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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation.

Magdalena River surface water and shoreline sediments were sampled for microplastic particles at three locations in the city of Neiva, Colombia: upstream, city center, and downstream of the raw wastewater outflow. The absence of an industrial and manufacturing sector in Neiva provided an opportunity to assess the impact of upstream agricultural practices, as well as municipal activities such as wastewater outflow and laundry washing, on the quantity, polymer composition, and morphology of microplastic particles produced per capita and entering a river system. Microplastic particle concentrations increased with downstream distance, with microfiber concentrations ranging from 0.097 to 0.135 fibers/L in the river water and 25.5 to 102.4 fibers/kg in shoreline sediment. Microplastic fragment concentrations were 0.013–0.028 fragments/L in surface water and 10.4–12.7 fragments/kg of sediment. Raman microscope and scanning electron microscopy identified the relative composition of the polymers comprising the microplastic particles was similar regardless of sampling site or whether the sample was collected from the surface water or shoreline sediments, with polypropylene and polyethylene comprising at least 75% of the total polymers in all samples. Average fiber widths of < 20 µm in all but one sample, along with the lack of acrylic and polyester fibers used predominantly in woven synthetic textiles, indicated that the degradation of nonwoven synthetic textiles is the predominant origin of these microplastic fibers in the Magdalena River.

Mitofusin 2 (Mfn2) is a key protein in mitochondrial fusion and it participates in the bridging of mitochondria to the endoplasmic reticulum (ER). Recent data indicate that Mfn2 ablation leads to ER stress. Here we report on the mechanisms by which Mfn2 modulates cellular responses to ER stress. Induction of ER stress in Mfn2‐deficient cells caused massive ER expansion and excessive activation of all three Unfolded Protein Response (UPR) branches (PERK, XBP‐1, and ATF6). In spite of an enhanced UPR, these cells showed reduced activation of apoptosis and autophagy during ER stress. Silencing of PERK increased the apoptosis of Mfn2‐ablated cells in response to ER stress. XBP‐1 loss‐of‐function ameliorated autophagic activity of these cells upon ER stress. Mfn2 physically interacts with PERK, and Mfn2‐ablated cells showed sustained activation of this protein kinase under basal conditions. Unexpectedly, PERK silencing in these cells reduced ROS production, normalized mitochondrial calcium, and improved mitochondrial morphology. In summary, our data indicate that Mfn2 is an upstream modulator of PERK. Furthermore, Mfn2 loss‐of‐function reveals that PERK is a key regulator of mitochondrial morphology and function. Mitochondrial–ER bridging protein mitofusin 2 (Mfn2) orchestrates mitochondrial metabolism and the UPR by suppressing PERK.

PurposeCancer patient survival rates are rapidly growing, and further data are needed on the impact of the disease beyond diagnosis and treatment phases. The aims of this study were to analyze the prevalence and sociodemographic and medical risk factors of clinical distress. Additionally, we also explore the relationship between unmet psychosocial needs and both clinical distress and subgroups of survival periods.MethodsA cross-sectional study of 450 women who at least 1 month before had completed the primary treatment for breast cancer was conducted. The Brief Symptom Inventory 18 and the Cancer Survivors Unmet Needs measure were used.ResultsOne in four women showed clinical distress related to unmet psychosocial needs. None of the sociodemographic and medical predictors was associated with clinical distress. Needs focused on the possibility of recurrence and its cognitive-emotional impact were the most frequent. Needs tended to decrease through periods of survival; however, there was a considerable level of unmet needs even among long-term survivors.ConclusionsThe findings highlight the relevance of extending psychosocial care beyond the breast cancer primary medical treatment. Early and regular screen for distress and unmet supportive needs permits to identify high-risk groups that likely benefit from targeted preventive interventions.

Key Points Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence bound by a specialized six-protein complex known as shelterin, which has fundamental roles in the protection of chromosomes and the regulation of telomerase activity at chromosome ends. Excessive telomere shortening and severe telomere uncapping trigger a DNA damage response at chromosome ends, which are then recognized as double-strand breaks. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DNA damage response. Studies with mouse models that support a role for these proteins in cancer susceptibility and ageing-related pathologies are discussed in this Review. Telomere dysfunction causes ageing and also constitutes a driving force for cellular transformation by causing genome instability. Molecular mechanisms underlying telomere-induced genomic instability are described. Anti-ageing activity of telomerase has been demonstrated in mice overexpressing TERT genetically engineered to be cancer-resistant by means of enhanced expression of the p53, p16 and ARF tumour suppressors. Telomere-maintenance is the main mechanism underlying the anti-ageing phenotype of TERT-transgenic mice. Telomere-independent functions of TERT have recently been described. Overexpression of TERT is a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity when in a complex with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP). Roles for the shelterin component RAP1 beyond its roles in telomeres have been uncovered. Mammalian RAP1 is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as a essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway. Telomerase and factors that influence its activity are very attractive targets for the treatment of degenerative diseases and cancer. TPP1 is involved in telomerase recruitment to telomeres. Drugs targeting TPP1 could certainly be a novel strategy for blocking the ultimate goal of telomerase, the lengthening of telomeres. Telomeres protect chromosomes from degradation and are therefore essential for ensuring genomic stability. These heterochromatic structures are bound by the shelterin complex, which regulates the activity of telomerase at the ends of chromosomes. This Review analyses the role of these telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as through their 'extracurriculum' activities as gene expression regulators by binding to non-telomeric sites. Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division. Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends. Telomere elongation is carried out by telomerase. Telomerase can also act as a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR. This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites.

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo , we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9. We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo . TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients or immune regulators, and this has an impact on tumorigenesis potential.

Background Spain as multiple other countries has been experiencing an increasing and sustained trend in the use of psychotropic medications since the mid 90s. Recent studies show public health measures implemented to control SARS-Cov2, such as mobility restrictions and the shutdown of nonessential activities increased mental suffering, even contributing to a higher number of anxiety, depression and insomnia disorders that could lead to an increase in the consumption of psychotropics. The aims were: 1) Evaluate the temporal trend in psychotropic consumption by pharmacological subgroup, sex, and age group 2) Estimate the effect of the COVID-19 pandemic in the use of psychotropic drugs. Methods We conducted a retrospective observational study, retrieving all prescriptions of anxiolytics, hypnotics and sedatives, and antidepressants dispensed in pharmacies of Asturias (Northern Spain) for Primary Care patients for the period 2018–2021. We presented the data expressed in Daily Defined Doses (DDDs) for 1000 persons/day (DHD). To estimate changes in DHDs by year and age group we conducted two multiple linear regressions (one for males and one for females) for every pharmacological subgroup studied. Changes were considered statistically significant when the regression coefficient was p  < 0.05. We used the Software R 4.1.0. Results For the studied period, the highest DHDs are for antidepressants, although all of the subgroups experienced an increase in consumption rates. Women consumed more psychotropic drugs than men. In 2021, 372 out of every 1000 women were taking daily 1 DDD of these drugs versus 184 out of every 1000 men. Consumption rates for all psychotropic drugs progressively increases with age. Conversely, the biggest increases in consumption were among the youngest age groups (0–14 and 15–29 years) for women, while for men there is more variability. The regression models suggest an upward trend in psychotropic consumption during all the period, especially remarkable from 2020, for both genders and all age groups. Conclusions - The consumption of psychotropic drugs has gradually increased over the last 4 years, with a significant boost starting in 2020 for both sexes, matching the start of the SARS-COV2 pandemic and the implementation of strict Public Health measures to contain it. - The increase observed on children and adolescents is a matter of concern.

TRF1 is an essential component of the telomeric protective complex or shelterin. We previously showed that dysfunctional telomeres in alveolar type II (ATII) cells lead to interstitial lung fibrosis. Here, we study the lung pathologies upon telomere dysfunction in fibroblasts, club and basal cells. TRF1 deficiency in lung fibroblasts, club and basal cells induced telomeric damage, proliferative defects, cell cycle arrest and apoptosis. While Trf1 deletion in fibroblasts does not spontaneously lead to lung pathologies, upon bleomycin challenge exacerbates lung fibrosis. Unlike in females, Trf1 deletion in club and basal cells from male mice resulted in lung inflammation and airway remodeling. Here, we show that depletion of TRF1 in fibroblasts, Club and basal cells does not lead to interstitial lung fibrosis, underscoring ATII cells as the relevant cell type for the origin of interstitial fibrosis. Our findings contribute to a better understanding of proper telomere protection in lung tissue homeostasis. Telomere dysfunction induced by TRF1 depletion in fibroblasts, club and basal cells did not lead to interstitial lung fibrosis, underscoring alveolar type II cells as the relevant cell type in pulmonary fibrosis.

Tubulointerstitial fibrosis associated with chronic kidney disease (CKD) represents a global health care problem. We previously reported that short and dysfunctional telomeres lead to interstitial renal fibrosis; however, the cell-of-origin of kidney fibrosis associated with telomere dysfunction is currently unknown. We induced telomere dysfunction by deleting the Trf1 gene encoding a telomere-binding factor specifically in renal fibroblasts in both short-term and long-term life-long experiments in mice to identify the role of fibroblasts in renal fibrosis. Short-term Trf1 deletion in renal fibroblasts was not sufficient to trigger kidney fibrosis but was sufficient to induce inflammatory responses, ECM deposition, cell cycle arrest, fibrogenesis, and vascular rarefaction. However, long-term persistent deletion of Trf1 in fibroblasts resulted in kidney fibrosis accompanied by an elevated urinary albumin-to-creatinine ratio (uACR) and a decrease in mouse survival. These cellular responses lead to the macrophage-to-myofibroblast transition (MMT), endothelial-to-mesenchymal transition (EndMT), and partial epithelial-to-mesenchymal transition (EMT), ultimately causing kidney fibrosis at the humane endpoint (HEP) when the deletion of Trf1 in fibroblasts is maintained throughout the lifespan of mice. Our findings contribute to a better understanding of the role of dysfunctional telomeres in the onset of the profibrotic alterations that lead to kidney fibrosis. Fibroblast telomere dysfunction: key driver of kidney fibrosis Chronic kidney disease, a condition that can lead to kidney failure and death, affects millions worldwide. It’s characterized by kidney fibrosis, a process where healthy kidney tissue becomes scar tissue. The exact cells that start this process were unknown. Researchers studied the role of a protein called TRF1, which protects the ends of chromosomes, in kidney fibroblasts, cells that make connective tissue. They removed TRF1 from these cells in mice and observed the effects. Results showed that removing TRF1 from fibroblasts increased fibrosis, inflammation, and kidney damage. Specifically, fibroblasts without TRF1 were more likely to change into myofibroblasts, leading to more scar tissue. Study concluded that TRF1 is vital in preventing kidney fibrosis by keeping fibroblasts healthy. This finding improves our understanding of CKD and suggests potential treatments targeting fibroblasts and TRF1 to fight kidney fibrosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Normal aging involves changes in the ability to acquire, consolidate and recall new information. It has been recently proposed that the reconsolidation process is also affected in older adults. Reconsolidation is triggered after reminder presentation, allowing memories to be modified: they can be impaired, strengthened or changed in their content. In young adults it was previously shown that the presentation of repetitive reminders induces memory strengthening one day after reactivation and the presentation of at least one reminder increases memory persistence several days after reactivation. However, until now this process has remained elusive in older adults. We hypothesize that older adults need a stronger reminder to induce memory strengthening through the reconsolidation process than young adults. To test this, we perform a three-day experiment. On day 1, participants learned 15 sound-word associations, on day 2 they received no reminders (NR group), one reminder (R group) or two rounds of reactivations (Rx2 group). Finally, they were tested on day 7. We found that, contrary to our hypothesis, older adults show a memory improvement triggered by repeated labilization/reconsolidation processes to an equal extent than young adults. These results open new perspectives into the use of reconsolidation to improve daily acquired information and the development of therapeutic home used tools to produce memory enhancement in healthy older adults or those with cognitive decline.