bluuebunny/crossref_metadata_2025_split huggingface dataset:
Localized diacylglycerol-dependent stimulation of Ras and Rap1 during phagocytosis
Authors: Botelho Roberto , Harrison Rene E. , C. Stone James , Hancock John F. , Philips Mark R. , Jongstra-Bilen Jenny , Mason David , Plumb Jonathan , R. Gold Michael , Grinstein Sergio 
Published: January 2023

<p>We describe a role for diacylglycerol in the activation of Ras and Rap1 at the phagosomal membrane. During phagocytosis, Ras density was similar on the surface and invaginating areas of the membrane, but activation was detectable only in the latter and in sealed phagosomes. Ras activation was associated with the recruitment of RasGRP3, a diacylglycerol-dependent Ras/Rap1 exchange factor. Recruitment to phagosomes of RasGRP3, which contains a C1 domain, parallels and appears to be due to the formation of diacylglycerol. Accordingly, Ras and Rap1 activation was precluded by antagonists of phospholipase C and of diacylglycerol binding. Ras is dispensable for phagocytosis but controls activation of extracellular signal-regulated kinase, which is partially impeded by diacylglycerol inhibitors. By contrast, cross-activation of complement receptors by stimulation of Fcgamma receptors requires Rap1 and involves diacylglycerol. We suggest a role for diacylglycerol-dependent exchange factors in the activation of Ras and Rap1, which govern distinct processes induced by Fcgamma receptor-mediated phagocytosis to enhance the innate immune response.</p>
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The PH domain from the Toxoplasma gondii PH-containing protein-1 (TgPH1) serves as an ectopic reporter of phosphatidylinositol 3-phosphate in mammalian cells
Authors: Chintaluri Krishna , Goulden Brady D. , Celmenza Camilyn , Saffi Golam , Miraglia Emily , R. V. Hammond Gerald , Botelho Roberto 
Published: January 2023

<p>Phosphoinositide (PtdInsP) lipids recruit effector proteins to membranes to mediate a variety of functions including signal transduction and membrane trafficking. Each PtdInsP binds to a specific set of effectors through characteristic protein domains such as the PH, FYVE and PX domains. Domains with high affinity for a single PtdInsP species are useful as probes to visualize the distribution and dynamics of that PtdInsP. The endolysosomal system is governed by two primary PtdInsPs: phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2], which are thought to localize and control early endosomes and lysosomes/late endosomes, respectively. While PtdIns(3)P has been analysed with mammalian-derived PX and FYVE domains, PtdIns(3,5)P2 indicators remain controversial. Thus, complementary probes against these PtdInsPs are needed, including those originating from non-mammalian proteins. Here, we characterized in mammalian cells the dynamics of the PH domain from PH-containing protein-1 from the parasite <em>Toxoplasma gondii</em> (TgPH1), which was previously shown to bind PtdIns(3,5)P2 <em>in vitro</em>. However, we show that TgPH1 retains membrane-binding in PIKfyve-inhibited cells, suggesting that TgPH1 is not a viable PtdIns(3,5)P2 marker in mammalian cells. Instead, PtdIns(3)P depletion using pharmacological and enzyme-based assays dissociated TgPH1 from membranes. Indeed, TgPH1 co-localized with Rab5-positive early endosomes. In addition, TgPH1 co-localized and behaved similarly to the PX domain of p40phox and FYVE domain of EEA1, which are commonly used as PtdIns(3)P indicators. Collectively, TgPH1 offers a complementary reporter for PtdIns(3)P derived from a non-mammalian protein and that is distinct from commonly employed PX and FYVE domain-based probes.</p>
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The Lysosome Signaling Platform: Adapting With the Times
Authors: Inpanathan Subothan , Botelho Roberto 
Published: January 2023

<p>Lysosomes are the terminal degradative compartment of autophagy, endocytosis and phagocytosis. What once was viewed as a simple acidic organelle in charge of macromolecular digestion has emerged as a dynamic organelle capable of integrating cellular signals and producing signal outputs. In this review, we focus on the concept that the lysosome surface serves as a platform to assemble major signaling hubs like mTORC1, AMPK, GSK3 and the inflammasome. These molecular assemblies integrate and facilitate cross-talk between signals such as amino acid and energy levels, membrane damage and infection, and ultimately enable responses such as autophagy, cell growth, membrane repair and microbe clearance. In particular, we review how molecular machinery like the vacuolar-ATPase proton pump, sestrins, the GATOR complexes, and the Ragulator, modulate mTORC1, AMPK, GSK3 and inflammation. We then elaborate how these signals control autophagy initiation and resolution, TFEB-mediated lysosome adaptation, lysosome remodeling, antigen presentation, inflammation, membrane damage repair and clearance. Overall, by being at the cross-roads for several membrane pathways, lysosomes have emerged as the ideal surveillance compartment to sense, integrate and elicit cellular behavior and adaptation in response to changing environmental and cellular conditions. </p>
Defective apoptotic cell contractility provokes sterile inflammation, leading to liver damage and tumour suppression
Authors: Julian Linda , Naylor Gregory , Wickman Grant R , Rath Nicola , Castino Giovanni , Stevenson David , Bryson Sheila , Munro June , McGarry Lynn , Mullin Margaret , Rice Alistair , Hernández Armandodel Del Río , Olson Michael 
Published: January 2023

<p>Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage-associated molecular pattern protein HMGB1 or signalling by its cognate receptor TLR4 lowered neutrophil infiltration and reduced liver damage. ROCK1nc mice also developed fewer diethylnitrosamine-induced hepatocellular carcinoma (HCC) tumours, while HMGB1 inhibition increased HCC tumour numbers. Thus, ROCK1 activation and consequent cell contraction are required to limit sterile inflammation and damage amplification following tissue-scale cell death. Additionally, these findings reveal a previously unappreciated role for acute sterile inflammation as an efficient tumour-suppressive mechanism.</p>
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MICAL1 Monooxygenase in Autosomal Dominant Lateral Temporal Epilepsy: Role in Cytoskeletal Regulation and Relation to Cancer
Authors: Olson Michael 
Published: January 2023

<p>Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy associated with mutations in the LGI1, RELN, and MICAL1 genes. A previous study linking ADLTE with two MICAL1 mutations that resulted in the substitution of a highly conserved glycine residue for serine (G150S) or a frameshift mutation that swapped the last three C-terminal amino acids for 59 extra residues (A1065fs) concluded that the mutations increased enzymatic activity and promoted cell contraction. The roles of the Molecule Interacting with CasL 1 (MICAL1) protein in tightly regulated semaphorin signaling pathways suggest that activating MICAL1 mutations could result in defects in axonal guidance during neuronal development. Further studies would help to illuminate the causal relationships of these point mutations with ADLTE. In this review, we discuss the proposed pathogenesis caused by mutations in these three genes, with a particular emphasis on the G150S point mutation discovered in MICAL1. We also consider whether these types of activating MICAL1 mutations could be linked to cancer. </p>
Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging
Authors: Floerchinger Alessia , Murphy Kendelle J , Latham Sharissa L. , C.Warren Sean , McCulloch Andrew T , Kyung Lee Young , Stoehr Janett , Mélénec Pauline , S.Guaman Cris , Metcalf Xanthe L , Lee Victoria , Zaratzian Anaiis , Da Silva Andrew , Tayao Michael , Rolo Sonia , Phimmachanh Monica , Sultani Ghazal , McDonald Laura , M. Mason Susan , Ferrari Nicola , M. Ooms Lisa , Johnsson Anna-Karin E , Spence Heather J , Olson Michael , Machesky Laura M. , Sansom Owen J , P. Morton Jennifer , Mitchell Christina A. , S. Samuel Michael , Croucher David R. , Welch Heidi C. E. , Blyth Karen , Caldon C. Elizabeth , Herrmann David , I Anderson Kurt , Timpson Paul , Nobis Max 
Published: January 2023

<p>Assessing drug response within live native tissue provides increased fidelity with regards to optimizing efficacy while minimizing off-target effects. Here, using longitudinal intravital imaging of a Rac1-Forster resonance energy transfer (FRET) biosensor mouse coupled with in vivo photoswitching to track intratumoral movement, we help guide treatment scheduling in a live breast cancer setting to impair metastatic progression. We uncover altered Rac1 activity at the center versus invasive border of tumors and demonstrate enhanced Rac1 activity of cells in close proximity to live tumor vasculature using optical window imaging. We further reveal that Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress and therefore improves overall anti-metastatic response to therapy during transit to secondary sites such as the lung. Collectively, this study demonstrates the utility of single-cell intravital imaging in vivo to demonstrate that Rac1 inhibition can reduce tumor progression and metastases in an autochthonous setting to improve overall survival. </p>
Hiobs Vaterschaft und die Trauer um seine Kinder
Authors: Marschall Anja 
Published: January 2023

Dieser Aufsatz überprüft die These, dass der Protagonist des Hiobbuches als klagender Vater charakterisiert ist. Prolog, Dialog und Epilog zeigen Hiob als trauernden und liebenden Vater, der sich mit Gesprächspartnern auseinandersetzt, die wiederum auf die Art seiner Trauer Bezug nehmen. Nach einer Untersuchung der Verwendung typischer Trauerverben und -riten wendet sich die Untersuchung Hiobs körperlicher, emotionaler und kognitiver Reaktion auf den Tod seiner Kinder zu. Durch den Abgleich mit anderen alttestamentlichen und altorientalischen Texten sowie mit der aktuellen exegetischen und kulturanthropologischen Forschung zeigt sich, dass Hiobs Morbidität und Todeswunsch Teil einer kulturtypischen, aber besonders verstärkten Trauerreaktion sind. Hiobs kognitive Verarbeitung bildet hingegen eine im Alten Israel unübliche Art der Trauerbewältigung ab. Gleichwohl zeigt sie große Übereinstimmungen mit bekannten Trauermustern wie der komplizierten Trauer und Disenfranchised grief. Die Parallelen zu Ergebnissen der zeitgenössischen Psychologie ermöglichen es, Hiobs Trauer als treibende Kraft der Klage und als Anstoß des Streits unter Freunden wahrzunehmen. Die negative Reaktion der Freunde auf Hiobs Trauer bestätigt, dass Hiob als trauernder Vater klagt und protestiert und als solcher Gottes Weltordnung in Frage stellt. Im Epilog des Hiobbuches erweist sich schließlich die Vaterschaft Hiobs als das überdauernde und stabilisierende Element im Narrativ des Lebens Hiobs.

This paper verifies the thesis that the protagonist of the Book of Job is delineated as a grieving father. The prologue, dialogue and epilogue show Job as a mourning and loving father engaging in dialogue with friends and God who themselves relate to Job’s grief. After examining the use of typical mourning verbs and rites, the study turns to Job’s physical, emotional, and cognitive reaction to the death of his children. By comparing Job’s expressions with other Old Testament and Ancient Near Eastern texts as well as with current exegetical and cultural anthropological scholarship, Job’s morbidity and death wish can be seen as a culturally typical but particularly intensified grief response. In contrast, Job’s cognitive processing represents a coping mechanism unusual in Ancient Israel. However, there are parallels to typical patterns of mourning known to contemporary psychology, such as complicated and disenfranchised grief. These allow to identify Job’s grief as the driving force of the lament and as the impetus of a dispute among friends. Their negative reaction to Job’s mourning confirms that Job laments and protests as a grieving father. Finally, in the epilogue of the book, Job’s fatherhood emerges as the enduring and stabilizing feature of the story.
PENGARUH MODEL PEMBELAJARAN DISCOVERY LEARNING UNTUK MENINGKATKAN BERPIKIR KREATIF PADA MATERI IPA SISWA KELAS V SDN 090 PEKANBARU
Authors: Meliansari Vika , Alpusari Mahmud , Alim Jesi Alexander 
Published: January 2023

Tujuan dari penelitian ini adalah, agar peneliti tau apakah ada pengaruh dari model pembelajaran Discovery learning terhadap materi IPA dengan meningkatkan cara berfikir kreatif anak dapat diterapkan pada siswa sekolah dasar nantinya. Subjek penelitian ini adalah siswa kelas V di SDN 090 Pekanbaru yang berjumlah 74 siswa dengan 2 kelas, satu kelas untuk kelas eskperimen dan satu kelas nya lagi untuk kelas kontrol. Penelitian ini menggunakan model pembelajaran Discovery learning. Pengetahuan IPA siswa pada kelas eksperimen dengan menerapkan model pembelajaran Discovery learning dilihat dari rata-rata Pretest kelas eskperimen 77,30 termasuk tingkatan pengetahuan kurang dan kelas kontrol 76,11 termasuk tingkatan pengetahuan yang kurang, kemudian dilaksanakan Posttest rata-rata nilai kelas eksperimen sebesar 88,22 sedangkan pada kelas kontrol dilihat rata-rata nilai Posttest sebesar 80,97 hasil Posttest kelas eksperimen termasuk tingkatan pengetahuan baik, sedangkan kelas kontrol termasuk tingkatan pengetahuan cukup. Setelah mengolah data pada kelas eksperimen dan kelas kontrol dengan menggunakan uji t Terdapat pengaruh penerapan model pembelajaran Discovery learning, berdasarkan uji t Ha diterima dan H0 ditolak dengan sig (2-tailed) 0,010 < 0,05, dan terhadap peningkatan hasil belajar IPA siswa kelas V SDN 090 Pekanbaru.

Tujuan dari penelitian ini adalah, agar peneliti tau apakah ada pengaruh dari model pembelajaran Discovery learning terhadap materi IPA dengan meningkatkan cara berfikir kreatif anak dapat diterapkan pada siswa sekolah dasar nantinya. Subjek penelitian ini adalah siswa kelas V di SDN 090 Pekanbaru yang berjumlah 74 siswa dengan 2 kelas, satu kelas untuk kelas eskperimen dan satu kelas nya lagi untuk kelas kontrol. Penelitian ini menggunakan model pembelajaran Discovery learning. Pengetahuan IPA siswa pada kelas eksperimen dengan menerapkan model pembelajaran Discovery learning dilihat dari rata-rata Pretest kelas eskperimen 77,30 termasuk tingkatan pengetahuan kurang dan kelas kontrol 76,11 termasuk tingkatan pengetahuan yang kurang, kemudian dilaksanakan Posttest rata-rata nilai kelas eksperimen sebesar 88,22 sedangkan pada kelas kontrol dilihat rata-rata nilai Posttest sebesar 80,97 hasil Posttest kelas eksperimen termasuk tingkatan pengetahuan baik, sedangkan kelas kontrol termasuk tingkatan pengetahuan cukup. Setelah mengolah data pada kelas eksperimen dan kelas kontrol dengan menggunakan uji t Terdapat pengaruh penerapan model pembelajaran Discovery learning, berdasarkan uji t Ha diterima dan H0 ditolak dengan sig (2-tailed) 0,010 < 0,05, dan terhadap peningkatan hasil belajar IPA siswa kelas V SDN 090 Pekanbaru.
The dynamic change of serotype distribution and antimicrobial resistance of pneumococcal isolates since PCV13 administration and COVID-19 control in Urumqi, China
Authors: Guo Meng-Yang , Shi Xing-Hai , Gao Wei , Tian Ju-Ling , Yuan Lin , Yang Juan , Wumaier Dilinuer , Cao Jiang , Abulimiti Reziwaguli , Zhang Wen-Li , Yao Kai-Hu 
Published: January 2023

ObjectiveThis study aims to analyze the serotype distribution and drug resistance of Streptococcus pneumoniae isolated from children aged 8 days to 7 years in Urumqi, China, between 2014 to 2021, during which PCV13 was introduced in the private sector’s immunization program and COVID-19 control was administrated in the last 2 years.MethodsSerotypes of S. pneumoniae isolates were determined by Quellung reaction, and their susceptibility against 14 antimicrobials were tested. According to the start year of PCV13 administration (2017) and COVID-19 control (2020), the study period was divided into three stages: 2014–2015, 2018–2019, and 2020–2021.ResultsA total of 317 isolates were involved in this study. The most common serotypes were type 19F (34.4%), followed by 19A (15.8%), 23F (11.7%), 6B (11.4%), and 6A(5.0%). The coverage rate of both PCV13 and PCV15 was 83.0%. The coverage of PCV20 was a little higher at 85.2%. The resistance rate against penicillin was 28.6% according to the breakpoints of oral penicillin, which would reach up to 91.8% based on the breakpoints of parenteral penicillin for meningitis. The resistance rates to erythromycin, clindamycin, tetracycline, and sulfamethoxazole-trimethoprim were 95.9%, 90.2%, 88.9%, and 78.8%, respectively. The PCV13 isolate was more resistant to penicillin than the non-PCV13 ones. There was not any significant change found in the serotype distribution since the PCV13 introduction and the COVID-19 control. The resistance rate against oral penicillin slightly elevated to 34.5% in 2018–2019 from 30.7% in 2014–2015 and then decreased significantly to 18.1% in 2020–2021 (χ2 = 7.716, P &lt; 0.05), while the resistance rate to ceftriaxone (non-meningitis) continuously declined from 16.0% in 2014–2015 to 1.4% in 2018–2019 and 0% in 2020–2021 (Fisher = 24.463, P &lt; 0.01).ConclusionThe common serotypes of S. pneumoniae isolated from children in Urumqi were types 19F, 19A, 23F, 6B, and 6A, which we found to have no marked change since the PCV13 introduction and the COVID-19 control However, the resistance rate to oral penicillin and ceftriaxone significantly declined in the COVID-19 control stage.
Gut microbial characteristical comparison reveals potential anti-aging function of Dubosiella newyorkensis in mice
Authors: Liu Tian-hao , Wang Juan , Zhang Chen-yang , Zhao Lin , Sheng Ying-yue , Tao Guo-shui , Xue Yu-zheng 
Published: January 2023

IntroductionPrevious study has indicated Dubosiella newyorkensis may act as a potential probiotic in age-related diseases. However, its detailed role in aging has not yet been promulgated. This study aimed to explore the potential anti-aging role of Dubosiella newyorkensis by comparing the anti-aging effect of resveratrol in young and old mice.MethodMeasurement of intestinal aging-related factors in colon and serum, and vascular endothelial function-related factors in serum were performed by enzyme-linked immunosorbent assay (ELISA). Gut microbial analysis of intestinal contents were identified by 16S rRNA gene sequencing.ResultsThe effect of Dubosiella newyorkensis on reducing malondialdehyde (MDA) and increasing superoxide dismutase (SOD) in aged mice were greater than that of resveratrol. While the effect of Dubosiella newyorkensis on nitric oxide (NO) level was less than that of resveratrol, the reduction of vascular endothelial growth factor (VEGF) and pentosidine (PTD) was better than that of resveratrol in young mice. In young mice, Dubosiella newyorkensis promoted an increase in the beneficial genus Lactobacillus, Bifidobacterium and Ileibacterium less effectively as compared with resveratrol treatment. In aged mice, Dubosiella newyorkensis promoted the increase of Bifidobacterium, Ileibacterium less effectively than resveratrol, and promoted the increase of Akkermansia, Staphylococcus, Verrucomicrobiota expression better as compared with resveratrol treatment. Both young and old mice showed the same results for the remaining markers, including changes in gut microbial composition and predictions of function.ConclusionDubosiella newyorkensis has similar anti-aging functions with resveratrol. Dubosiella newyorkensis may even be more effective than resveratrol in reducing oxidative stress, improving vascular endothelial function, and redistributing gut microbiota. The research provides an innovative strategy of Dubosiella newyorkensis to improve aging.
Transcutaneous electrical acupoint stimulation for the prevention of postoperative delirium in elderly surgical patients: A systematic review and meta-analysis
Authors: Huang Kai-Yu , Liang Shuang , Chen Lei , Xu Yong-Yi , Grellet Antoine 
Published: January 2023

ObjectiveThis systematic review and meta-analysis aimed to evaluate the preventive effect of transcutaneous electrical acupoint stimulation on postoperative delirium in elderly surgical patients.MethodsPubMed, CENTRAL, China National Knowledge Infrastructure, and WanFang databases were searched for randomized controlled trials regarding the effect of transcutaneous electrical acupoint stimulation on preventing postoperative delirium in elderly patients undergoing any type of surgery. The primary outcome was the incidence of postoperative delirium. The secondary outcome was the duration of postoperative delirium. All analyses were conducted using RevMan 5.3 and Stata 13.0 software.ResultsTwelve trials with 991 participants were included, and most of them were at high/unclear risk of bias. Meta-analysis showed transcutaneous electrical acupoint stimulation could reduce the incidence of postoperative delirium (RR = 0.40, 95%CI = 0.29 to 0.55, p &lt; 0.00001) and shorten the duration of postoperative delirium (MD = –0.97 days, 95%CI = −1.72 to −0.22, p = 0.01). Subgroup analyses demonstrated that transcutaneous electrical acupoint stimulation reduced the incidence of postoperative delirium in elderly patients undergoing orthopedic surgery and thoracic surgery, but not digestive surgery; transcutaneous electrical acupoint stimulation with dilatational wave and with continuous wave were both beneficial; and transcutaneous electrical acupoint stimulation was favored when compared to blank and sham control.ConclusionTranscutaneous electrical acupoint stimulation could reduce the incidence of postoperative delirium and shorten the duration of postoperative delirium in elderly surgical patients. The findings should be interpreted with caution due to weak evidence. High-quality, large sample, and multi-center trials are needed to further confirm the preliminary findings.Systematic review registration: https://inplasy.com/inplasy-2022-7-0096/, identifier: INPLASY202270096.