This work reports the simple and inexpensive fabrication of homemade paper-based carbon-printed electrodes (HP C-PEs), aiming to produce an alternative way to generate electrochemical biosensors to ...all and promoting their wide use. This is especially important in times of pandemics, considering the excellent features of electrochemical biosensing, which may ensure portability, low-cost and quick responses.
HP C-PEs were fabricated using a standard cellulose filter paper that was first modified with wax, to make it hydrophobic. Then, the electrodes were manually printed on top of this cellulose/wax substrate. The electrodes were designed by having standard configurations for potentiometric and electrochemical readings, combining two or three electrodes. In general, both electrode systems showed excellent electrochemical and mechanical features, which were better in specific cases than commercial devices. The 3-electrode system displayed high current levels with low peak-to-peak potential separation, yielding highly stable signals after consecutive electrode bending that corresponded to high active areas. The possibility of modifying the devices with polymers produced in-situ was also explored and proven successful, providing also advantageous features when compared to other devices. The 2-electrode system was also proven highly stable and capable of subsequent use in potentiometric sensing development.
Overall, the fabrication process of the 2- and 3-electode systems described herein may be employed in laboratories to produce successful electrochemical biosensors, with the final devices displaying excellent electrochemical and mechanical features. This procedure offers the advantages of being simple and inexpensive, when compared to other commercial devices, while using materials that are promptly available and that may undergo a worldwide use.
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•Homemade carbon-printed electrodes on inexpensive paper substrate fabricated with a simple, easy and cost-effective way.•Fabricated electrodes have special mechanical properties such as rigidity and flexibility.•Excellent electrochemical characteristics and mechanical features, better in specific cases than commercial devices.•Performance of electropolymerization thoroughly studied using various electroactive monomers.•Successful pseudo-reference characteristics of the reference electrode in the two-electrode system.
Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which ...preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer.
Dog training methods range broadly from those using mostly positive punishment and negative reinforcement (aversive-based) to those using primarily positive reinforcement (reward-based). Although ...aversive-based training has been strongly criticized for negatively affecting dog welfare, there is no comprehensive research focusing on companion dogs and mainstream techniques, and most studies rely on owner-reported assessment of training methods and dog behavior. The aim of the present study was to evaluate the effects of aversive- and reward-based training methods on companion dog welfare within and outside the training context. Ninety-two companion dogs were recruited from three reward-based schools (Group Reward, n = 42), and from four aversive-based schools, two using low proportions of aversive-based methods (Group Mixed, n = 22) and two using high proportions of aversive-based methods (Group Aversive, n = 28). For evaluating welfare during training, dogs were video recorded for three sessions and six saliva samples were collected, three at home (baseline levels) and three after training (post-training levels). Video recordings were used to examine the frequency of stress-related behaviors (e.g., lip lick, yawn) and the overall behavioral state of the dog (e.g., tense, relaxed), and saliva samples were analyzed for cortisol concentration. For evaluating welfare outside the training context, dogs participated in a cognitive bias task. Results showed that dogs from Group Aversive displayed more stress-related behaviors, were more frequently in tense and low behavioral states and panted more during training, and exhibited higher post-training increases in cortisol levels than dogs from Group Reward. Additionally, dogs from Group Aversive were more 'pessimistic' in the cognitive bias task than dogs from Group Reward. Dogs from Group Mixed displayed more stress-related behaviors, were more frequently in tense states and panted more during training than dogs from Group Reward. Finally, although Groups Mixed and Aversive did not differ in their performance in the cognitive bias task nor in cortisol levels, the former displayed more stress-related behaviors and was more frequently in tense and low behavioral states. These findings indicate that aversive-based training methods, especially if used in high proportions, compromise the welfare of companion dogs both within and outside the training context.
Sonia Fizek's Playing at Distance: Borderlands of Video Game Aesthetic navigates the intricate intersection of digital technology, aesthetics, and play in the context of video games, challenging ...conventional ideas of player agency. This critical recension delves into the book's contributions, highlighting its innovative exploration of mediated distance, interactivity, delegation, automation, ambience, spectacle, and the evolving nature of player engagement. While acknowledging its theoretical depth, this review emphasizes the book's significance in reshaping our understanding of video game aesthetics and the complex relationship between humans, machines, and digital play.
Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However ...the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes.
Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs.
We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-β1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer.
Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.
Bronchiectasis is a condition characterized by abnormal and irreversible bronchial dilation resulting from lung tissue damage and can be categorized into two main groups: cystic fibrosis (CF) and ...non-CF bronchiectasis (NCFB). Both diseases are marked by recurrent infections, inflammatory exacerbations, and lung damage. Given that infections are the primary drivers of disease progression, characterization of the respiratory microbiome can shed light on compositional alterations and susceptibility to antimicrobial drugs in these cases compared to healthy individuals.
To assess the microbiota in the two studied diseases, 35 subjects were recruited, comprising 10 NCFB and 13 CF patients and 12 healthy individuals. Nasopharyngeal swabs and induced sputum were collected, and total DNA was extracted. The DNA was then sequenced by the shotgun method and evaluated using the SqueezeMeta pipeline and R.
We observed reduced species diversity in both disease cohorts, along with distinct microbial compositions and profiles of antimicrobial resistance genes, compared to healthy individuals. The nasopharynx exhibited a consistent microbiota composition across all cohorts. Enrichment of members of the Burkholderiaceae family and an increased Firmicutes/Bacteroidetes ratio in the CF cohort emerged as key distinguishing factors compared to NCFB group. Staphylococcus aureus and Prevotella shahii also presented differential abundance in the CF and NCFB cohorts, respectively, in the lower respiratory tract. Considering antimicrobial resistance, a high number of genes related to antibiotic efflux were detected in both disease groups, which correlated with the patient's clinical data.
Bronchiectasis is associated with reduced microbial diversity and a shift in microbial and resistome composition compared to healthy subjects. Despite some similarities, CF and NCFB present significant differences in microbiome composition and antimicrobial resistance profiles, suggesting the need for customized management strategies for each disease.
Background & Aims Although smoking is a leading risk factor for pancreatic ductal adenocarcinoma (PDAC), little is known about the mechanisms by which smoking promotes initiation or progression of ...PDAC. Methods We studied the effects of nicotine administration on pancreatic cancer development in Kras +/LSLG12Vgeo ;Elas-tTA/tetO-Cre (Ela-KRAS) mice, Kras +/LSLG12D ;Trp53+/LSLR172H;Pdx-1-Cre (KPC) mice (which express constitutively active forms of KRAS), and C57/B6 mice. Mice were given nicotine for up to 86 weeks to produce blood levels comparable with those of intermediate smokers. Pancreatic tissues were collected and analyzed by immunohistochemistry and reverse transcriptase polymerase chain reaction; cells were isolated and assayed for colony and sphere formation and gene expression. The effects of nicotine were also evaluated in primary pancreatic acinar cells isolated from wild-type, nAChR7a−/− , Trp53−/− , and Gata6−/− ; Trp53−/− mice. We also analyzed primary PDAC cells that overexpressed GATA6 from lentiviral expression vectors. Results Administration of nicotine accelerated transformation of pancreatic cells and tumor formation in Ela-KRAS and KPC mice. Nicotine induced dedifferentiation of acinar cells by activating AKT–ERK–MYC signaling; this led to inhibition of Gata6 promoter activity, loss of GATA6 protein, and subsequent loss of acinar differentiation and hyperactivation of oncogenic KRAS. Nicotine also promoted aggressiveness of established tumors as well as the epithelial–mesenchymal transition, increasing numbers of circulating cancer cells and their dissemination to the liver, compared with mice not exposed to nicotine. Nicotine induced pancreatic cells to acquire gene expression patterns and functional characteristics of cancer stem cells. These effects were markedly attenuated in K-Ras+/LSL-G12D ; Trp53+/LSLR172H ; Pdx-1-Cre mice given metformin. Metformin prevented nicotine-induced pancreatic carcinogenesis and tumor growth by up-regulating GATA6 and promoting differentiation toward an acinar cell program. Conclusions In mice, nicotine promotes pancreatic carcinogenesis and tumor development via down-regulation of Gata6 to induce acinar cell dedifferentiation.
Dogs play an important role in our society as companions and work partners, and proper training of these dogs is pivotal. For companion dogs, training helps preventing or managing dog behavioral ...problems-the most frequently cited reason for relinquishing and euthanasia, and it promotes successful dog-human relationships and thus maximizes benefits humans derive from bonding with dogs. For working dogs, training is crucial for them to successfully accomplish their jobs. Dog training methods range widely from those using predominantly aversive stimuli (aversive methods), to those combining aversive and rewarding stimuli (mixed methods) and those focusing on the use of rewards (reward methods). The use of aversive stimuli in training is highly controversial and several veterinary and animal protection organizations have recommended a ban on pinch collars, e-collars and other techniques that induce fear or pain in dogs, on the grounds that such methods compromise dog welfare. At the same time, training methods based on the use of rewards are claimed to be more humane and equally or more effective than aversive or mixed methods. This important discussion, however, has not always been based in solid scientific evidence. Although there is growing scientific evidence that training with aversive stimuli has a negative impact on dog welfare, the scientific literature on the efficacy and efficiency of the different methodologies is scarce and inconsistent. Hence, the goal of the current study is to investigate the efficacy and efficiency of different dog training methods. To that end, we will apply different dog training methods in a population of working dogs and evaluate the outcome after a period of training. The use of working dogs will allow for a rigorous experimental design and control, with randomization of treatments. Military (n = 10) and police (n = 20) dogs will be pseudo-randomly allocated to two groups. One group will be trained to perform a set of tasks (food refusal, interrupted recall, dumbbell retrieval and placing items in a basket) using reward methods and the other group will be trained for the same tasks using mixed methods. Later, the dogs will perform a standardized test where they will be required to perform the trained behaviors. The reliability of the behaviors and the time taken to learn them will be assessed in order to evaluate the efficacy and efficiency, respectively, of the different training methods. This study will be performed in collaboration with the Portuguese Army and with the Portuguese Public Security Police (PSP) and integrated with their dog training programs.
A 52-year-old male, without significant past medical history, is referred for new onset constipation, hematochezia and significant weight loss. Blood tests were unremarkable. A colonoscopy was ...performed, showing reddish, hematocystic and friable mucosa in a circumferential pattern in the rectum, with similar patches throughout the whole colon, one of them infiltrating the ileocecal valve. Biopsies were obtained and revealed spindle cell proliferation immunoreactive for CD34 and herpesvirus 8 (HHV-8), compatible with Kaposi's sarcoma (KS). HIV serologies were subsequently done, with a positive result, the patient then reporting previous heterosexual unprotected sexual activities. He was started on highly active antiretroviral therapy (HAART) and chemotherapy with liposomal doxorubicin, with a favorable outcome to this date. KS is a low-grade tumor of the vascular endothelium that requires infection with HHV-8. HIV-related KS is more commonly diagnosed in homosexual males with uncontrolled HIV infection and is associated with a variable clinical course. The gastrointestinal tract is involved in up to 51% of patients, but since the majority is clinically silent (70%), visceral involvement is probably underestimated. The treatment goal is symptomatic relief, and may range from HAART alone to a combination with systemic chemotherapy, depending on disease extent. We present this case given its endoscopic exuberance, with biopsies showing an HIV-defining condition, in a patient unaware of his diagnosis.
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