding to its first intron enhancer region., (© 2023. The Author(s).)

The capability to simultaneously apply different molecular tools to visualize a wide variety of changes in genetic expression and tissue composition in Schmidtea mediterranea has always been of great interest. The most commonly used techniques are fluorescent in situ hybridization (FISH) and immunofluorescence (IF) detection. Here, we describe a novel way to perform both protocols together adding the possibility to combine them with fluorescent-conjugated lectin staining to further broaden the detection of tissues. We also present a novel lectin fixation protocol to enhance the signal, which could be useful when single-cell resolution is required., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Forkhead box (Fox) genes belong to the "winged helix" transcription factor superfamily. The function of some Fox genes is well known, such as the role of foxO in controlling metabolism and longevity and foxA in controlling differentiation of endodermal tissues. However, the role of some Fox factors is not yet well characterized. Such is the case of FoxK genes, which are mainly studied in mammals and have been implicated in diverse processes including cell proliferation, tissue differentiation and carcinogenesis. Planarians are free-living flatworms, whose importance in biomedical research lies in their regeneration capacity. Planarians possess a wide population of pluripotent adult stem cells, called neoblasts, which allow them to regenerate any body part after injury. In a recent study, we identified three foxK paralogs in the genome of Schmidtea mediterranea . In this study, we demonstrate that foxK1 inhibition prevents regeneration of the ectodermal tissues, including the nervous system and the epidermis. These results correlate with foxK1 expression in neoblasts and in neural progenitors. Although the triggering of wound genes expression, polarity reestablishment and proliferation was not affected after foxK1 silencing, the apoptotic response was decreased. Altogether, these results suggest that foxK1 would be required for differentiation and maintenance of ectodermal tissues., Competing Interests: 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., (Copyright © 2022 Coronel-Córdoba, Molina, Cardona, Fraguas, Pascual-Carreras, Saló, Cebrià and Adell.)

The forkhead box (Fox) genes encode transcription factors that control several key aspects of development. Present in the ancestor of all eukaryotes, Fox genes underwent several duplications followed by loss and diversification events that gave rise to the current 25 families. However, few Fox members have been identified from the Lophotrochozoa clade, and specifically from planarians, which are a unique model for understanding development, due to the striking plasticity of the adult. The aim of this study was to identify and perform evolutionary and functional studies of the Fox genes of lophotrochozoan species and, specifically, of the planarian Schmidtea mediterranea. Generating a pipeline for identifying Forkhead domains and using phylogenetics allowed us the phylogenetic reconstruction of Fox genes. We corrected the annotation for misannotated genes and uncovered a new family, the QD, present in all metazoans. According to the new phylogeny, the 27 Fox genes found in Schmidtea mediterranea were classified into 12 families. In Platyhelminthes, family losses were accompanied by extensive gene diversification and the appearance of specific families, the A(P) and N(P). Among the newly identified planarian Fox genes, we found a single copy of foxO, which shows an evolutionary conserved role in controlling cell death.

An organizer is defined as a group of cells that secrete extracellular proteins that specify the fate of surrounding cells according to their concentration. Their function during embryogenesis is key in patterning new growing tissues. Although organizers should also participate in adult development when new structures are regenerated, their presence in adults has only been identified in a few species with striking regenerative abilities, such as planarians. Planarians provide a unique model to understand the function of adult organizers, since the presence of adult pluripotent stem cells provides them with the ability to regenerate any body part. Previous studies have shown that the differential activation of the WNT/β-catenin signal in each wound is fundamental to establish an anterior or a posterior organizer in the corresponding wound. Here, we identify the receptors that mediate the WNT/β-catenin signal in posterior-facing wounds. We found that Wnt1-Fzd1-LRP5/6 signaling is evolutionarily conserved in executing a WNT/β-catenin signal to specify cell fate and to trigger a proliferative response. Our data allow a better understanding of the mechanism through which organizers signal to a "competent" field of cells and integrate the patterning and growth required during de novo formation of organs and tissues.

Although many examples of simulated and real microgravity demonstrating their profound effect on biological systems are described in literature, few reports deal with hypergravity and vibration effects, the levels of which are severely increased during the launch preceding the desired microgravity period. Here, we used planarians, flatworms that can regenerate any body part in a few days. Planarians are an ideal model to study the impact of launch-related hypergravity and vibration during a regenerative process in a "whole animal" context. Therefore, planarians were subjected to 8.5 minutes of 4 g hypergravity (i.e. a human-rated launch level) in the Large Diameter Centrifuge (LDC) and/or to vibrations (20-2000 Hz, 11.3 G rms ) simulating the conditions of a standard rocket launch. The transcriptional levels of genes (erg-1 , runt-1 , fos, jnk , and yki ) related with the early stress response were quantified through qPCR. The results show that early response genes are severely deregulated after static and dynamic loads but more so after a combined exposure of dynamic (vibration) and static (hypergravity) loads, more closely simulating real launch exposure profiles. Importantly, at least four days after the exposure, the transcriptional levels of those genes are still deregulated. Our results highlight the deep impact that short exposures to hypergravity and vibration have in organisms, and thus the implications that space flight launch could have. These phenomena should be taken into account when planning for well-controlled microgravity studies., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Control of cell number is crucial to define body size during animal development and to restrict tumoral transformation. The cell number is determined by the balance between cell proliferation and cell death. Although many genes are known to regulate those processes, the molecular mechanisms underlying the relationship between cell number and body size remain poorly understood. This relationship can be better understood by studying planarians, flatworms that continuously change their body size according to nutrient availability. We identified a novel gene family, blitzschnell ( bls ), that consists of de novo and taxonomically restricted genes that control cell proliferation:cell death ratio. Their silencing promotes faster regeneration and increases cell number during homeostasis. Importantly, this increase in cell number leads to an increase in body size only in a nutrient-rich environment; in starved planarians, silencing results in a decrease in cell size and cell accumulation that ultimately produces overgrowths. bls expression is downregulated after feeding and is related to activity of the insulin/Akt/mTOR network, suggesting that the bls family evolved in planarians as an additional mechanism for restricting cell number in nutrient-fluctuating environments., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Freshwater planarians are well known for their remarkable plasticity and regenerative capabilities. Most studies of planarian regeneration have specifically examined regeneration after transverse or longitudinal sectioning or during homeostasis in intact adults. However, tissue transplantation, first performed over a century ago, constitutes another important tool in the study of regeneration in planarians, and can be easily performed given this species' extraordinary healing capacity and its lack of a circulatory system. Studies conducted to date have demonstrated the viability of transplantations involving a variety of tissue types of different positional identities, affecting any of the 3 main body axes. Moreover, these grafting experiments have shown that tissues possess axial positional identities, which are retained following transplantation. The confrontation between different positional identities that occurs after any type of tissue transplantation is resolved by the formation of a blastema, consisting of undifferentiated tissue produced by adult pluripotent stem cells (neoblasts). This blastema intercalates the positional identities of the graft and host tissues. The recent discovery of pathways involved in planarian growth, patterning, and organogenesis, as well as corresponding molecular markers, makes tissue transplantation a vital new tool with which to explore pattern formation. Here, we discuss the different grafting approaches used in planarians, and the corresponding intercalary regenerative response, placing particular emphasis on the respective contributions of donor and host tissue. Moreover, we discuss the temporal induction of blastema formation, and present new molecular data on the generation of an ectopic anterior/posterior axis in response to dorsal/ventral confrontations between host and donor tissue., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The possibility of humans to live outside of Earth on another planet has attracted the attention of numerous scientists around the world. One of the greatest difficulties is that humans cannot live in an extra-Earth environment without proper equipment. In addition, the consequences of chronic gravity alterations in human body are not known. Here, we used planarians as a model system to test how gravity fluctuations could affect complex organisms. Planarians are an ideal system, since they can regenerate any missing part and they are continuously renewing their tissues. We performed a transcriptomic analysis of animals submitted to simulated microgravity (Random Positioning Machine, RPM) (s-µg) and hypergravity (8 g), and we observed that the transcriptional levels of several genes are affected. Surprisingly, we found the major differences in the s-µg group. The results obtained in the transcriptomic analysis were validated, demonstrating that our transcriptomic data is reliable. We also found that, in a sensitive environment, as under Hippo signaling silencing, gravity fluctuations potentiate the increase in cell proliferation. Our data revealed that changes in gravity severely affect genetic transcription and that these alterations potentiate molecular disorders that could promote the development of multiple diseases such as cancer.

The Hippo pathway plays a key role in regulating cell turnover in adult tissues, and abnormalities in this pathway are consistently associated with human cancers. Hippo was initially implicated in the control of cell proliferation and death, and its inhibition is linked to the expansion of stem cells and progenitors, leading to larger organ size and tumor formation. To understand the mechanism by which Hippo directs cell renewal and promotes stemness, we studied its function in planarians. These stem cell-based organisms are ideal models for the analysis of the complex cellular events underlying tissue renewal in the whole organism. hippo RNA interference (RNAi) in planarians decreased apoptotic cell death, induced cell cycle arrest, and could promote the dedifferentiation of postmitotic cells. hippo RNAi resulted in extensive undifferentiated areas and overgrowths, with no effect on body size or cell number. We propose an essential role for hippo in controlling cell cycle, restricting cell plasticity, and thereby preventing tumoral transformation.

Tissue transplantation is an important tool for in vivo studies of pattern organization and axis establishment or maintenance in planarians. Further, transplants can inform on cell movements under different regenerative conditions or genetic backgrounds. Here, we detail classical grafting strategies that have been variously employed in planarian research over the last few decades. These protocols remain similarly useful for addressing current and future questions in the field and the step-by-step protocol that we provide allows facile adaptation of this important method into the experimental repertoire of a laboratory.

Why some animals can regenerate and others not has fascinated biologists since the first examples of regeneration were reported. Although many animal phyla include species with some regenerative ability, mainly restricted to particular cell types or tissues, there are some other species capable of regenerating complex structures, such as the vertebrate limb and heart. More remarkably, there are some examples of animals that can regenerate the whole body from a tiny piece of them. Understanding how regeneration is triggered and achieved in these animals is fundamental not only to understand this fascinating primary biological question, but also because of its implications for the field of regenerative medicine. Here, we discuss one of the models with higher regenerative capabilities: the freshwater planarians. Two key features make planarians an attractive model to study regeneration: the presence of adult pluripotent stem cells and the permanent activation of the morphogenetic mechanisms that instruct cell fate. Here, we revise our current knowledge of key events that lead to successful regeneration including: how heterogeneous is the stem cell population; what are the immediate changes at the gene level after amputation and what triggers the regenerative response; how is axial polarity re-established; how do the different cell types differentiate from lineage-committed progenitors and how is size and organ proportionality controlled. Finally, we point out some open questions that the field needs to address in the near future.

How adult stem cells differentiate into different cell types remains one of the most intriguing questions in regenerative medicine. Pioneer factors are transcription factors that can bind to and open chromatin, and are among the first elements involved in cell differentiation. We used the freshwater planarian Schmidtea mediterranea as a model system to study the role of the gata456 family of pioneer factors in gut cell differentiation during both regeneration and maintenance of the digestive system. Our findings reveal the presence of two members of the gata456 family in the Schmidtea mediterranea genome; Smed-gata456-1 and Smed-gata456-2. Our results show that Smed-gata456-1 is the only ortholog with a gut cell-related function. Smed-gata456-1 is essential for the differentiation of precursors into intestinal cells and for the survival of these differentiated cells, indicating a key role in gut regeneration and maintenance. Furthermore, tissues other than the gut appear normal following Smed-gata456-1 RNA interference (RNAi), indicating a gut-specific function. Importantly, different neoblast subtypes are unaffected by Smed-gata456-1(RNAi), suggesting that 1) Smed-gata456-1 is involved in the differentiation and maintenance, but not in the early determination, of gut cells; and 2) that the stem cell compartment is not dependent on a functional gut.

Background: The freshwater planarian Schmidtea mediterranea is recognised as a valuable model for research into adult stem cells and regeneration. With the advent of the high-throughput sequencing technologies, it has become feasible to undertake detailed transcriptional analysis of its unique stem cell population, the neoblasts. Nonetheless, a reliable reference for this type of studies is still lacking., Results: Taking advantage of digital gene expression (DGE) sequencing technology we compare all the available transcriptomes for S. mediterranea and improve their annotation. These results are accessible via web for the community of researchers. Using the quantitative nature of DGE, we describe the transcriptional profile of neoblasts and present 42 new neoblast genes, including several cancer-related genes and transcription factors. Furthermore, we describe in detail the Smed-meis-like gene and the three Nuclear Factor Y subunits Smed-nf-YA, Smed-nf-YB-2 and Smed-nf-YC., Conclusions: DGE is a valuable tool for gene discovery, quantification and annotation. The application of DGE in S. mediterranea confirms the planarian stem cells or neoblasts as a complex population of pluripotent and multipotent cells regulated by a mixture of transcription factors and cancer-related genes.

Planarians are flatworms, which belong to the phylum Platyhelminthes. They have been a classical subject of study due to their amazing regenerative ability, which relies on the existence of adult totipotent stem cells. Nowadays they are an emerging model system in the field of developmental, regenerative, and stem cell biology. In this study we analyze the effect of a simulated microgravity and a hypergravity environment during the process of planarian regeneration and embryogenesis. We demonstrate that simulated microgravity by means of the random positioning machine (RPM) set at a speed of 60 °/s but not at 10 °/s produces the dead of planarians. Under hypergravity of 3 g and 4 g in a large diameter centrifuge (LDC) planarians can regenerate missing tissues, although a decrease in the proliferation rate is observed. Under 8 g hypergravity small planarian fragments are not able to regenerate. Moreover, we found an effect of gravity alterations in the rate of planarian scission, which is its asexual mode of reproduction. No apparent effects of altered gravity were found during the embryonic development.

Matrix metalloproteinases (MMPs) are major executors of extracellular matrix remodeling and, consequently, play key roles in the response of cells to their microenvironment. The experimentally accessible stem cell population and the robust regenerative capabilities of planarians offer an ideal model to study how modulation of the proteolytic system in the extracellular environment affects cell behavior in vivo. Genome-wide identification of Schmidtea mediterranea MMPs reveals that planarians possess four mmp-like genes. Two of them (mmp1 and mmp2) are strongly expressed in a subset of secretory cells and encode putative matrilysins. The other genes (mt-mmpA and mt-mmpB) are widely expressed in postmitotic cells and appear structurally related to membrane-type MMPs. These genes are conserved in the planarian Dugesia japonica. Here we explore the role of the planarian mmp genes by RNA interference (RNAi) during tissue homeostasis and regeneration. Our analyses identify essential functions for two of them. Following inhibition of mmp1 planarians display dramatic disruption of tissues architecture and significant decrease in cell death. These results suggest that mmp1 controls tissue turnover, modulating survival of postmitotic cells. Unexpectedly, the ability to regenerate is unaffected by mmp1(RNAi). Silencing of mt-mmpA alters tissue integrity and delays blastema growth, without affecting proliferation of stem cells. Our data support the possibility that the activity of this protease modulates cell migration and regulates anoikis, with a consequent pivotal role in tissue homeostasis and regeneration. Our data provide evidence of the involvement of specific MMPs in tissue homeostasis and regeneration and demonstrate that the behavior of planarian stem cells is critically dependent on the microenvironment surrounding these cells. Studying MMPs function in the planarian model provides evidence on how individual proteases work in vivo in adult tissues. These results have high potential to generate significant information for development of regenerative and anti cancer therapies.

Planarians represent an excellent model to study the processes of body axis and organ re-specification during regeneration. Previous studies have revealed a conserved role for the bone morphogenetic protein (BMP) pathway and its intracellular mediators Smad1/5/8 and Smad4 in planarian dorsoventral (DV) axis re-establishment. In an attempt to gain further insight into the role of this signalling pathway in planarians, we have isolated and functionally characte-rized the inhibitory Smads (I-Smads) in Schmidtea mediterranea. Two I-Smad homologues have been identified: Smed-smad6/7-1 and Smed-smad6/7-2. Expression of smad6/7-1 was detected in the parenchyma, while smad6/7-2 was found to be ex-pressed in the central nervous system and the eyes. Neither single smad6/7-1 and smad6/7-2 nor double smad6/7-1,-2 silencing gave rise to any apparent disruption of the DV axis. However, both regenerating and intact smad6/7-2 (RNAi) planarians showed defects in eye morphogenesis and displayed small, rounded eyes that lacked the anterior subpopulation of photoreceptor cells. The number of pigment cells was also reduced in these animals at later stages of regeneration. In contrast, after low doses of Smed-bmp(RNAi), planarians regenerated larger eyes in which the anterior subpopulation of photoreceptor cells was expanded. Our results suggest that Smed-smad6/7-2 and Smed-bmp control the re-specification and maintenance of anterior photoreceptor cell number in S. mediterranea.

Analysis of anteroposterior (AP) axis specification in regenerating planarian flatworms has shown that Wnt/β-catenin signaling is required for posterior specification and that the FGF-like receptor molecule nou-darake (ndk) may be involved in restricting brain regeneration to anterior regions. The relationship between re-establishment of AP identity and correct morphogenesis of the brain is, however, still poorly understood. Here we report the characterization of two axin paralogs in the planarian Schmidtea mediterranea. Although Axins are well known negative regulators of Wnt/β-catenin signaling, no role in AP specification has previously been reported for axin genes in planarians. We show that silencing of Smed-axin genes by RNA interference (RNAi) results in two-tailed planarians, a phenotype previously reported after silencing of Smed-APC-1, another β-catenin inhibitor. More strikingly, we show for the first time that while early brain formation at anterior wounds remains unaffected, subsequent development of the brain is blocked in the two-tailed planarians generated after silencing of Smed-axin genes and Smed-APC-1. These findings suggest that the mechanisms underlying early brain formation can be uncoupled from the specification of AP identity by the Wnt/β-catenin pathway. Finally, the posterior expansion of the brain observed following Smed-ndk RNAi is enhanced by silencing Smed-APC-1, revealing an indirect relationship between the FGFR/Ndk and Wnt/β-catenin signaling systems in establishing the posterior limits of brain differentiation., (Copyright © 2011 Elsevier Inc. All rights reserved.)