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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons resulting in a progressive and irreversible muscular paralysis. Advances in large-scale genetics and genomics have revealed intronic hexanucleotide repeat expansions in the gene encoding C9ORF72 as a main genetic cause of ALS and frontotemporal dementia (FTD), the second most common cause of early-onset dementia after Alzheimer's disease. Novel insights regarding the underlying pathogenic mechanisms of C9ORF72 seem to suggest a synergy of loss and gain of toxic function during disease. C9ORF72, thus far, has been found to be involved in homeostatic cellular pathways, such as actin dynamics, regulation of membrane trafficking, and macroautophagy. All these pathways have been found compromised in the pathogenesis of ALS. In this review, we aim to summarize recent findings on the function of C9ORF72, particularly in the macroautophagy pathway, hinting at a requirement to maintain the fine balance of macroautophagy to prevent neurodegeneration.

Gastric cancer, a prevalent and fatal form of cancer worldwide, is manifested at different age ranges during the lifespan. Approximately one-third of newly diagnosed gastric cancer cases are early-onset gastric cancer (EO-GC), which affects individuals under the age of 50 years. EO-GC tends to be more aggressive than late-onset gastric cancer (L-GC), with a faster and multifocal disease progression. Furthermore, EO-GC is associated with early metastatic disease. Recent research has underscored the need for a deeper understanding of EO-GC that promotes therapeutic approaches specific to EO-GC. The present study determined the main transcriptomic differences between EO-GC and L-GC. Transcriptomic expression data from The Cancer Genome Atlas-Stomach Adenocarcinoma were explored to elucidate whether age is associated with a specific genomic expression pattern and is associated with gastric cancer. Subsequently, a differential gene expression analysis of the EO-GC vs. L-GC groups was performed, providing new insights into EO-GC gene expression characteristics and their association with survival outcomes. Furthermore, the study focused on whether the influence of representative gene expression in EO-GC cases (KLHL4, MAGEL2, CYP8B1, RNLS, CLDN6, MIOX, PNMA5 and ACTL8 genes) may be associated with its aggressive phenotype and methylation profiles of these patients. In this review, the necessity of incorporating age as a crucial element in understanding the disparities in outcomes for EO-GC cases in public datasets was discussed. Furthermore, this insight may be useful for targeted early personalized clinical interventions to improve patient prognosis and survival rates in EO-GC cases.

Amyotrophic lateral sclerosis (ALS) is a disabling and fatal neurological disease, which is characterized by the loss of motor neuron function in the brain and spinal cord. Due to genetic complexity, ALS disease is not well understood. By applying a bioinformatic approach, referred to as convergent analysis, we identified the poorly characterized protein FAM120A as a new candidate gene related to RNA metabolism, a process known to be affected during ALS disease. We studied Fam120A in the context of ALS in vivo and in vitro using an ALS mouse model and a cellular model. We found that Fam120A mRNA levels were decreased in the pre-symptomatic stage in the spinal cord of SOD1 G93A mice, while Fam120A protein levels were decreased at the symptomatic stage. Fam120A was expressed mainly in neurons in the spinal cord. Overexpression of FAM120A in a motor neuron cell culture model decreased the levels of SOD1 G93A aggregates. In summary, our results warrant further studies of FAM120A in the context of ALS, since it appears to be involved in disease progression and might have a role in proteostasis maintenance.

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.

Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal paralytic disorder associated with motor neuron death. Mutant superoxide dismutase 1 (SOD1) misfolding and aggregation have been linked to familial ALS, with the accumulation of abnormal wild-type SOD1 species being also observed in postmortem tissue of sporadic ALS cases. Both wild-type and mutated SOD1 are reported to contribute to motoneuron cell death. The autophagic pathway has been shown to be dysregulated in ALS. Recent evidence suggests a dual time-dependent role of autophagy in the progression of the disease. PACER, also called RUBCNL (Rubicon-like), is an enhancer of autophagy and has been found diminished in its levels during ALS pathology in mice and humans. Pacer loss of function disturbs the autophagy process and leads to the accumulation of SOD1 aggregates, as well as sensitizes neurons to death. Therefore, here we investigated if constitutive overexpression of PACER in neurons since early development is beneficial in an in vivo model of ALS. We generated a transgenic mouse model overexpressing human PACER in neurons, which then was crossbred with the mutant SOD1 G93A ALS mouse model. Unexpectedly, PACER/SOD1 G93A double transgenic mice exhibited an earlier disease onset and shorter lifespan than did littermate SOD1 G93A mice. The overexpression of PACER in neurons in vivo and in vitro increased the accumulation of SOD1 aggregates, possibly due to impaired autophagy. These results suggest that similar to Pacer loss-of function, Pacer gain-of function is detrimental to autophagy, increases SOD1 aggregation and worsens ALS pathogenesis. In a wider context, our results indicate the requirement to maintain a fine balance of PACER protein levels to sustain proteostasis.

Aging constitutes the main risk factor for the development of neurodegenerative diseases. This represents a major health issue worldwide that is only expected to escalate due to the ever-increasing life expectancy of the population. Interestingly, axonal degeneration, which occurs at early stages of neurodegenerative disorders (ND) such as Alzheimer's disease, Amyotrophic lateral sclerosis, and Parkinson's disease, also takes place as a consequence of normal aging. Moreover, the alteration of several cellular processes such as proteostasis, response to cellular stress and mitochondrial homeostasis, which have been described to occur in the aging brain, can also contribute to axonal pathology. Compelling evidence indicate that the degeneration of axons precedes clinical symptoms in NDs and occurs before cell body loss, constituting an early event in the pathological process and providing a potential therapeutic target to treat neurodegeneration before neuronal cell death. Although, normal aging and the development of neurodegeneration are two processes that are closely linked, the molecular basis of the switch that triggers the transition from healthy aging to neurodegeneration remains unrevealed. In this review we discuss the potential role of axonal degeneration in this transition and provide a detailed overview of the literature and current advances in the molecular understanding of the cellular changes that occur during aging that promote axonal degeneration and then discuss this in the context of ND.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal and challenging gastrointestinal (GI) malignancies. Predominant driver mutations for this cancer include KRAS, which is present in >90% of cases, alongside inactivating mutations in various tumor suppressor genes, such as CDKN2A, TP53 and SMAD4. The present case report explores a case of early onset pancreatic cancer in a 45-year-old patient with cancer antigen 19-9 (CA 19-9) levels within the minimal range, a finding typically associated with advanced disease. Specifically, the tumor exhibited an atypical somatic molecular profile, characterized by mutations in the ERBB2, MSH3, MUC1/MUC16 genes and the absence of KRAS mutations (KRAS wild type), which is an uncommon occurrence in PDAC. The presence of liver metastases and vascular invasion at diagnosis, coupled with the lack of response to standard FOLFIRINOX treatment, underscored the aggressiveness of the disease and highlighted the need to explore novel targeted therapies. The patient underwent surgery and has maintained a favorable response to date. This case of PDAC in a relatively young patient underscored a distinctive molecular profile that especially lacked KRAS mutations whilst featuring alterations in ERBB2, MSH3 and MUC1/MUC16, potentially indicating a unique subgroup with unique biological and treatment responses. Additionally, CA19-9 levels within the minimal range suggest the need to identify alternative novel biomarkers with adequate sensitivity and specificity. This is because in >80% PDAC cases with stage II disease and beyond, CA-19-9 levels are elevated. The rarity of the present case, combined with the rapid progression despite FOLFIRINOX treatment, suggests that additional human epidermal growth factor receptor 2-targeted therapies may be necessary during disease progression.

Mesenchymal stem cells (MSC) have emerged as a promising tool to treat inflammatory diseases, such as inflammatory bowel disease (IBD), due to their immunoregulatory properties. Frequently, IBD is modeled in mice by using dextran sulfate sodium (DSS)-induced colitis. Recently, the modulation of autophagy in MSC has been suggested as a novel strategy to improve MSC-based immunotherapy. Hence, we investigated a possible role of Pacer, a novel autophagy enhancer, in regulating the immunosuppressive function of MSC in the context of DSS-induced colitis. We found that Pacer is upregulated upon stimulation with the pro-inflammatory cytokine TNFα, the main cytokine released in the inflammatory environment of IBD. By modulating Pacer expression in MSC, we found that Pacer plays an important role in regulating the autophagy pathway in this cell type in response to TNFα stimulation, as well as in regulating the immunosuppressive ability of MSC toward T-cell proliferation. Furthermore, increased expression of Pacer in MSC enhanced their ability to ameliorate the symptoms of DSS-induced colitis in mice. Our results support previous findings that autophagy regulates the therapeutic potential of MSC and suggest that the augmentation of autophagic capacity in MSC by increasing Pacer levels may have therapeutic implications for IBD.

Hymenoglossum cruentum (Hymenophyllaceae) is a poikilohydric, homoiochlorophyllous desiccation-tolerant (DT) epiphyte fern. It can undergo fast and frequent dehydration-rehydration cycles. This fern is highly abundant at high-humidity/low-light microenvironments within the canopy, although rapid changes in humidity and light intensity are frequent. The objective of this research is to identify genes associated to desiccation-rehydration cycle in the transcriptome of H. cruentum to better understand the genetic dynamics behind its desiccation tolerance mechanism. H. cruentum plants were subjected to a 7 days long desiccation-rehydration process and then used to identify key expressed genes associated to its capacity to dehydrate and rehydrate. The relative water content (RWC) and maximum quantum efficiency ( F v/ F m) of H. cruentum fronds decayed to 6% and 0.04, respectively, at the end of the desiccation stage. After re-watering, the fern showed a rapid recovery of RWC and F v/ F m (ca. 73% and 0.8, respectively). Based on clustering and network analysis, our results reveal key genes, such as UBA/TS-N , DYNLL , and LHC , orchestrating intracellular motility and photosynthetic metabolism; strong balance between avoiding cell death and defense ( CAT3 , AP2/ERF ) when dehydrated, and detoxifying pathways and stabilization of photosystems ( GST , CAB2 , and ELIP9 ) during rehydration. Here we provide novel insights into the genetic dynamics behind the desiccation tolerance mechanism of H. cruentum .

Herein, we report the biochemical and functional characterization of a novel Ca(2+)-activated nucleoside diphosphatase (apyrase), CApy, of the intracellular gut pathogen Cryptosporidium. The purified recombinant CApy protein displayed activity, substrate specificity and calcium dependency strikingly similar to the previously described human apyrase, SCAN-1 (soluble calcium-activated nucleotidase 1). CApy was found to be expressed in both Cryptosporidium parvum oocysts and sporozoites, and displayed a polar localization in the latter, suggesting a possible co-localization with the apical complex of the parasite. In vitro binding experiments revealed that CApy interacts with the host cell in a dose-dependent fashion, implying the presence of an interacting partner on the surface of the host cell. Antibodies directed against CApy block Cryptosporidium parvum sporozoite invasion of HCT-8 cells, suggesting that CApy may play an active role during the early stages of parasite invasion. Sequence analyses revealed that the capy gene shares a high degree of homology with apyrases identified in other organisms, including parasites, insects and humans. Phylogenetic analysis argues that the capy gene is most likely an ancestral feature that has been lost from most apicomplexan genomes except Cryptosporidium, Neospora and Toxoplasma.