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This study was conducted to investigate the effects of dietary inclusion of the encapsulated thyme essential oil (TEO), oregano essential oil (OEO) mixture and probiotic on growth performance, immune response and intestinal morphology of broiler chickens. A total of 490 one-day-old Ross 308 broiler chicks were randomly divided into seven treatments consisting of five replicates (n=14). Birds were fed with 1) basal diet (control), and a basal diet containing; 2) 10 mg Avilamicine antibiotic, 3) 200 mg/kg encapsulated TEO+OEO mixture, 4) 200 mg/kg non-capsulated TEO+OEO mixture, 5) Pronigeb® (probiotic), 6) Pronigeb® with 200 mg/kg non-capsulated TEO+OEO mixture and 7) Pronigeb® with 200 mg/kg encapsulated TEO+OEO mixture. Results revealed that birds fed diet containing antibiotic, encapsulated TEO+OEO mixture with and without probiotic had significantly higher body weight gain (BWG) compared with control and non-capsulated TEO+OEO mixture groups on day 42 (P < 0.05). Dietary inclusion of TEO+OEO in capsulated form and also in along to probiotic increased humoral immunity in broiler chickens compared with other groups (P < 0.05). Birds fed the diet supplemented with different types of additives showed significantly higher dinitrochlorobenzene (DNCB) compared with the control group at 32 days of age (P < 0.05). Dietary inclusion of the encapsulated EOs with and without probiotic both significantly increased villus length and villus width in comparison to other groups (P < 0.05). The highest and lowest ratios were observed for the control group and probiotic+encapsulated TEO+OEO group respectively. These results indicate that feeding birds with diet containing encapsulated EOs alone or together with probiotic could improve BWG, immune responses and intestinal morphology in broiler chickens.

This study examines the effect of high-velocity oxy-fuel (HVOF) coatings of Inconel, aluminum, and Colmonoy on the corrosion resistance of stainless steel substrates. The coated samples were characterized using SEM, XRD, and EDS techniques. Impedance and Tafel tests were used to investigate the coatings corrosion responses at 40, 50, and 60 °C. Inconel-coated specimens showed superior corrosion behavior thanks to the Cr2O3 layers formed between the lamella structures of the coating, preventing chloride ions from diffusing across the coating. Although the Nyquist curve indicated oxide layer formation for the Al-coated sample, the Tafel test results showed severe corrosion. [ABSTRACT FROM AUTHOR]

In this study, a simple mathematical model is introduced to predict the stress–strain curves under the occurrence of minor dynamic recrystallization. In this regard, first, with the assumption of nonlinear variation of strain-hardening rate versus strain, a mathematical equation was derived to obtain the strain-hardening rate. Then, using the Voce's equation, a new mathematical model was developed to predict the hot deformation behavior of metallic alloys at high strain rates. The most important feature of the proposed model is its simplicity so that the only constant of the stress–strain equation can easily be interpolated at different temperatures and strain rates. Accordingly, it was found that the defined material constant varies linearly and exponentially with strain rate and temperature, respectively. The high correlation factors (average correlation factor, r 2 = 0.85) obtained from regression analysis showed that the model can provide a precise estimation of flow stress curves for the defined deformation conditions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Change in the lower extremity alignments in the frontal plane and muscle activation patterns during pedaling is associated with patellofemoral pain (PFP) and iliotibial band (ITB) syndrome. Therefore, the aim of the present study was to determine the effect of band loop on kinematic and electromyography of lower extremities during pedaling. Materials and Methods: In this descriptive study, Kinematic information of the lower extremity and the electromyographic activity of muscles of 30 male students (normal=15, Genuvarum (GV)=15) in the Movafaghian Clinic in Tehran were recorded during pedaling with and without band loop in 10 pedaling cycles of last 30 seconds. Independent t-test and paired t-test were used to analyze the data. Results: The results showed a significant difference in the gluteus medius (Gmed) muscle activation (p=0.001) and Gmed/tensor fasciae latae (TFL) activity ratio in both groups (normal p= 0.042, GV p= 0.045), onset of TFL (p=0.007) and offset of Gmed activity (p=0.018) in the normal group, and the onset of Gmed muscle (p=0.048), offset of Gmed (p=0.047) and mean knee abduction angle (p=0.047) in the GV group. Also, the results showed a significant difference in TFL activation with and without the loop across the two groups (with loop p= 0.001, without loop p= 0.003) and the mean (p=0.021) and maximum knee abduction angle (p=0.027) without loop between the two groups. Conclusion: Pedaling with loop band can be an effective method to increase the function and activation of Gmed muscle while decreasing TFL, improving knee kinematics in the frontal plane and knee stability to prevent injury in the normal and GV groups. [ABSTRACT FROM AUTHOR]

Within Iran, there is little archaeological evidence for relationships between newly arrived Early Trans‐Caucasian (ETC) or Kura‐Araxes settlers and earlier inhabitants and contact with neighbouring cultures, or for their apparently abrupt end. Based on the evidence, the Iranian Kura‐Araxes was not a simple 'copy' of the Caucasian Kura‐Araxes package. Ceramic traditions show local peculiarities, and all are elements suggesting that the Kura‐Araxes traditions went through processes of adaptation, change and re‐elaboration according to local tastes and technologies. In this study, an archaeometric approach to ceramics in the Kolyaei Plain of central Zagros contributes to the discussion of contact and exchange between indigenous communities and several cultural spheres of influence on the Early Bronze Age (beginning in the fourth millennium bce). Morphological data, as well as the mineralogical and chemical composition of ceramics, were applied to determine the major and trace elements of the pottery shards. Based on the trace element profiles, it can be suggested that all the pottery shards are in the same group and they strongly are local products. The ceramic provenance indicates the same patterns of material interactions during the ETC or Kura‐Araxes in all the sites within the Kolyaei Plain. [ABSTRACT FROM AUTHOR]

Abstract: A simple, efficient, and environmentally benign method has been developed for the synthesis of 2-amino-4H-chromenes under the heterogeneous catalysis of nanocrystalline magnesium oxide in aqueous media in excellent yields at room temperature. This method provides a green and improved pathway for the synthesis of chromenes in the terms of excellent yields, short reaction times and reusability catalyst. [Copyright &y& Elsevier]

The effect of microbial consortia on the alteration of petroleum residual structure and portions was studied, which can propose an alternative or complementary method for stringent upgrading heavy crude oil methods, which consist of heavy and complex hydrocarbons. Biological processing of petroleum heavy fractions and residua may provide an alternative or complementary process in refining heavy crudes—the dominant refinery feed in the future—with less severe process conditions and higher selectivity to upgrade heavy fractions of crude oil. The primary objective was to observe the ability of an indigenous bacterial consortium taken from a soil bellow the vacuum column contaminated with vacuum residue (VR) for several decades from the Tehran refinery distillation unit, in degradation of residua components. Enrichment with VR, as sole source of carbon and energy, is the selected biosurfactant-producing microbial consortium. The biodegradation of net VR using indigenous consortia from this specific ecosystem was studied. The considered period of biodegradation of these heavy hydrocarbons was remarkably shorter than usual studies. Bacterial growth and VR biodegradation ability of this consortium analyzed with SARA test in 20 days. Studying the inoculum size and aeration effect revealed the significance of oxygen for this consortia activity and the similarity of 7% and 5% inoculation on alteration percentage of alkane, aromatic, and asphaltene and resin in VR. Results study revealed a 30.4%, 6.9%, and 9.4% decrease in the asphaltene, aromatics, and saturated aliphatic contents of VR, respectively, in only 20 days in 30°C at 150 rpm. [ABSTRACT FROM PUBLISHER]

Dosimetric parameters of a dedicated stereotactic linear accelerator have been investigated using measurements and Monte Carlo simulations. This linac has a unique built in multileaf collimation (MLC) system with the maximum opening of 16×21 cm2 and 4 mm leaf width at the isocenter and has successfully been modeled for the first time using the Monte Carlo simulation. The high resolution MLC, combined with its relatively large maximum field size, opens up a new opportunity for expanding stereotactic radiation treatment techniques from traditionally treating smaller targets to larger ones for both cranial and extracranial lesions. Dosimetric parameters of this linac such as accuracy of leaf positioning and field shaping, leakage and transmission, percentage depth doses, off-axes dose profiles, and dose penumbras were measured and calculated for different field sizes, depths, and source to surface distances. In addition, the ability of the linac in accurate dose delivery of several treatment plans, including intensity modulated radiation therapy (IMRT), performed on phantom and patients was determined. Ionization chamber, photon diode detector, films, several solid water phantoms, and a water tank were used for the measurements. The MLC leaf positioning to any particular point in the maximum aperture was accurate with a standard deviation of 0.29 mm. Maximum and average leakages were 1.7% and 1.1% for the reference field of 10.4×9.6 cm2. Measured penumbra widths (80%–20%) for this field at source axis distance (SAD) of 100 cm at a depth of 1.5 cm (dmax) were 3.2 and 4 mm for the leaf-sides and leaf-ends, respectively. The corresponding results at 10 cm depth and SAD=100 cm were 5.4 and 6.3 mm. Monte Carlo results generally agreed with the measurements to within 1% and or 1 mm, with respective uncertainties of 0.5% and 0.2 mm. The linac accuracy in delivering non-IMRT treatment plans was better than 1%. Ionization chamber dosimetry results for a phantom IMRT plan in the high dose and low dose regions were -0.5% and +3.6%, respectively. Dosimetry results at isocenter for three patients’ IMRT plans were measured to be within 3% of their corresponding treatment plans. Film dosimetry was also used to compare dose distributions of IMRT treatment plans and delivered cumulative doses at different cross sectional planes. [ABSTRACT FROM AUTHOR]

Abstract Background RNA interference is a gene regulatory mechanism that employs small RNA molecules such as microRNA. Previous work has shown that HIV-1 produces TAR viral microRNA. Here we describe the effects of the HIV-1 TAR derived microRNA on cellular gene expression. Results Using a variation of standard techniques we have cloned and sequenced both the 5' and 3' arms of the TAR miRNA. We show that expression of the TAR microRNA protects infected cells from apoptosis and acts by down-regulating cellular genes involved in apoptosis. Specifically, the microRNA down-regulates ERCC1 and IER3, protecting the cell from apoptosis. Comparison to our cloned sequence reveals possible target sites for the TAR miRNA as well. Conclusion The TAR microRNA is expressed in all stages of the viral life cycle, can be detected in latently infected cells, and represents a mechanism wherein the virus extends the life of the infected cell for the purpose of increasing viral replication.

Abstract Background Hodgkin's lymphoma (HL) survivors who undergo radiotherapy experience increased risks of second cancers (SC) and cardiac sequelae. To reduce such risks, extended-field radiotherapy (RT) for HL has largely been replaced by involved field radiotherapy (IFRT). While it has generally been assumed that IFRT will reduce SC risks, there are few data that quantify the reduction in dose to normal tissues associated with modern RT practice for patients with mediastinal HL, and no estimates of the expected reduction in SC risk. Methods Organ-specific dose-volume histograms (DVH) were generated for 41 patients receiving 35 Gy mantle RT, 35 Gy IFRT, or 20 Gy IFRT, and integrated organ mean doses were compared for the three protocols. Organ-specific SC risk estimates were estimated using a dosimetric risk-modeling approach, analyzing DVH data with quantitative, mechanistic models of radiation-induced cancer. Results Dose reductions resulted in corresponding reductions in predicted excess relative risks (ERR) for SC induction. Moving from 35 Gy mantle RT to 35 Gy IFRT reduces predicted ERR for female breast and lung cancer by approximately 65%, and for male lung cancer by approximately 35%; moving from 35 Gy IFRT to 20 Gy IFRT reduces predicted ERRs approximately 40% more. The median reduction in integral dose to the whole heart with the transition to 35 Gy IFRT was 35%, with a smaller (2%) reduction in dose to proximal coronary arteries. There was no significant reduction in thyroid dose. Conclusion The significant decreases estimated for radiation-induced SC risks associated with modern IFRT provide strong support for the use of IFRT to reduce the late effects of treatment. The approach employed here can provide new insight into the risks associated with contemporary IFRT for HL, and may facilitate the counseling of patients regarding the risks associated with this treatment.

Purpose/Objective(s): The purpose of this study was to retrospectively evaluate the dosimetric coverage of I-125 plaque brachytherapy (IBT) specific to juxtapapillary choroidal melanoma (JCM) using the Plaque Simulator treatment planning system. Materials and Methods: Thirty patients with medium-sized JCM treated using COMS IBT and loaded non-uniformly but with circular symmetry, were identified from a prospective database. The distance from the tumor edge to the optic disk ranged from 0.75-2.5 mm, the median tumour thickness and longest diameter was 4.3 mm and 9.9 mm, respectively. The proximity of the tumor to the optic nerve did not allow the round plaque to be centered over the tumor, so the tumor edge closest to the optic nerve did not receive the dose specified as per the COMS study. Initially these cases were planned with an in-house treatment planning system, and each case was replanned with the Plaque Simulator treatment planning system (BEBIG, Germany) for accurate dosimetric evaluations. Results: With all corrections for dose calculation "ON" in the Plaque Simulator, mean dose to the tumor edge nearestthe optic nerve was significantly lowerthan COMS recommendations (61 Gy vs. 69Gy, p<0.02). However, the tumour control rate was 90%, eye preservation rate was 90%, and rate of developing systemic metastases was 7%. Complications included cataract in 53%, neovascular glaucoma in 10%, retinopathy in 53%, and papillopathy in 33% of patients which was comparable to previously reported COMS outcomes. Conclusion Despite relative underdosing secondary to the physical impediment of the optic nerve for JCM, our results imply that the tumor edge may not need as high a dose as compared to the tumor apex. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Proteogenomics is a growing "multi-omics" research area that combines mass spectrometry-based proteomics and high-throughput nucleotide sequencing technologies. Proteogenomics has helped in genomic annotation for organisms whose complete genome sequences became available by using high-throughput DNA sequencing technologies. Apart from genome annotation, this multi-omics approach has also helped researchers confirm expression of variant proteins belonging to unique proteoforms that could have resulted from single-nucleotide polymorphism (SNP), insertion and deletions (Indels), splice isoforms, or other genome or transcriptome variations.A proteogenomic study depends on a multistep informatics workflow, requiring different software at each step. These integrated steps include creating an appropriate protein sequence database, matching spectral data against these sequences, and finally identifying peptide sequences corresponding to novel proteoforms followed by variant classification and functional analysis. The disparate software required for a proteogenomic study is difficult for most researchers to access and use, especially those lacking computational expertise. Furthermore, using them disjointedly can be error-prone as it requires setting up individual parameters for each software. Consequently, reproducibility suffers. Managing output files from each software is an additional challenge. One solution for these challenges in proteogenomics is the open-source Web-based computational platform Galaxy. Its capability to create and manage workflows comprised of disparate software while recording and saving all important parameters promotes both usability and reproducibility. Here, we describe a workflow that can perform proteogenomic analysis on a Galaxy-based platform. This Galaxy workflow facilitates matching of spectral data with a customized protein sequence database, identifying novel protein variants, assessing quality of results, and classifying variants along with visualization against the genome., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Fatigue leads to an acute decline in muscle strength, altered patterns of lower extremity muscle activation, changes in hip and knee kinematics. In terms of the effects of fatigue on knee joint kinematics during plyometric training, there is still a lack of knowledge regarding kinematic differences between athletes who passed the ACL reconstructions rehabilitation period and healthy athletes. Therefore, this study aimed to compare lower limb joint kinematic parameters between reconstructed cruciate ligament and healthy control soccer players during jump landing in a fatigued setting., Methods: Lower limb kinematic parameters were recorded in 20 professional soccer players (age, 24.95 ± 2.92 years; body mass, 77.20 ± 12.88 kg; height, 1.77 ± 3.19 m) during jump landing task before and after the fatigue protocol. The control group consisted of healthy subjects and the experimental group consisted of subjects with ACL reconstruction by thigh transplantation. Kinematic data was recorded with 4 cameras to measure lower limb angles at first foot contact and maximum range of motion., Results: The results showed that before fatigue, there was only a significant difference between the two groups in the maximum range of motion of the non-involved hip joint (P = 0.022) and angle of the involved hip at first contact (P = 0.049). In other data on joint range of motion or initial contact angle, no significant difference was observed between the two groups (P > 0.05). After fatigue protocol, there was a significant difference in initial foot contact in non-involved (P = 0.030), and involved (P = 0.020) hip joint angles between the two groups. However, no significant difference in initial contact angle or range of motion of other joints was observed between the groups., Conclusions: This study shows that plyometric fatigue does not contribute to numerous changes in contact angles and range of motion in lower extremity joints in healthy soccer players and those with a history of cruciate ligament repairs., (© 2024. The Author(s).)

Blastocystis is the most common gastrointestinal protozoan parasite of humans and many vertebrates. This study was carried out to investigate the prevalence and determination subtype (ST) of Blastocystis in domestic ruminants of Shahrekord County, southwestern Iran. In this descriptive cross-sectional study, 330 ruminant fecal samples (107 cows, 115 sheep, and 108 goats) were evaluated by parasitological methods (direct wet mount microscopic examination and formalin-ether concentration), Giemsa staining, In vitro xenic culture (The modified Dobell and Laidlaw culture method), polymerase chain reaction, and sequencing from 2018 to 2019, then data were analyzed using SPSS software version 21. The overall Blastocystis positive in ruminants was 14.2% and the frequency of Blastocystis sp. in cattle, sheep, and goats were 0.93%, 17.4%, and 24.1% respectively. Molecular diagnosis techniques revealed that ruminants were infected with four STs (genotypes) of Blastocystis including ST5(21.3%), ST7(2.1%), ST10(17.1%) and ST14(57.4%). Also, the STs identified in cows were ST10, and the observed STs in sheep were ST5 (40%), ST7 (3%), ST10 (5%), ST14 (45%), and one unknown subspecies. Goats were infected by ST5 (7.7%), ST10 (23.1%), and ST14 (69.2%). In this study, ST14 was identified as the most common subtype of Blastocystis sp. that was not common between humans and livestock, meanwhile, ST5 and ST7 are common between humans and animals accounted 21.3% and 2.1% of the positive cases, respectively, and reinforces the hypothesis that ruminants are reservoirs of blastocystosis in humans., (© 2024. The Author(s).)

Introduction: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised., Methods: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation., Results: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC + ) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub + ), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5 + ( P =0.018) and LAMB3 + ( P =0.050) expression, as well as a significant activation of Wnt-specific ( P =0.014) and Notch-specific ( P =0.021) genes, especially in precursors of suprabasal and secretory cells., Conclusion: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pulmonary vascular disease (PVD) affects the majority of preterm neonates with bronchopulmonary dysplasia (BPD) and significantly determines long-term mortality through undetected progression into pulmonary hypertension. Our objectives were to associate characteristics of pulmonary artery (PA) flow and cardiac function with BPD-associated PVD near term using advanced magnetic resonance imaging (MRI) for improved risk stratification., Methods: Preterms <32 weeks postmenstrual age (PMA) with/without BPD were clinically monitored including standard echocardiography and prospectively enrolled for 3 T MRI in spontaneous sleep near term (AIRR (Attention to Infants at Respiratory Risks) study). Semi-manual PA flow quantification (phase-contrast MRI; no BPD n=28, mild BPD n=35 and moderate/severe BPD n=25) was complemented by cardiac function assessment (cine MRI)., Results: We identified abnormalities in PA flow and cardiac function, i.e. increased net forward volume right/left ratio, decreased mean relative area change and pathological right end-diastolic volume, to sensitively detect BPD-associated PVD while correcting for PMA (leave-one-out area under the curve 0.88, sensitivity 0.80 and specificity 0.81). We linked these changes to increased right ventricular (RV) afterload (RV-arterial coupling (p=0.02), PA mid-systolic notching (t2; p=0.015) and cardiac index (p=1.67×10 -8 )) and correlated echocardiographic findings. Identified in moderate/severe BPD, we successfully applied the PA flow model in heterogeneous mild BPD cases, demonstrating strong correlation of PVD probability with indicators of BPD severity, i.e. duration of mechanical ventilation (r s =0.63, p=2.20×10 -4 ) and oxygen supplementation (r s =0.60, p=6.00×10 -4 )., Conclusions: Abnormalities in MRI PA flow and cardiac function exhibit significant, synergistic potential to detect BPD-associated PVD, advancing the possibilities of risk-adapted monitoring., Competing Interests: Conflict of interest: No authors have any potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

The efficiency of perovskite/silicon tandem solar cells has exceeded the previous record for III-V-based dual-junction solar cells. This shows the high potential of perovskite solar cells in multi-junction applications. Perovskite/perovskite/silicon triple-junction solar cells are now the next step to achieve efficient and low-cost multi-junction solar cells with an efficiency potential even higher than that for dual-junction solar cells. Here we present a perovskite/perovskite/silicon triple-junction solar cell with an open circuit voltage of >2.8 V, which is the record value reported for this structure so far. This is achieved through employing a gas quenching method for deposition of the top perovskite layer as well as optimization of interlayers between perovskite subcells. Moreover, for the measurement of our triple-junction solar cells, precise measurement procedures are implemented to ensure the reliability and accuracy of the reported values., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (Fi O 2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-β pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area. NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Introduction: Inflammation is a key driver of morbidity in the vulnerable preterm infant exposed to pre- and postnatal hazards and significantly contributes to chronic lung disease, i.e. bronchopulmonary dysplasia (BPD). However, the early changes in innate immunity associated with BPD development are incompletely understood., Methods: In very immature preterm infants below 32 weeks gestational age (GA; n=30 infants), monocyte subtypes were identified by Flow Cytometry at birth and throughout the postnatal course including intracellular TNF expression upon LPS stimulation. Complementing these measurements, cytokine end growth factor expression profiles (Luminex ® xMAP ® ; n=110 infants) as well as gene expression profiles (CodeLink TM Human I Bioarray; n=22) were characterized at birth., Results: The abundance of monocyte subtypes differed between preterm and term neonates at birth. Specifically, CD14 ++ CD16 + (intermediate) monocytes demonstrated a dependency on PMA and elevated levels of nonclassical (CD14 + CD16 ++ ) monocytes characterized preterm infants with developing BPD. Postnatally, lung injury was associated with an increase in intermediate monocytes, while high levels of nonclassical monocytes persisted. Both subtypes were revealed as the main source of intracellular TNF-α expression in the preterm infant. We identified a cytokine and growth factor expression profile in cord blood specimen of preterm infants with developing BPD that corresponded to the disease-dependent regulation of monocyte abundances. Multivariate modeling of protein profiles revealed FGF2, sIL-2 Rα, MCP-1, MIP1a, and TNF-α as predictors of BPD when considering GA. Transcriptome analysis demonstrated genes predicting BPD to be overrepresented in inflammatory pathways with increased disease severity characterized by the regulation of immune and defense response pathways and upstream regulator analysis confirmed TNF-α, interleukin (IL) -6, and interferon α as the highest activated cytokines in more severe disease. Whereas all BPD cases showed downstream activation of chemotaxis and activation of inflammatory response pathways , more severe cases were characterized by an additional activation of reactive oxygen species (ROS) synthesis., Discussion: In the present study, we identified the early postnatal presence of nonclassical (CD14 + CD16 ++ ) and intermediate (CD14 ++ CD16 + ) monocytes as a critical characteristic of BPD development including a specific response pattern of monocyte subtypes to lung injury. Pathophysiological insight was provided by the protein and transcriptome signature identified at birth, centered around monocyte and corresponding granulocyte activation and highlighting TNFα as a critical regulator in infants with developing BPD. The disease severity-dependent expression patterns could inform future diagnostic and treatment strategies targeting the monocytic cell and its progeny., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Windhorst, Heydarian, Schwarz, Oak, Förster, Frankenberger, Gonzalez Rodriguez, Zhang, Ehrhardt, Hübener, Flemmer, Hossain, Stoeger, Schulz and Hilgendorff.)

High mobility group A1 (HMGA1) chromatin regulators are upregulated in diverse tumors where they portend adverse outcomes, although how they function in cancer remains unclear. Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors characterized by dense desmoplastic stroma composed predominantly of cancer-associated fibroblasts and fibrotic tissue. Here, we uncover an epigenetic program whereby HMGA1 upregulates FGF19 during tumor progression and stroma formation. HMGA1 deficiency disrupts oncogenic properties in vitro while impairing tumor inception and progression in KPC mice and subcutaneous or orthotopic models of PDAC. RNA sequencing revealed HMGA1 transcriptional networks governing proliferation and tumor-stroma interactions, including the FGF19 gene. HMGA1 directly induces FGF19 expression and increases its protein secretion by recruiting active histone marks (H3K4me3, H3K27Ac). Surprisingly, disrupting FGF19 via gene silencing or the FGFR4 inhibitor BLU9931 recapitulates most phenotypes observed with HMGA1 deficiency, decreasing tumor growth and formation of a desmoplastic stroma in mouse models of PDAC. In human PDAC, overexpression of HMGA1 and FGF19 defines a subset of tumors with extremely poor outcomes. Our results reveal what we believe is a new paradigm whereby HMGA1 and FGF19 drive tumor progression and stroma formation, thus illuminating FGF19 as a rational therapeutic target for a molecularly defined PDAC subtype.