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Author(s):  
Rita A. Costa ◽  
Zélia Velez ◽  
Peter C. Hubbard

Exposure to high PCO2/low pH seawater induces behavioural alterations in fish; a possible explanation for this is a reversal of Cl−/HCO3− currents through GABAA receptors (the GABAA receptor theory). However, the main evidence for this is that gabazine, a GABAA receptor antagonist, reverses these effects when applied to the water, assuming that exposure to systems other than the CNS would be without effect. Here, we show the expression of both metabotropic and ionotropic GABA receptors, and the presence of GABAA receptor protein, in the olfactory epithelium (OE) of gilthead seabream. Furthermore, exposure of the OE to muscimol (a specific GABAA receptor agonist) increases or decreases the apparent olfactory sensitivity to some odorants. Thus, although the exact function of GABAA receptors in the OE is not yet clear, this may complicate the interpretation of studies wherein water-borne gabazine is used to reverse the effects of high CO2 levels on olfactory-driven behaviour in fish.


2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.


2022 ◽  
Author(s):  
Qingyan Li ◽  
Huixia Zhao ◽  
Weiwei Dong ◽  
Na Guan ◽  
Yanyan Hu ◽  
...  

Abstract Colorectal cancer (CRC) is the most commonly diagnosed form of cancer worldwide. Though significant advances in prevention and diagnosis, CRC is still one of the leading causes of cancer-related mortality globally. RAB27A, the member of RAB27 family of small GTPases, is the critical protein for intracellular secretion and was reported to promote tumor progression. However, it is controversial for the role of RAB27A in CRC progression, so we explored the exact function of RAB27A in CRC development in this study. Based on the stable colon cancer cell lines of RAB27A knockdown and ectopic expression, we found that RAB27A knockdown inhibited SW480 colon cancer cell proliferation and clone formation, whereas ectopic expression of RAB27A in RKO colon cancer cells facilitated cell proliferation and clone formation, indicating that RAB27A is critical for colon cancer cell growth. In addition, our data demonstrated that the migration and invasion of colon cancer cells were suppressed by RAB27A knockdown, but promoted by RAB27A ectopic expression. Therefore, RAB27A was identified as an onco-protein in mediating CRC development, which may be a valuable prognostic indicator and potential therapeutic target for CRC.


Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 152
Author(s):  
Ping Zhang ◽  
Zhichao Yao ◽  
Shuai Bai ◽  
Hongyu Zhang

Peptidoglycan recognition proteins (PGRPs) are key regulators in insects’ immune response, functioning as sensors to detect invading pathogens and as scavengers of peptidoglycan (PGN) to reduce immune overreaction. However, the exact function of PGRPs in Bactrocera dorsalis is still unclear. In this study, we identified and functionally characterized the genes BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 in B. dorsalis. The results showed that BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 all have an amidase-2 domain, which has been shown to have N-Acetylmuramoyl-l-Alanine amidase activity. The transcriptional levels of BdPGRP-LB and BdPGRP-SC2 were both high in adult stages and midgut tissues; BdPGRP-SB1 was found most abundantly expressed in the 2nd instar larvae stage and adult fat body. The expression of BdPGRP-LB and BdPGRP-SB1 and AMPs were significantly up-regulated after injury infected with Escherichia coli at different time points; however, the expression of BdPGRP-SC2 was reduced at 9 h, 24 h and 48 h following inoculation with E. coli. By injection of dsRNA, BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 were knocked down by RNA-interference. Silencing of BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2 separately in flies resulted in over-activation of the Imd signaling pathway after bacterial challenge. The survival rate of the ds-PGRPs group was significantly reduced compared with the ds-egfp group after bacterial infection. Taken together, our results demonstrated that three catalytic PGRPs family genes, BdPGRP-LB, BdPGRP-SB1 and BdPGRP-SC2, are important negative regulators of the Imd pathway in B. dorsalis.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tova Wasserman-Bruck ◽  
Boger-May Boger-May ◽  
Derek Rubadeux ◽  
Katelyn Ruley-Haase ◽  
David L. Boone

Background and Objectives: Gastrokine-1 (Gkn1) is a protein produced solely in the stomach and secreted into the lumen of the gut. Gkn1 has a BRICHOS domain which is anti-amyloidogenic. While the exact function of Gkn1 is not yet completely understood, Gkn1 has a protective role against IBD in induced models of colitis. Since microbes secrete amyloid to facilitate biofilm formation, we hypothesized that Gkn1 may play a protective role against IBD by inhibiting amyloid formation by biofilm forming microbes in the gut. We examined the effects of varying concentrations of Gkn1 on known biofilm forming microbes to determine if there was a dose responsive inhibitory effect of Gkn1 on biofilm formation.  Methods: Bacterial colonies from Adherent Invasive E. coli and E. faecalis were cultured and incubated at 37 degrees Celsius overnight. The samples were then diluted 1:100 and inoculated into 96-well costar microassay plates with concentrations of Gkn1 ranging from 0.00075 to 0.025 mg/ml. At 8, 24, or 48 hour time points the plates were then washed to remove planktonic bacteria, and adherent biofilms were stained with crystal violet. Biofilm formation was analyzed by comparing the OD590/OD600 against a control.   Results:  Using a one-way ANOVA, we determined that there is dose response inhibition of biofilm formation with Gkn1, with the greatest inhibition of biofilm formation at concentrations of Gkn1 between 0.00312 and 0.0125 mg/ml.  Conclusions:  A dose response inhibition of Gkn1 on biofilm formation was identified. Since Gkn1 has demonstrated a protective role against IBD in induced colitis, targeting intestinal luminal amyloids may be a potential therapeutic approach for IBD.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lisa M. Schulte ◽  
An Martel ◽  
Raciel Cruz-Elizalde ◽  
Aurelio Ramírez-Bautista ◽  
Franky Bossuyt

Abstract Background Efficient transfer of chemical signals is important for successful mating in many animal species. Multiple evolutionary lineages of animals evolved direct sex pheromone transmission during traumatic mating—the wounding of the partner with specialized devices—which helps to avoid signal loss to the environment. Although such direct transmission modes of so-called allohormone pheromones are well-documented in invertebrates, they are considered rare in vertebrates. Males of several species of the frog genus Plectrohyla (Hylidae, Anura) have elongated teeth and develop swollen lips during the breeding season. Here we investigated the possibility that these structures are used to scratch the females’ skin and apply allohormone pheromones during traumatic mating in several Plectrohyla species. Results Our behavioural observations revealed that males press their upper jaw onto the females’ dorsum during amplexus, leaving small skin scratches with their teeth. Histological examinations of the males’ lips identified specialized mucus glands, resembling known amphibian pheromone glands. Whole-transcriptome sequencing of these breeding glands showed high expression of sodefrin precursor-like factor (SPF) proteins, which are known to have a pheromone function in multiple amphibian species. Conclusions Our study suggests SPF delivery via traumatic mating in several anuran species: the males have specialized breeding glands in the lips for production and secretion and use their elongated teeth as wounding devices for application. We hypothesize that these SPF proteins end up in the females’ circulatory system, where understanding their exact function will require further molecular, physiological and behavioural testing.


Author(s):  
Ryota Takaoka ◽  
Kotaro Kuyama ◽  
Hirofumi Yatani ◽  
Shoichi Ishigaki ◽  
Hiroki Kayashima ◽  
...  

Abstract Objectives The FTO gene has been reported as an obesity-associated gene and is also considered a risk gene for osteoarthritis (OA). However, its exact function is unclear, and there is conflicting evidence on the involvement of FTO polymorphisms in OA via obesity. The purpose of this study was to determine the effects of FTO polymorphism rs8044769 alleles on OA in the temporomandibular joint (TMJ), which is minimally affected by body weight. Materials and methods A total of 324 TMJs (113 with OA and 211 without OA, serving as controls) from 162 Japanese patients with temporomandibular disorders and undergoing MRI examination were analyzed. Genotyping was conducted, and multivariate analysis was performed after adjusting for the effects of age, sex, body mass index, and TMJ disc abnormalities. Results Mean age, BMI, and sex did not differ between the TMJs with OA and the TMJs without OA, but a significant difference was found for positional and dynamic disc abnormalities (P < 0.05). The allele frequency of FTO polymorphisms also differed significantly between the TMJs with OA and the TMJs without OA (P = 0.011). Moreover, logistic regression analysis showed no significant association between BMI (P = 0.581) and the occurrence of TMJOA but also indicated that the CC allele of rs8044769 is a risk factor for TMJOA (P = 0.040). Conclusions Our results show that rs8044769 in the FTO gene might be involved in TMJOA. Clinical relevance The present study provides a basis for a deeper understanding of the mechanism underlying degenerative skeletal diseases and the more effective selection and development of treatment strategies based on the patients’ genetic characteristics.


2021 ◽  
Author(s):  
◽  
Vaughan Trounson

<p>The genus Bartonellae represents an increasing number of emerging bacterial pathogens that utilises an unusual infection strategy, parasitising the red blood cells of their mammalian host. The most common species to infect humans are B. henselae and B. quintana. B. henselae is transmitted between cats by the cat flea, although occasionally infects humans via cat scratches or bites, causing cat-scratch disease (CSD). CSD is characterised by enlarged tender lymph nodes and fever. B. henselae also infects the endothelial cells of both its hosts; likely a factor in disease progression. B. quintana, the cause of trench fever during WWI, is spread people by the body louse. Trench fever is characterised by relapsing fever, headache, and bone pain. B. quintana is also able to infect human endothelial cells. These bacteria secrete a range of Bartonella effector proteins (Beps) via a Type IV secretion system, directly into endothelial cells, subverting host cell processes and resulting in internalisation of the bacteria.  Beps have a range of functions, many of which are not fully characterised. B. henselae secretes three Beps (BepA-C) that contain a filamentation induced by cAMP (Fic) domain and a Bartonella Intracellular Delivery (BID) domain, with BepA being the best studied. BepA’s BID domain is responsible for intracellular delivery as well as inhibition of apoptosis by the host cell, however the exact function of the Fic domain remains unknown. Fic-containing bacterial toxins catalyse the transfer of an AMP moiety from ATP onto a host cell protein. This AMPylation frequently inactivates these proteins resulting in disrupted host cell processes and cytotoxicity. BepA has previously been shown to possess AMPylation activity, although the host target protein(s) are unknown. Evidence suggests that these proteins are novel targets.  The aim of this study was to create protein constructs containing these Fic domains, and to develop techniques to identify the host cell target proteins post AMPylation. To this end, both a fluorescent ATP analogue and a fluorescent click chemistry based approach were utilised. While no target protein was identified, a basic methodology was developed for protein production and target protein identification that could be further developed.</p>


2021 ◽  
Author(s):  
◽  
Vaughan Trounson

<p>The genus Bartonellae represents an increasing number of emerging bacterial pathogens that utilises an unusual infection strategy, parasitising the red blood cells of their mammalian host. The most common species to infect humans are B. henselae and B. quintana. B. henselae is transmitted between cats by the cat flea, although occasionally infects humans via cat scratches or bites, causing cat-scratch disease (CSD). CSD is characterised by enlarged tender lymph nodes and fever. B. henselae also infects the endothelial cells of both its hosts; likely a factor in disease progression. B. quintana, the cause of trench fever during WWI, is spread people by the body louse. Trench fever is characterised by relapsing fever, headache, and bone pain. B. quintana is also able to infect human endothelial cells. These bacteria secrete a range of Bartonella effector proteins (Beps) via a Type IV secretion system, directly into endothelial cells, subverting host cell processes and resulting in internalisation of the bacteria.  Beps have a range of functions, many of which are not fully characterised. B. henselae secretes three Beps (BepA-C) that contain a filamentation induced by cAMP (Fic) domain and a Bartonella Intracellular Delivery (BID) domain, with BepA being the best studied. BepA’s BID domain is responsible for intracellular delivery as well as inhibition of apoptosis by the host cell, however the exact function of the Fic domain remains unknown. Fic-containing bacterial toxins catalyse the transfer of an AMP moiety from ATP onto a host cell protein. This AMPylation frequently inactivates these proteins resulting in disrupted host cell processes and cytotoxicity. BepA has previously been shown to possess AMPylation activity, although the host target protein(s) are unknown. Evidence suggests that these proteins are novel targets.  The aim of this study was to create protein constructs containing these Fic domains, and to develop techniques to identify the host cell target proteins post AMPylation. To this end, both a fluorescent ATP analogue and a fluorescent click chemistry based approach were utilised. While no target protein was identified, a basic methodology was developed for protein production and target protein identification that could be further developed.</p>


Author(s):  
Michelle Broekhuizen ◽  
A. H. Jan Danser ◽  
Irwin K. M. Reiss ◽  
Daphne Merkus

(L-)tryptophan is metabolized via the kynurenine pathway into several kynurenine metabolites with distinct functions. Dysfunction of the kynurenine pathway can lead to impairments in vascular regulation, immune regulation, and tolerance. The first and rate limiting enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is highly expressed in the placenta and reduced in placentas from complicated pregnancies. IDO is essential during pregnancy, as IDO inhibition in pregnant mice resulted in fetal loss. However, the exact function of placental IDO, as well as its exact placental localization, remain controversial. This review identified that two isoforms of IDO; IDO1 and IDO2, are differently expressed between placental cells, suggesting spatial segregation. Furthermore, this review summarizes how the placental kynurenine pathway is altered in pregnancy complications, including recurrent miscarriage, preterm birth, preeclampsia, and fetal growth restriction. Importantly, we describe that these alterations do not affect maternally circulating metabolite concentrations, suggesting that the kynurenine pathway functions as a local signaling pathway. In the placenta, it is an important source of de novo placental NAD+ synthesis and regulates fetal tryptophan and kynurenine metabolite supply. Therefore, kynurenine pathway interventions might provide opportunities to treat pregnancy complications, and this review discusses how such treatment could affect placental function and pregnancy development.


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