Antimicrobial peptide LL-37 and recombinant human mannose-binding lectin express distinct age- and pathogen-specific antimicrobial activity in human newborn cord blood in vitro

Background: There is a need to prevent and treat infection in newborns. One approach is administration of antimicrobial proteins and peptides (APPs) such as LL-37, a membrane-active cathelicidin antimicrobial peptide, and mannose-binding lectin (MBL), a pattern-recognition protein that binds to microbial surface polysaccharides resulting in opsonization and complement activation. Low plasma/serum levels of LL-37 and of MBL have been correlated with infection and exogenous administration of these agents may enhance host defense. Methods: The antimicrobial activity of LL-37 (15 µg/ml) or rMBL (0.5, 2 and 10 µg/ml) was tested in hirudin-anticoagulated preterm and term human cord blood (N = 12-14) against Staphylococcus aureus (SA) USA 300 (2x10 4 CFU/ml), Staphylococcus epidermis (SE) 1457 (2x10 4 CFU/ml) and Candida albicans (CA) SC5314 (1x10 4 CFU/ml). After incubation (1, 45, or 180 min), CFUs were enumerated by plating blood onto agar plates. Supernatants were collected for measurement of MBL via ELISA. Results: Preterm cord blood demonstrated impaired endogenous killing capacity against SA and SE compared to term blood. Addition of LL-37 strongly enhanced antimicrobial/antifungal activity vs SA, SE and CA in term blood and SE and CA in preterm blood. By contrast, rMBL showed modest fungistatic activity vs CA in a sub-analysis of term newborns with high basal MBL levels. Baseline MBL levels varied within preterm and term cohorts with no correlation to gestational age. In summary, exogenous LL-37 demonstrated significant antimicrobial activity against SA, SE and CA in term and SE and CA in preterm human blood tested in vitro. rMBL demonstrated modest antifungal activity in term cord blood of individuals with high baseline MBL levels. Conclusions: To the extent that our in vitro results predict the effects of APPs in vivo, development of APPs for prevention and treatment of infection should take into account host age as well as the target pathogen

Pertanggung jawaban hukum terhadap pelaksanaan Perjanjian pemberangkatan ibadah haji antara Biro penyelenggara ibadah haji khusus Dengan calon jamaah haji plus (studi kasus di pt. Nur ramadhan wisata cabang yogyakarta)

Penelitian ini bertujuan untuk mengetahui hak serta kewajiban antara PT. Nur Ramadhan Wisata Cabang Yogyakarta terhadap Calon Jamaah Haji yang akan melakukan ibadah haji di Tanah Suci, untuk mengetahui pelaksanaan perjanjian PT. Nur Ramadhan Wisata Cabang Yogyakarta terhadap pemberangkatan calon jamaah Haji Plus, dan untuk mengetahui bagaimana tanggung jawab hukum yang dilakukan apabila salah satu pihak melakukan wanprestasi. Metode penelitian yang digunakan bersifat yuridis empiris yang bersifat deskriptif yakni pada Kantor PT. Nur Ramadhan Wisata Cabang Yogyakarta. Sumber data terdiri dari data primer dan data sekunder. Sedangkan metode pengumpulan data melalui tiga tahap yaitu kepustakaan, observasi dan wawancara dengan narasumber yakni pimpinan PT. Nur Ramadhan Wisata Cabang Yogyakarta. Hasil penelitian menunjukkan bahwa hak penyelenggara adalah menetapkan biaya dan menerima biaya pemberangkatan Haji Plus, sedangkan kewajiban penyelenggara adalah melayani calon jemaah haji dari mulai pemberangkatan sampai memulangkan jemaah haji. Adapun pelaksanaan perjanjian pemberangkatan Ibadah Haji Plus antara Biro Penyelenggara Ibadah Haji Khusus dengan calon jamaah Haji plus secara tertulis agar masing-masing mendapatkan suatu perlindungan, serta untuk mengantisipasi adanya wanprestasi antara kedua belah pihak, serta tanggung jawab hukum yang dilakukan apabila salah satu pihak melakukan wanprestasi dapat diselesaikan dengan damai yakni musyawarah dan apabila belum dapat menerima tentang pelanggaran dapat melakukan tuntutan di Pengadilan

SMYD3 impedes small cell lung cancer sensitivity to alkylation damage through RNF113A methylation-phosphorylation cross-talk

Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with dismal survival, limited therapeutic options, and rapid development of chemoresistance. We identified the lysine methyltransferase SMYD3 as a major regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 impairs its interaction with the phosphatase PP4, controlling its phosphorylation levels. This cross-talk between posttranslational modifications acts as a key switch in promoting and maintaining RNF113A E3 ligase activity, essential for its role in alkylation damage response. In turn, SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. Our study sheds light on a novel role of SMYD3 in cancer, uncovering this enzyme as a mediator of alkylation damage sensitivity and providing a rationale for small-molecule SMYD3 inhibition to improve responses to established chemotherapy. SIGNIFICANCE: SCLC rapidly becomes resistant to conventional chemotherapy, leaving patients with no alternative treatment options. Our data demonstrate that SMYD3 upregulation and RNF113A methylation in SCLC are key mechanisms that control the alkylation damage response. Notably, SMYD3 inhibition sensitizes cells to alkylating agents and promotes sustained SCLC response to chemotherapy. This article is highlighted in the In This Issue feature, p. 2007

PENGARUH WORD OF MOUTH, PERCEIVED QUALITY, DAN PRICE PERCEPTION TERHADAP KEPUTUSAN PEMBELIAN PRODUK ROTI AOKA (Studi pada Konsumen AOKA di Solo Raya)

ABSTRAK Penelitian ini bertujuan untuk mengetahui pengaruh Word of Mouth, Perceived Quality dan Price Perception terhadap Keputusan Pembelian Produk Roti AOKA (Studi pada Konsumen AOKA di Solo Raya). Penelitian ini menggunakan metode kuantitatif. Teknik pengambilan sampel yang digunakan adalah teknik non probability sampling jenis purposive sampling dengan jumlah sampel sebanyak 210 responden se-Solo Raya. Metode pengumpulan data menggunakan kuesioner, kemudian dianalisis menggunakan bantuan software IBM SPSS Versi 24. Hasil penelitian membuktikan bahwa word of mouth, perceived quality dan price perception secara parsial dan simultan memiliki pengaruh yang signifikan terhadap keputusan pembelian produk roti AOKA. Variabel yang paling berpengaruh positif dan signifikan pada keputusan pembelian produk AOKA adalah word of mouth, dengan koefisien regresi sebesar 6,808 dan tingkat signifikansi 0,000. Temuan penelitian ini memberikan kerangka konseptual mengenai faktor yang memengaruhi keputusan pembelian. Keputusan pembelian dapat ditingkatkan dengan memperhatikan word of mouth, perceived quality, dan price perception. Hal ini ditunjukkan dengan respon konsumen yang setuju bahwa, mereka membeli roti AOKA atas rekomendasi dari orang lain melalui word of mouth, mempertimbangkan keunggulan kualitas yang dirasakan, serta kesesuaian harga dengan kualitas yang diterimanya. Namun, beberapa konsumen beranggapan bahwa kemasan roti AOKA kurang menarik dibandingkan roti lain, maka perusahaan disarankan untuk menciptakan inovasi produk terutama pada kemasan agar dapat menarik konsumen untuk melakukan pembelian produk. Kata Kunci: Word of Mouth, Perceived Quality, Price Perception, Keputusan Pembelia

Gut microbiome and antibiotic resistance effects during travelers\u27 diarrhea treatment and prevention

The travelers\u27 gut microbiome is potentially assaulted by acute and chronic perturbations (e.g., diarrhea, antibiotic use, and different environments). Prior studies of the impact of travel and travelers\u27 diarrhea (TD) on the microbiome have not directly compared antibiotic regimens, and studies of different antibiotic regimens have not considered travelers\u27 microbiomes. This gap is important to be addressed as the use of antibiotics to treat or prevent TD-even in moderate to severe cases or in regions with high infectious disease burden-is controversial based on the concerns for unintended consequences to the gut microbiome and antimicrobial resistance (AMR) emergence. Our study addresses this by evaluating the impact of defined antibiotic regimens (single-dose treatment or daily prophylaxis) on the gut microbiome and resistomes of deployed servicemembers, using samples collected during clinical trials. Our findings indicate that the antibiotic treatment regimens that were studied generally do not lead to adverse effects on the gut microbiome and resistome and identify the relative risks associated with prophylaxis. These results can be used to inform therapeutic guidelines for the prevention and treatment of TD and make progress toward using microbiome information in personalized medical care

Leptin-dependent Phosphorylation of PTEN Mediates Actin Restructuring and Activation of ATP-sensitive K+ Channels

Leptin activates multiple signaling pathways in cells, including the phosphatidylinositol 3-kinase pathway, indicating a degree of cross-talk with insulin signaling. The exact mechanisms by which leptin alters this signaling pathway and how it relates to functional outputs are unclear at present. A previous study has established that leptin inhibits the activity of the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10), an important tumor suppressor and modifier of phosphoinositide signaling. In this study we demonstrate that leptin phosphorylates multiple sites on the C-terminal tail of PTEN in hypothalamic and pancreatic β-cells, an action not replicated by insulin. Inhibitors of the protein kinases CK2 and glycogen synthase kinase 3 (GSK3) block leptin-mediated PTEN phosphorylation. PTEN phosphorylation mutants reveal the critical role these sites play in transmission of the leptin signal to F-actin depolymerization. CK2 and GSK3 inhibitors also prevent leptin-mediated F-actin depolymerization and consequent ATP-sensitive K+ channel opening. GSK3 kinase activity is inhibited by insulin but not leptin in hypothalamic cells. Both hormones increase N-terminal GSK3 serine phosphorylation, but in hypothalamic cells this action of leptin is transient. Leptin, not insulin, increases GSK3 tyrosine phosphorylation in both cell types. These results demonstrate a significant role for PTEN in leptin signal transmission and identify GSK3 as a potential important signaling node contributing to divergent outputs for these hormones

Dynamical (e, 2e) Studies Using Tetrahydrofuran As a DNA Analog

Triple differential cross sections for the electron-impact ionization of the outer valence orbital of tetrahydrofuran have been measured using the (e, 2e) technique. The measurements have been performed with coplanar asymmetric kinematics, at an incident electron energy of 250 eV and at an ejected electron energy of 10 eV, over a range of momentum transfers. The experimental results are compared with theoretical calculations carried out using the molecular three-body distorted wave model. The results obtained are important for gaining an understanding of electron driven processes at a molecular level and for modeling energy deposition in living tissue