Incidence and outcomes of fever of unknown origin after kidney transplant in the modern era.

BACKGROUND: While presumably less common with modern molecular diagnostic and imaging techniques, fever of unknown origin (FUO) remains a challenge in kidney transplant recipients (KTRs). Additionally, the impact of FUO on patient and graft survival is poorly described. METHODS: A cohort of adult KTRs between January 1, 1995 and December 31, 2018 was followed at the University of Wisconsin Hospital. Patients transplanted from January 1, 1995 to December 31, 2005 were included in the "early era"; patients transplanted from January 1, 2006 to December 31, 2018 were included in the "modern era". The primary objective was to describe the epidemiology and etiology of FUO diagnoses over time. Secondary outcomes included rejection, graft and patient survival. RESULTS: There were 5590 kidney transplants at our center during the study window. FUO was identified in 323 patients with an overall incidence rate of .8/100 person-years. Considering only the first 3 years after transplant, the incidence of FUO was significantly lower in the modern era than in the early era, with an Incidence Rate Ratio (IRR) per 100 person-years of .48; 95% CI: .35-.63; p < .001. A total of 102 (31.9%) of 323 patients had an etiology determined within 90 days after FUO diagnosis: 100 were infectious, and two were malignancies. In the modern era, FUO remained significantly associated with rejection (HR = 44.1; 95% CI: 16.6-102; p < .001) but not graft failure (HR = 1.21; 95% CI: .68-2.18; p = .52) total graft loss (HR = 1.17; 95% CI: .85-1.62; p = .34), or death (HR = 1.17; 95% CI: .79-1.76; p = .43. CONCLUSIONS: FUO is less common in KTRs during the modern era. Our study suggests infection remains the most common etiology. FUO remains associated with significant increases in risk of rejection, warranting further inquiry into the management of immunosuppressive medications in SOT recipients in the setting of FUO.

Radiographic and CT features of metallosis in a lame dog after total hip replacement: the cloud sign.

A 2-year-old female American Akita was referred for CT of the pelvis and hindlimbs due to a left hindlimb lameness after a left total hip replacement. Referral radiographs and CT images demonstrated amorphous soft-tissue and mineral opacities surrounding the proximal femur and the prosthetic stem, consistent with the "cloud sign" reported as a characteristic of metallosis in humans. Dorsomedial displacement of the prosthetic head, multiple foci of geographic osteolysis alongside the "cloud sign", presumed pseudotumor lesions, and medial iliac lymphadenopathy were also identified with CT. Metallosis was confirmed based on ultrasound-guided cytology, revision surgery, and histopathology.

Reorganization of thalamocortical connections in congenitally blind humans.

Cross-modal plasticity in blind individuals has been reported over the past decades showing that nonvisual information is carried and processed by "visual" brain structures. However, despite multiple efforts, the structural underpinnings of cross-modal plasticity in congenitally blind individuals remain unclear. We mapped thalamocortical connectivity and assessed the integrity of white matter of 10 congenitally blind individuals and 10 sighted controls. We hypothesized an aberrant thalamocortical pattern of connectivity taking place in the absence of visual stimuli from birth as a potential mechanism of cross-modal plasticity. In addition to the impaired microstructure of visual white matter bundles, we observed structural connectivity changes between the thalamus and occipital and temporal cortices. Specifically, the thalamic territory dedicated to connections with the occipital cortex was smaller and displayed weaker connectivity in congenitally blind individuals, whereas those connecting with the temporal cortex showed greater volume and increased connectivity. The abnormal pattern of thalamocortical connectivity included the lateral and medial geniculate nuclei and the pulvinar nucleus. For the first time in humans, a remapping of structural thalamocortical connections involving both unimodal and multimodal thalamic nuclei has been demonstrated, shedding light on the possible mechanisms of cross-modal plasticity in humans. The present findings may help understand the functional adaptations commonly observed in congenitally blind individuals.

Regeneration in starved planarians depends on TRiC/CCT subunits modulating the unfolded protein response.

Planarians are able to stand long periods of starvation by maintaining adult stem cell pools and regenerative capacity. The molecular pathways that are needed for the maintenance of regeneration during starvation are not known. Here, we show that down-regulation of chaperonin TRiC/CCT subunits abrogates the regeneration capacity of planarians during starvation, but TRiC/CCT subunits are dispensable for regeneration in fed planarians. Under starvation, they are required to maintain mitotic fidelity and for blastema formation. We show that TRiC subunits modulate the unfolded protein response (UPR) and are required to maintain ATP levels in starved planarians. Regenerative defects in starved CCT-depleted planarians can be rescued by either chemical induction of mild endoplasmic reticulum stress, which leads to induction of the UPR, or by the supplementation of fatty acids. Together, these results indicate that CCT-dependent UPR induction promotes regeneration of planarians under food restriction.

Tnfaip2/exoc3-driven lipid metabolism is essential for stem cell differentiation and organ homeostasis.

Lipid metabolism influences stem cell maintenance and differentiation but genetic factors that control these processes remain to be delineated. Here, we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout impairs differentiation of embryonic stem cells (ESCs), and knockdown of the planarian para-ortholog, Smed-exoc3, abrogates in vivo tissue homeostasis and regeneration-processes that are driven by somatic stem cells. When stimulated to differentiate, Tnfaip2-deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of vimentin (Vim)-a known inducer of LD formation. Smed-exoc3 depletion also causes a strong reduction of TAGs in planarians. The study shows that Tnfaip2 acts epistatically with and upstream of Vim in impairing cellular reprogramming. Supplementing palmitic acid (PA) and palmitoyl-L-carnitine (the mobilized form of PA) restores the differentiation capacity of Tnfaip2-deficient ESCs and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel role of Tnfaip2 and exoc3 in controlling lipid metabolism, which is essential for ESC differentiation and planarian organ maintenance.

It is not all about regeneration: Planarians striking power to stand starvation.

All living forms, prokaryotes as eukaryotes, have some means of adaptation to food scarcity, which extends the survival chances under extreme environmental conditions. Nowadays we know that dietary interventions, including fasting, extends lifespan of many organisms and can also protect against age-related diseases including in humans. Therefore, the capacity of adapting to periods of food scarcity may have evolved billions of years ago not only to allow immediate organismal survival but also to be able to extend organismal lifespan or at least to lead to a healthier remaining lifespan. Planarians have been the center of attention since more than two centuries because of their astonishing power of full body regeneration that relies on a large amount of adult stem cells or neoblasts. However, they also present an often-overlooked characteristic. They are able to stand long time starvation. Planarians have adapted to periods of fasting by shrinking or degrowing. Here we will review the published data about starvation in planarians and conclude with the possibility of starvation being one of the processes that rejuvenate the planarian, thus explaining the historical notion of non-ageing planarians.

Safety of Antithymocyte Globulin in Patients Undergoing Liver Transplantation With Livers From Donation After Circulatory Death Donors.

Background: Studies suggest that rabbit-antithymocyte globulin (rATG) decreases biliary complications (BCs) after donation-after-circulatory-death-donor liver transplantation (DCD LTx), but safety data are lacking. Objective: Our aim was to assess the safety of rATG for this indication. The secondary end point was efficacy of rATG for this indication. Methods: Adult recipients of DCD LTx were divided into 2 cohorts: protocolized use of rATG in the modern era (July 1, 2013, to December 31, 2016) and a historical control without rATG (January 1, 2005, to June 30, 2013). Incidence of infection, leukopenia, and thrombocytopenia were compared for the safety assessment, incidence of BCs, ischemic cholangiopathy (IC), and transplant outcomes for the efficacy assessment. Results: A total of 83 patients met inclusion criteria: 42 in the historical cohort and 41 in the modern cohort. The modern cohort had significantly fewer bacterial infections at 3 months (historical 54.8% vs modern 23%; P = 0.004) and 1 year (historical 62.1% vs modern 34.2%, P = 0.004). The modern cohort also had fewer fungal infections at these time points (historical 33.3% and 47.9% vs modern 15% and 15%; P = 0.001). There were no significant differences in platelet or white blood cell reduction between groups. There was a nonsignificant, but numerical, trend toward reduced IC/BC in the modern cohort at 1 year (IC: historical 30.1% vs modern 13.2%, P = 0.08; BC: historical 51% vs modern 37.5%, P = 0.13). There was no difference in graft/patient survival. Conclusion and Relevance: Our data suggest no major safety issues with rATG in DCD LTx. Our study should ease clinical apprehension surrounding rATG use for this indication. Future prospective studies are needed to further evaluate the role of rATG and its impact on efficacy end points.

PBX/extradenticle is required to re-establish axial structures and polarity during planarian regeneration.

Recent advances in a number of systems suggest many genes involved in orchestrating regeneration are redeployed from similar processes in development, with others being novel to the regeneration process in particular lineages. Of particular importance will be understanding the architecture of regenerative genetic regulatory networks and whether they are conserved across broad phylogenetic distances. Here, we describe the role of the conserved TALE class protein PBX/Extradenticle in planarians, a representative member of the Lophotrocozoa. PBX/Extradenticle proteins play central roles in both embryonic and post-embryonic developmental patterning in both vertebrates and insects, and we demonstrate a broad requirement during planarian regeneration. We observe that Smed-pbx has pleiotropic functions during regeneration, with a primary role in patterning the anterior-posterior (AP) axis and AP polarity. Smed-pbx is required for expression of polarity determinants notum and wnt1 and for correct patterning of the structures polarized along the AP axis, such as the brain, pharynx and gut. Overall, our data suggest that Smed-pbx functions as a central integrator of positional information to drive patterning of regeneration along the body axis.

SMG-1 and mTORC1 act antagonistically to regulate response to injury and growth in planarians.

Planarian flatworms are able to both regenerate their whole bodies and continuously adapt their size to nutrient status. Tight control of stem cell proliferation and differentiation during these processes is the key feature of planarian biology. Here we show that the planarian homolog of the phosphoinositide 3-kinase-related kinase (PIKK) family member SMG-1 and mTOR complex 1 components are required for this tight control. Loss of smg-1 results in a hyper-responsiveness to injury and growth and the formation of regenerative blastemas that remain undifferentiated and that lead to lethal ectopic outgrowths. Invasive stem cell hyper-proliferation, hyperplasia, hypertrophy, and differentiation defects are hallmarks of this uncontrolled growth. These data imply a previously unappreciated and novel physiological function for this PIKK family member. In contrast we found that planarian members of the mTOR complex 1, tor and raptor, are required for the initial response to injury and blastema formation. Double smg-1 RNAi experiments with tor or raptor show that abnormal growth requires mTOR signalling. We also found that the macrolide rapamycin, a natural compound inhibitor of mTORC1, is able to increase the survival rate of smg-1 RNAi animals by decreasing cell proliferation. Our findings support a model where Smg-1 acts as a novel regulator of both the response to injury and growth control mechanisms. Our data suggest the possibility that this may be by suppressing mTOR signalling. Characterisation of both the planarian mTORC1 signalling components and another PIKK family member as key regulators of regeneration and growth will influence future work on regeneration, growth control, and the development of anti-cancer therapies that target mTOR signalling.

Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms.

In most sexually reproducing animals, replication and maintenance of telomeres occurs in the germ line and during early development in embryogenesis through the use of telomerase. Somatic cells generally do not maintain telomere sequences, and these cells become senescent in adults as telomeres shorten to a critical length. Some animals reproduce clonally and must therefore require adult somatic mechanisms for maintaining their chromosome ends. Here we study the telomere biology of planarian flatworms with apparently limitless regenerative capacity fueled by a population of highly proliferative adult stem cells. We show that somatic telomere maintenance is different in asexual and sexual animals. Asexual animals maintain telomere length somatically during reproduction by fission or when regeneration is induced by amputation, whereas sexual animals only achieve telomere elongation through sexual reproduction. We demonstrate that this difference is reflected in the expression and alternate splicing of the protein subunit of the telomerase enzyme. Asexual adult planarian stem cells appear to maintain telomere length over evolutionary timescales without passage through a germ-line stage. The adaptations we observe demonstrate indefinite somatic telomerase activity in proliferating stem cells during regeneration or reproduction by fission, and establish planarians as a pertinent model for studying telomere structure, function, and maintenance.

Functional synthetic Antennapedia genes and the dual roles of YPWM motif and linker size in transcriptional activation and repression.

Segmental identity along the anteroposterior axis of bilateral animals is specified by Hox genes. These genes encode transcription factors, harboring the conserved homeodomain and, generally, a YPWM motif, which binds Hox cofactors and increases Hox transcriptional specificity in vivo. Here we derive synthetic Drosophila Antennapedia genes, consisting only of the YPWM motif and homeodomain, and investigate their functional role throughout development. Synthetic peptides and full-length Antennapedia proteins cause head-to-thorax transformations in the embryo, as well as antenna-to-tarsus and eye-to-wing transformations in the adult, thus converting the entire head to a mesothorax. This conversion is achieved by repression of genes required for head and antennal development and ectopic activation of genes promoting thoracic and tarsal fates, respectively. Synthetic Antennapedia peptides bind DNA specifically and interact with Extradenticle and Bric-à-brac interacting protein 2 cofactors in vitro and ex vivo. Substitution of the YPWM motif by alanines abolishes Antennapedia homeotic function, whereas substitution of YPWM by the WRPW repressor motif, which binds the transcriptional corepressor Groucho, allows all proteins to act as repressors only. Finally, naturally occurring variations in the size of the linker between the homeodomain and YPWM motif enhance Antennapedia repressive or activating efficiency, emphasizing the importance of linker size, rather than sequence, for specificity. Our results clearly show that synthetic Antennapedia genes are functional in vivo and therefore provide powerful tools for synthetic biology. Moreover, the YPWM motif is necessary--whereas the entire N terminus of the protein is dispensable--for Antennapedia homeotic function, indicating its dual role in transcriptional activation and repression by recruiting either coactivators or corepressors.

The planarian regeneration transcriptome reveals a shared but temporally shifted regulatory program between opposing head and tail scenarios.

BACKGROUND: Planarians can regenerate entire animals from a small fragment of the body. The regenerating fragment is able to create new tissues and remodel existing tissues to form a complete animal. Thus different fragments with very different starting components eventually converge on the same solution. In this study, we performed an extensive RNA-seq time-course on regenerating head and tail fragments to observe the differences and similarities of the transcriptional landscape between head and tail fragments during regeneration. RESULTS: We have consolidated existing transcriptomic data for S. mediterranea to generate a high confidence set of transcripts for use in genome wide expression studies. We performed a RNA-seq time-course on regenerating head and tail fragments from 0 hours to 3 days. We found that the transcriptome profiles of head and tail regeneration were very different at the start of regeneration; however, an unexpected convergence of transcriptional profiles occurred at 48 hours when head and tail fragments are still morphologically distinct. By comparing differentially expressed transcripts at various time-points, we revealed that this divergence/convergence pattern is caused by a shared regulatory program that runs early in heads and later in tails.Additionally, we also performed RNA-seq on smed-prep(RNAi) tail fragments which ultimately fail to regenerate anterior structures. We find the gene regulation program in response to smed-prep(RNAi) to display the opposite regulatory trend compared to the previously mentioned share regulatory program during regeneration. Using annotation data and comparative approaches, we also identified a set of approximately 4,800 triclad specific transcripts that were enriched amongst the genes displaying differential expression during the regeneration time-course. CONCLUSION: The regeneration transcriptome of head and tail regeneration provides us with a rich resource for investigating the global expression changes that occurs during regeneration. We show that very different regenerative scenarios utilize a shared core regenerative program. Furthermore, our consolidated transcriptome and annotations allowed us to identity triclad specific transcripts that are enriched within this core regulatory program. Our data support the hypothesis that both conserved aspects of animal developmental programs and recent evolutionarily innovations work in concert to control regeneration.

The TALE class homeobox gene Smed-prep defines the anterior compartment for head regeneration.

Planaria continue to blossom as a model system for understanding all aspects of regeneration. They provide an opportunity to understand how the replacement of missing tissues from preexisting adult tissue is orchestrated at the molecular level. When amputated along any plane, planaria are capable of regenerating all missing tissue and rescaling all structures to the new size of the animal. Recently, rapid progress has been made in understanding the developmental pathways that control planarian regeneration. In particular Wnt/beta-catenin signaling is central in promoting posterior fates and inhibiting anterior identity. Currently the mechanisms that actively promote anterior identity remain unknown. Here, Smed-prep, encoding a TALE class homeodomain, is described as the first gene necessary for correct anterior fate and patterning during planarian regeneration. Smed-prep is expressed at high levels in the anterior portion of whole animals, and Smed-prep(RNAi) leads to loss of the whole brain during anterior regeneration, but not during lateral regeneration or homeostasis in intact worms. Expression of markers of different anterior fated cells are greatly reduced or lost in Smed-prep(RNAi) animals. We find that the ectopic anterior structures induced by abrogation of Wnt signaling also require Smed-prep to form. We use double knockdown experiments with the S. mediterranea ortholog of nou-darake (that when knocked down induces ectopic brain formation) to show that Smed-prep defines an anterior fated compartment within which stem cells are permitted to assume brain fate, but is not required directly for this differentiation process. Smed-prep is the first gene clearly implicated as being necessary for promoting anterior fate and the first homeobox gene implicated in establishing positional identity during regeneration. Together our results suggest that Smed-prep is required in stem cell progeny as they form the anterior regenerative blastema and is required for specifying anterior cell fates and correct patterning.

[Asociación de exposición a humo de camiones en adolescentes con asma de un centro de referencia del noreste de México].

Objective: To compare whether adolescents who are exposed to truck smoke have a higher prevalence of asthma symptomatology versus those who are not exposed. Methods: A cross-sectional, descriptive, and comparative study. Adolescents aged 13 and 14 years were included and completed a self-report questionnaire. Subjects were selected following the same methodology as in ISAAC phase III. They underwent an epidemiological survey for the presence of symptoms. Ex- posure to truck smoke was defined as passing trucks most of the day as perceived by the patient. The distribution was assessed with the Kolmogorov-Smirnov test. Comparisons with Chi-square or Student's t-test, as appropriate. A value of p³0.05 was considered statistically significant. Results: A total of 492 patients were included. The demographic variables can be seen in Table 1. When performing the association between the groups of ad- olescents with asthma exposed to truck smoke, a significant difference was found in the prevalence of respiratory symptomatology and asthma (26.0% vs 9.6%, p=0.000) (Table 1). Conclusions: Adolescent patients with asthma who are exposed to truck smoke demonstrated a significant difference in the presence of respiratory symptom- atology and asthma compared to patients without exposure.

Objetivo: Comparar si los adolescentes que están expuestos a humo de camiones tienen mayor prevalencia de sintomatología de asma contra quienes no están expuestos. Métodos: Estudio transversal, descriptivo y comparativo. Se incluyeron adolescentes de 13 y 14 años de edad quienes completaron un cuestionario autoinfor- mado. Los sujetos se seleccionaron siguiendo la misma metodología que en la fase III de ISAAC. Se les realizó una encuesta epidemiológica para la presencia de síntomas. Exposición al humo de camiones se definió como el paso de camiones la mayoría del día a percepción del paciente. La distribución fue evaluada con la prueba de Kolmogórov-Smirnov. Comparaciones con prueba de Chi-cuadrada o T de Student, según corresponda. Un valor de p £ 0.05 fue considerado estadísticamente significativo. Resultados: Se incluyeron un total de 492 pacientes. Las variables demográficas se pueden observar en la Tabla 1. Al realizar la asociación entre los grupos de adolescentes con asma que se encuentran expuestos a humo de camiones se encontró una diferencia significativa en la prevalencia de sintomatología respira- toria y asma (26.0% vs 9.6%, p = 0.000). Conclusiones: Los pacientes adolescentes con asma que se encuentran expuestos al humo de camiones demostraron tener diferencia significativa en la presencia de sintomatología respiratoria y asma en comparación con los pacientes sin exposición.

Molecular Surveillance of Canine Degenerative Myelopathy in Breeding Kennels from Romania.

Canine degenerative myelopathy (CDM) is a spontaneous neurodegenerative disease. Genetically, CDM is an autosomal recessive disease with incomplete penetrance, most commonly caused by a genetic mutation in exon 2 of gene SOD1 (c.118G > A). This study aimed to determine the mutant allele frequency associated with CDM in various dog breeds from Romania. Dogs (n = 230) from 26 breeds were included in the study. Genotyping using the PCR-RFLP technique was performed on DNA extracted from oral swabs. The results revealed that 204 dogs were homozygous for the wild-type allele (G/G), 16 were heterozygous (A/G), and 10 were homozygous for the mutant allele (A/A). The mutant allele was identified in Wire Fox Terrier, Romanian Mioritic Shepherd, German Shepherd, Rottweiler, Belgian Shepherd, and Czechoslovakian Wolfdog breeds. The mutant allele frequency (A) within the tested population was 0.0783. The results for Belgian Shepherd, German Shepherd, and Romanian Mioritic Shepherd were in Hardy-Weinberg equilibrium, but a departure was observed for Rottweiler. The current study included a first screening of the Romanian Bucovina Shepherd, Romanian Mioritic Shepherd, and Caucasian Shepherd breeds. Genetic testing for the mutation associated with CDM is important in order to avoid the risk of the emergence of dogs homozygous for the SOD1:c118G > A allele.

A Rare Case of Empagliflozin-Induced Euglycemic Diabetic Ketoacidosis Obscured by Alkalosis.

Empagliflozin-induced euglycemic diabetic ketoacidosis is a life-threatening metabolic complication of diabetes mellitus characterized by metabolic acidosis, ketonemia, and relatively normal serum glucose levels. We present a rare case of empagliflozin-induced diabetic ketoacidosis obscured by alkalosis. This case report aims to create awareness among clinicians about this entity and consider this diagnosis in their differential, especially in patients taking sodium-glucose co-transporter (SGLT-2) inhibitors who present to the hospital with unspecific symptoms that may not suggest DKA.

Emphysematous Pyelonephritis Complicated With Hyperglycemic Hyperosmolar State and Sepsis: A Case Report and Literature Review.

Emphysematous pyelonephritis (EPN) is an acute life-threatening necrotizing infection of the renal parenchyma and perirenal tissues. There are multiple treatment strategies for EPN depending on the initial classification; over the last three decades, the treatment approach has favored kidney sparing strategies and the use of nephrectomy only as salvage therapy. We report a case involving a patient with unilateral emphysematous pyelonephritis complicated with hyperglycemic hyperosmolar state (HHS), sepsis, and multiple risk factors associated with poor prognosis who was successfully treated with conservative management sparing nephrectomy. This case report aims to create awareness among clinicians that even in the presence of multiple risk factors for poor prognosis, conservative management should be considered before nephrectomy.

Immune response in COVID-19: what is next?

The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.

Quantification of Reducing Sugars Based on the Qualitative Technique of Benedict.

Determination of reducing sugars is carried out routinely in the food industry, in biological research, or pharmaceutical and biomedical quality control to estimate metabolically assimilable sugars. Widespread detection methods are complex, expensive, or highly polluting. Here, we propose the use of spectrophotometric quantification for reducing sugars (Benedictq) based on the qualitative method of Benedict. The protocol was validated, to verify its reproducibility and precision. With the proposed method (Benedictq), the reducing sugar glucose can be determined in a range of 0.167-10 mg mL-1, with an R 2 of 0.997 and accuracy (expressed as % of recovery) greater than 97%. Other reducing sugars, such as maltose, fructose, and lactose, showed similar values. The method robustness was verified for pH values greater than or equal to 4. In the case of protein presence, a correction is proposed in the range of 0-1.67 mg mL-1. Modifications implemented in the protocol reduce cost, working time, and reaction volumes with respect to the original assay without detriments in accuracy and precision. In addition, waste reduction represents an important contribution of the method.

Downregulation of mTOR Signaling Increases Stem Cell Population Telomere Length during Starvation of Immortal Planarians.

Reduction of caloric intake delays and prevents age-associated diseases and extends the life span in many organisms. It may be that these benefits are due to positive effects of caloric restriction on stem cell function. We use the planarian model Schmidtea mediterranea, an immortal animal that adapts to long periods of starvation by shrinking in size, to investigate the effects of starvation on telomere length. We show that the longest telomeres are a general signature of planarian adult stem cells. We also observe that starvation leads to an enrichment of stem cells with the longest telomeres and that this enrichment is dependent on mTOR signaling. We propose that one important effect of starvation for the rejuvenation of the adult stem cell pool is through increasing the median telomere length in somatic stem cells. Such a mechanism has broad implications for how dietary effects on aging are mediated at the whole-organism level.