A case report of successful combined intra-arterial immunotherapy and cytokine genetic therapy treatment in a patient with recurrent glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor with very poor prognosis due to frequent recurrence and short overall survival (OS) time, which according to different sources, is not longer than 17 months after the diagnosis. Infiltrative growth pattern often leads to tumor propagation into functionally significant brain areas while surgery is cytoreductive and does not necessarily alter the prognosis. Many patients are in the working age, thus finding conservative approaches to the treatment of this type of neoplasms is of utmost importance. The aim of the work is to demonstrate the effectiveness of treatment of GBM using cytokine genetic therapy (CGT) and present an algorithm for patient management. CASE DESCRIPTION: This paper describes the first case of successful intra-arterial (IA) bevacizumab therapy with following CGT of a 46-year-old patient with recurrent GBM after a combined treatment. Sixteen courses of 15 mg/kg IA bevacizumab with hyperosmolar opening of blood-brain barrier (BBB) resulted in stabilization of the neoplastic process. After that, 9 courses of CGT with recombinant interferon gamma (IFN-γ) and tumor necrosis factor (TNF)-thymosin α1 were performed. Both magnetic resonance imaging (MRI) with contrast and positron emission tomography (PET) confirmed a complete response to the combined treatment. OS time is currently more than 25 months from the diagnosis. The observation continues. CONCLUSIONS: This case study expands the range of treatment options for GBM, especially in the context of intolerance and high toxicity of cytostatic drugs, and may lead to improved recurrence-free survival (RFS).

Health effects and user perceptions of the US Customs and Border Patrol One™ mobile application: A qualitative analysis among asylum seekers at the Mexico-US border.

Background: The number of migrants at the Mexico-US border has increased to historic levels, and frequently changing immigration policy impacts this population as they await entry into the US. This study evaluated the usability and health effects of the Customs and Border Protection (CBP) One™ mobile application among asylum seekers near the US port of entry in Reynosa, Mexico. Methods: We conducted semi-structured qualitative interviews with 20 asylum seekers in Reynosa, Mexico, in February 2023. Our objective was to explore the subjective experiences of migrants, usability of CBP One™, and presence of perceived health effects from using the application. Interviews were conducted until saturation occurred, transcribed verbatim into Word, coded in NVivo using a validated, team-based coding methodology, and analyzed according to internal domains, external domains, and health effects regarding CBP One™. Results: Twenty participants originated from eight countries throughout Latin America and the Caribbean. In total, 18 subthemes were identified among internal, external, and effects domains. Internal themes included a confusing application interface (80%), technical malfunction (60%), and perceived racial bias from the photo-capture features (15%). External themes challenging CBP One™ use included unavailable appointment slots (80%), inequity and inaccessibility (35%), and inadequate internet (25%). Most perceived effects were negative (85%), including worsening mental health effects (40%), exacerbation of pre-existing physical conditions (35%), and forgoing health expenditures to pay for internet (25%). Conclusions: Our findings suggest that asylum seekers at the Reynosa port of entry perceive CBP One™ negatively, with detrimental effects towards their mental and physical health. This study highlights how immigration policy can influence health and suggests that more creative and humane approaches are needed for people seeking asylum at the Mexico-US border.

Outcomes of COVID-19 in 24 hospitalized liver transplant recipients: an observational study.

BACKGROUND: Although liver transplant (LT) recipients are considered a population at risk of severe features of coronavirus disease 2019 (COVID-19), data in this regard are scarce and controversial. In this study, we reported the outcome of 24 cases of LT recipients who were hospitalized due to COVID-19 and investigated the role-playing factors in the severity of the disease. METHODS: In this single-center, analytic case-series study, eligible patients were among LT recipients who were hospitalized due to the diagnosis of COVID-19 based on positive results of polymerase chain reaction. Participants were categorized as severe COVID-19 if they were admitted to the intensive care unit, experienced respiratory failure demanding mechanical ventilation, or eventually died. Demographic and clinical data, COVID-19 symptoms and specific treatments, laboratory biomarkers, and immunosuppressive regimens and their alteration during the admission were recorded. Analysis was done using SPSS software. RESULTS: Twenty-four hospitalized LT patients were included, of which nine had severe and fifteen had non-severe COVID-19. Out of 9 patients with severe COVID-19, four sadly died. The analysis and comparison between the two groups revealed longer hospital stays (P = 0.02), lower lymphocyte counts (P = 0.002), and higher levels of C-reactive protein (CRP) (P = 0.006) in patients with severe COVID-19. Patients with non-severe COVID-19 had higher doses of tacrolimus and mycophenolate in their baseline immunosuppressive regimen (both P = 0.02). CONCLUSION: Lymphopenia and high CRP levels are associated with more severe forms of COVID-19 in LT patients. Mycophenolate may have protective properties against severe COVID-19. The role of severity indicators in LT patients with COVID-19 needs to be systematically recognized.

The common Sting1 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice.

The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.

The human health risks assessment posed by the presence of heavy metals in the rice varieties available in the Neyshabur market.

The present study was designed to determine the levels of heavy metals (Cu, Pb, Ni, Cr, Zn, Mn, Cd, and Co), Mn, and As in Iranian-grown rice and imported rice consumed in Neyshabur City. For this research, 90 samples from 30 different brands widely consumed in this city were collected. The content of heavy metals and the health risks associated with their use were then studied. The study found that Zn (14.21 mg kg-1) had the highest content in Iranian and imported rice varieties, whereas Cd (0.02 mg kg-1) had the lowest value. The health risk assessment was also done in three scenarios and separately for two types of rice. The results showed that the total hazard quotient (i.e., THQ) was measured for all metals and all three scenarios, and for both types of rice, it is THQ > 1, which indicates the risk of non-carcinogenic in rice. The cancer risk for three scenarios and two types of imported and Iranian rice is in the unsafe range for As (8.80 × 10-4 to 7.00 × 10-3), Ni (4.60 × 10-4 to 3.60 × 10-3) and Cr (2.20 × 10-4 to 1.90 × 10-3) and negligible for Pb (1.09 × 10-6 to 1.49 × 10-5) and Cd (7.83 × 10-6 to 8.20 × 10-5).

Integrating remote sensing and geophysical data for mapping potential gold mineralization localities at Abu Marawat area, central Eastern Desert, Egypt.

Abu Marawat area in the Central Eastern Desert of Egypt is a very promising mineralization district located in the Golden Triangle area. The current study provides an integrated approach from multisource datasets including; remote sensing, airborne geophysical spectrometry and magnetic data supported by field studies and spectroscopic analyses for delineating potential mineralization localities. Several remote sensing techniques were adopted including; Band Ratios, Relative Band Depth, Mineralogical Indices, Spectral Angle Mapper, and Constrained Energy Minimization. These techniques showed that the alteration mineral assemblage is mainly, kaolinite, sericite, and iron oxides, with less abundant chlorite, epidote, and carbonates. In addition, the radiometry data were processed to map the localities with the highest possibility of potassic alteration abundance by integrating the potassium distribution, K/eTh ratio, and the F-parameter maps. The surface and subsurface linear structural features were also mapped using Digital Elevation Model (DEM) and aeromagnetic data, respectively. The surface linear structures were found exhibiting E-W and NE-SW trends, while, the subsurface structures showed dominant NW-SE trend. All the depicted fault trends match well with the local and regional geological and tectonic setting of the study area suggesting structural control on the mineralization in this area. Integration between the results obtained from both the remote sensing and the geophysical data was conducted by a GIS weighted overlay model. The obtained mineralization potentiality map highlights eight potential localities for mineralization. The accuracy of the adopted methodology was demonstrated through fieldwork and spectral analyses; several alteration indicators were observed, including quartz veins, iron oxides, kaolinite, malachite, montmorillonite, chlorite, talc, and sericite alteration indicator minerals. The adopted remote sensing-geophysical approach showed being very effective for mapping the hydrothermal gold-related alteration zones, and is recommended for other similar investigations.

Engineering hemin-loaded hyaluronan needle-like microparticles with photoprotective properties against UV-induced tissue damage.

This study aimed to develop hyaluronan (HA)-based hydrogel microparticles (MPs) loaded with hemin to address the limitations of traditional macroscale hydrogels. The objective is to design MPs such that they can modulate their physicochemical properties. Given the widespread use of ultraviolet C (UVC) light in various industries and the need for protective measures against accidental exposure, this study evaluated the potential of hemin-loaded MPs to protect human dermal fibroblasts from oxidative stress and cell death caused by UVC exposure. Multiple MP formulations were developed and analysed for size, surface charge, swelling behaviour, degradation rate, and radical scavenging capabilities, both with and without hemin loading. The most promising formulations were tested against UVC-exposed cells to assess cell viability, intracellular nitric oxide (˙NO) and reactive oxygen species levels, and protein carbonylation. The fabricated particles were in the form of microneedles, and the degree of their crosslinking and the role of hemin in the chemical crosslinking reaction were found to influence the surface charge and hydrodynamic diameter of the MPs. Increased crosslinking resulted in reduced swelling, slower degradation, and decreased hemin release rate. MPs with a higher degree of swelling were capable of releasing hemin into the culture medium, leading to enhanced bilirubin generation in dermal fibroblasts following cellular uptake. Pre-treatment with these MPs protected the cells from UVC-induced cell death, nitrosative stress, and protein carbonylation. These findings highlight the potential of the studied MPs to release hemin and to minimise the harmful effects of UVC on dermal fibroblasts.

Preterm birth risk stratification through longitudinal heart rate and HRV monitoring in daily life.

Preterm birth (PTB) remains a global health concern, impacting neonatal mortality and lifelong health consequences. Traditional methods for estimating PTB rely on electronic health records or biomedical signals, limited to short-term assessments in clinical settings. Recent studies have leveraged wearable technologies for in-home maternal health monitoring, offering continuous assessment of maternal autonomic nervous system (ANS) activity and facilitating the exploration of PTB risk. In this paper, we conduct a longitudinal study to assess the risk of PTB by examining maternal ANS activity through heart rate (HR) and heart rate variability (HRV). To achieve this, we collect long-term raw photoplethysmogram (PPG) signals from 58 pregnant women (including seven preterm cases) from gestational weeks 12-15 to three months post-delivery using smartwatches in daily life settings. We employ a PPG processing pipeline to accurately extract HR and HRV, and an autoencoder machine learning model with SHAP analysis to generate explainable abnormality scores indicative of PTB risk. Our results reveal distinctive patterns in PTB abnormality scores during the second pregnancy trimester, indicating the potential for early PTB risk estimation. Moreover, we find that HR, average of interbeat intervals (AVNN), SD1SD2 ratio, and standard deviation of interbeat intervals (SDNN) emerge as significant PTB indicators.

Open Versus Endoscopic Approach for Thoracic Disk Herniations: Equivalent Short-Term Outcomes With Significantly Different Costs.

BACKGROUND AND OBJECTIVES: Open thoracic diskectomy often requires significant bone resection and fusion, whereas an endoscopic thoracic diskectomy offers a less invasive alternative. Therefore, we sought to compare one-level open vs endoscopic thoracic diskectomy regarding (1) perioperative outcomes, (2) neurological recovery, and (3) total cost. METHODS: A single-center, retrospective, cohort study using prospectively collected data of patients undergoing one-level thoracic diskectomy was undertaken from 2018 to 2023. The primary exposure variable was open vs endoscopic. The primary outcome was perioperative outcomes and neurological recovery. Secondary outcomes were total cost of care. Multivariable regression analysis controlled for age, body mass index, sex, symptom onset, disk characteristics, operative time, and length of stay. RESULTS: Of 29 patients undergoing thoracic diskectomy, 17 were open and 12 were endoscopic. Preoperative demographics, symptoms, and radiographic findings were comparable between the cohorts. Perioperatively, open surgery had significantly higher mean length of stay (4.9 ± 1.5 vs 0.0 ± 0.0 days, P < .001), median (IQR) longer operative time (342.8 [68.4] vs 141.5 [36] minutes, P < .001), and more blood loss (350 [390] vs 6.5 [20] mL; P < .001). 16 (94%) open patients required fusion vs 0 endoscopic (P < .001). Postoperative opioid use (P = .119), readmission (P = .665), reoperation (P = .553), and rate of neurological improvement (P > .999) were similar between the 2 groups. Financially, open surgical median costs were 7x higher than endoscopic ($59 792 [$16 118] vs $8128 [$1848]; P < .001), driven by length of stay (ß = $2261/night, P < .001), open surgery (ß = $24 106, P < .001), and number of pedicle screws (ß = $1829/screw, P = .002) on multivariable analysis. On sensitivity analysis, open surgery was never cost-efficient against endoscopic surgery and excess endoscopic revision rates of 86% above open revision rates were required for break-even costs between the surgical approaches. CONCLUSION: Endoscopic thoracic diskectomy was associated with decreased length of stay, operative time, blood loss, and total cost compared with the open approach, with similar neurological outcomes. These findings may help patients and surgeons seek endoscopic approach as a less morbid and less costly alternative.

MerTK-dependent efferocytosis by monocytic-MDSCs mediates resolution of post-lung transplant ischemia-reperfusion injury.

Lung transplantation (LTx) outcomes are impeded by ischemia-reperfusion injury (IRI) and subsequent chronic lung allograft dysfunction (CLAD). We examined the undefined role of MerTK (receptor Mer tyrosine kinase) on monocytic myeloid-derived suppressor cells (M-MDSCs) in efferocytosis to facilitate resolution of lung IRI. Single-cell RNA sequencing of lung tissue and bronchoalveolar lavage (BAL) from post-LTx patients were analyzed. Murine lung hilar ligation and allogeneic orthotopic LTx models of IRI were used with Balb/c (WT), Cebpb-/- (MDSC-deficient), Mertk-/- or MerTK-CR (cleavage resistant) mice. A significant downregulation in MerTK-related efferocytosis genes in M-MDSC populations of CLAD patients was observed compared to healthy subjects. In the murine IRI model, significant increase in M-MDSCs, MerTK expression, efferocytosis and attenuation of lung dysfunction was observed in WT mice during injury resolution that was absent in Cebpb-/- and Mertk-/- mice. Adoptive transfer of M-MDSCs in Cebpb-/- mice significantly attenuated lung dysfunction and inflammation. Additionally, in a murine orthotopic LTx model, increases in M-MDSCs were associated with resolution of lung IRI in the transplant recipients. In vitro studies demonstrated the ability of M-MDSCs to efferocytose apoptotic neutrophils in a MerTK-dependent manner. Our results suggest that MerTK-dependent efferocytosis by M-MDSCs can substantially contribute to the resolution of post-LTx IRI.

Revisiting the Posterior Approach for Cervical Radiculopathy Utilizing Endoscopic Techniques: A Favorable Short-Term Outcome and Cost Comparison With Anterior Cervical Discectomy and Fusion.

BACKGROUND: Cervical radiculopathy is a spine ailment frequently requiring surgical decompression via anterior cervical discectomy and fusion (ACDF) or posterior foraminotomy/discectomy. While endoscopic posterior foraminotomy/discectomy is gaining popularity, its financial impact remains understudied despite equivalent randomized long-term outcomes to ACDF. In a cohort of patients undergoing ACDF vs endoscopic posterior cervical foraminotomy/discectomy, we sought to compare the total cost of the surgical episode while confirming an equivalent safety profile and perioperative outcomes. METHODS: A single-center retrospective cohort study of patients with unilateral cervical radiculopathy undergoing ACDF or endoscopic cervical foraminotomy between 2018 and 2023 was undertaken. Primary outcomes included the total cost of care for the initial surgical episode (not charges or reimbursement). Perioperative variables and neurological recovery were recorded. Multivariable analysis tested age, body mass index, race, gender, insurance type, operative time, and length of stay. RESULTS: A total of 38 ACDF and 17 endoscopic foraminotomy/discectomy operations were performed. All patients underwent single-level surgery except for 2 two-level endoscopic decompressions. No differences were found in baseline characteristics and symptom length except for younger age (46.8 ± 9.4 vs 57.6 ± 10.3, P = 0.002) and more smokers (18.4% vs 11.8%, P = 0.043) in the ACDF group. Actual hospital costs for the episode of surgical care were markedly higher in the ACDF cohort (mean ±95% CI; $27,782 ± $2011 vs $10,103 ± $720, P < 0.001) driven by the ACDF approach (ß = $17,723, P < 0.001) on multivariable analysis. On sensitivity analysis, ACDF was never cost-efficient compared with endoscopic foraminotomy, and endoscopic failure rates of 64% were required for break-even cost. ACDF was associated with significantly longer operative time (167.7 ± 22.0 vs 142.7 ± 27.4 minutes, P < 0.001) and length of stay (1.1 ± 0.5 vs 0.1 ± 0.2 days, P < 0.001). No significant difference was found regarding 90-day neurological improvement, readmission, reoperation, or complications. CONCLUSION: Compared with patients treated with a single-level ACDF for unilateral cervical radiculopathy, endoscopic posterior cervical foraminotomy/discectomy can achieve a similar safety profile, pain relief, and neurological recovery at considerably less cost. These findings may help patients and surgeons revisit offering the posterior cervical foraminotomy/discectomy utilizing endoscopic techniques. CLINICAL RELEVANCE: Endoscopic posterior cervical foraminotomy/discectomy offers comparable safety, pain relief, and neurological recovery to traditional methods but at a significantly lower cost.

Examining Hemin and its Derivatives: Induction of Heme-Oxygenase-1 Activity and Oxidative Stress in Breast Cancer Cells through Collaborative Experimental Analysis and Molecular Dynamics Simulations.

Hemin triggers intracellular reactive oxygen species (ROS) accumulation and enhances heme oxygenase-1 (HOX-1) activity, indicating its potential as an anticancer agent, though precise control of its intracellular levels is crucial. The study explores the impact of hemin and its derivatives, hemin-tyrosine, and hemin-styrene (H-Styr) conjugates on migration, HOX-1 expression, specific apoptosis markers, mitochondrial functions, and ROS generation in breast cancer cells. Molecular docking and dynamics simulations were used to understand the interactions among HOX-1, heme, and the compounds. Hemin outperforms its derivatives in inducing HOX-1 expression, exhibiting pro-oxidative effects and reducing cell migration. Molecular simulations show that heme binds favorably to HOX-1, followed by the other compounds, primarily through van der Waals and electrostatic forces. However, only van der Waals forces determine the H-Styr complexation. These interactions, influenced by metalloporphyrin characteristics, provide insights into HOX-1 regulation and ROS generation, potentially guiding the development of breast cancer therapies targeting oxidative stress.

Clinical Effectiveness of Anterior Cervical Discectomy and Fusion Using Tritanium C Anterior Cervical Cage vs. PEEK Cage.

Introduction: Anterior cervical discectomy and fusion (ACDF) has proven to be a clinically efficient and cost-effective method for treating patients with degenerative cervical spine conditions. New intervertebral implant products are being developed to improve fusion and stability while decreasing complications. This study assesses the effectiveness of Tritanium C (Tri-C) Anterior Cervical Cage (Stryker) in the treatment of degenerative disk disease (DDD) of the cervical spine compared with polyetheretherketone (PEEK) cages. Methods: A retrospective cohort analysis was conducted using data prospectively collected from two institutions. Patients who underwent ACDFs for DDD using either the Tri-C cage or PEEK cage were identified. The patients' demographics, comorbidities, operative variables, and baseline patient-reported outcomes (PROs) were collected. PROs included the Neck Disability Index (NDI) and numeric rating scale (NRS) for neck and arm pain. The primary outcomes included 3- and 12-month PROs as well as the rates of 90-day readmission, 90-day reoperation, and perioperative complication. The radiographic outcomes included rates of subsidence, cage movement, and successful fusion within 12 months. Multivariate linear regression models were run to identify variables predictive of 12-month PROs. Results: A total of 275 patients who underwent ACDF were included in this study and were divided into two groups: PEEK (n=213) and Tri-C (n=62). Both groups showed improvement in neck and arm pain and NDI postoperatively. When Tri-C and PEEK were compared, no significant differences were observed in the 3- or 12-month changes in neck or arm pain or NDI. Furthermore, there were no differences in the rates of 90-day readmission, 90-day reoperation, and perioperative complication. Regression analysis revealed that Tri-C vs. PEEK was not a significant predictor of any outcome. Conclusions: Our results indicate that the use of porous titanium Tri-C cage during ACDFs is an effective method for managing cervical DDD in terms of PROs, perioperative morbidity, and radiologic parameters. No significant difference was observed in any clinical outcome between patients undergoing ACDF using the Tri-C cage and those in whom the PEEK cage was used. Level of Evidence: III.

A rare case of spontaneous hemoperitoneum in a bone marrow transplant recipient on VV-ECMO.

A 53-year-old man with acute myeloid leukemia received an allogeneic hematopoietic cell transplant (HCT) from a matched unrelated donor. One month after his transplantation, he developed ARDS requiring initiation of VV-ECMO. He suffered from pancytopenia, managed with frequent transfusions, granulocyte-colony stimulating factor (G-CSF) and weekly thrombopoietin receptor agonist. On ECMO day 17, the patient developed severe hypotension after insertion of a chest tube for a large right-sided pneumothorax. CT angiography of the abdomen showed hemoperitoneum. Exploratory laparotomy revealed approximately 4 L of blood and a ruptured splenic hilum. A splenectomy was performed. Unfortunately, the patient continued to require multiple daily blood products and his condition continued to decline despite two reoperations. His family chose to discontinue ECMO and he passed away peacefully. Spontaneous splenic rupture after GM-CSF has never been reported in patients on VV-ECMO. This manuscript reviews the literature regarding the pathophysiology and clinical manifestation of this rare occurrence.

Costs of Community-Based Viral Hepatitis Screening in Cameroon Using Point-of-Care Technologies.

This cost analysis of a community-based viral hepatitis screening program in Cameroon found an investment of $3.52 per person screened, $50.63 per new diagnosis of hepatitis B, $159.45 per new diagnosis of hepatitis C, and $47.97 per new diagnosis of either hepatitis B or C.

Targeting Macrophage Polarization for Reinstating Homeostasis following Tissue Damage.

Tissue regeneration and remodeling involve many complex stages. Macrophages are critical in maintaining micro-environmental homeostasis by regulating inflammation and orchestrating wound healing. They display high plasticity in response to various stimuli, showing a spectrum of functional phenotypes that vary from M1 (pro-inflammatory) to M2 (anti-inflammatory) macrophages. While transient inflammation is an essential trigger for tissue healing following an injury, sustained inflammation (e.g., in foreign body response to implants, diabetes or inflammatory diseases) can hinder tissue healing and cause tissue damage. Modulating macrophage polarization has emerged as an effective strategy for enhancing immune-mediated tissue regeneration and promoting better integration of implantable materials in the host. This article provides an overview of macrophages' functional properties followed by discussing different strategies for modulating macrophage polarization. Advances in the use of synthetic and natural biomaterials to fabricate immune-modulatory materials are highlighted. This reveals that the development and clinical application of more effective immunomodulatory systems targeting macrophage polarization under pathological conditions will be driven by a detailed understanding of the factors that regulate macrophage polarization and biological function in order to optimize existing methods and generate novel strategies to control cell phenotype.

Transcription Attenuation in Synthetic Promoters in Nonoverlapping Tandem Formation.

Closely spaced promoters are ubiquitous in prokaryotic and eukaryotic genomes. How their structure and dynamics relate remains unclear, particularly for tandem formations. To study their transcriptional interference, we engineered two pairs and one trio of synthetic promoters in nonoverlapping, tandem formation, in single-copy plasmids transformed into Escherichia coli cells. From in vivo measurements, we found that these promoters in tandem formation can have attenuated transcription rates. The attenuation strength can be widely fine-tuned by the promoters' positioning, natural regulatory mechanisms, and other factors, including the antibiotic rifampicin, which is known to hamper RNAP promoter escape. From this, and supported by in silico models, we concluded that the attenuation in these constructs emerges from premature terminations generated by collisions between RNAPs elongating from upstream promoters and RNAPs occupying downstream promoters. Moreover, we found that these collisions can cause one or both RNAPs to falloff. Finally, the broad spectrum of possible, externally regulated, attenuation strengths observed in our synthetic tandem promoters suggests that they could become useful as externally controllable regulators of future synthetic circuits.

Effect of Lactiplantibacillus plantarum on the growth, hemato-biochemical, inflammation, apoptosis, oxidative stress markers, involved gens and histopathological alterations in growing rabbits challenged with aflatoxin B1.

Aflatoxin B1 (AFB1) is a significant pollutant found in food and feed, posing a threat to public health. The objective of this study was to assess the effect of Lactiplantibacillus plantarum (LACP) against AFB1 in growing rabbits by investigating growth, serum metabolites, immunity, antioxidant capacity, and inflammatory response. A total of 60 growing male rabbits (721.5 ± 2.68g) were allocated to 4 experimental groups. The control group receiving only a basal diet, the AFB1 group (0.3 mg AFB1/kg diet), the LACP group (1 × 109 cfu/g /kg diet), and the combination group (1 × 109 cfu/g + 0.3 mg AFB1/kg diet; AFB1+ LACP) for 8 wk. The administration of AFB1 alone significantly decreased the final body weight, body gain, and feed intake, while significantly increasing the feed conversion ratio (P < 0.05). A significant decline in total proteins and globulins, along with elevated levels of hepatic enzymes (AST, ALP, ALT, and GGT) and renal function markers (creatinine and uric acid), were observed in the AFB1-contaminated group (P < 0.05). Immunoglobulins (IgG and IgM) were significantly decreased, alongside a significant elevation of triglycerides, direct bilirubin, and indirect bilirubin in growing rabbits fed diets with AFB1 (P < 0.05). Supplementing the AFB1 diet with LACP restored the growth reduction, improved liver (AST, ALP, ALT, and GGT) and kidney (creatinine and uric acid) functions, and enhanced immune markers in rabbit serum (P < 0.05). Antioxidant indices (SOD, GSH, and CAT) were significantly decreased in the AFB1 group (P < 0.05). However, the addition of LACP to the AFB1-contaminated diets improved antioxidant capacity and malondialdehyde (MDA) and protein carbonylation (PC) in hepatic tissues of rabbits (P < 0.05). Serum interlukin-4 (IL-4) and interferon gamma (IFN-γ) levels were significantly increased in the AFB1 group (P < 0.05), but the addition of LACP significantly reversed this elevation. AFB1 downregulated the expression of immune-inflammatory genes such Nrf2, IL-10, and BCL-2 genes, while up-regulating the caspase-3 (CASP3) gene (P < 0.05). Supplementing AFB1 diet with LACP significantly decreased the expression of immune-inflammatory genes (Nrf2, IL-10, and BCL-2) and reduced the expression of the apoptotic-related gene CASP3. This study highlights the potential of L. plantarum (1 × 109 cfu/g /kg diet) as a protective agent against AFB1 in growing rabbits by enhancing antioxidant and immune function and reducing apoptosis and inflammation pathways.

Assessment of climate change on river streamflow under different representative concentration pathways.

Climate change and excessive greenhouse gas emissions profoundly impact hydrological cycles, particularly in arid and semi-arid regions, necessitating assessments of their effects on water resource management, agriculture, soil fertility, nutrient transport, hydropower generation, and flood risk. This study investigates climate change repercussions on streamflow in the Zarrineh River Basin, Iran, across three decadal intervals (2020-2029, 2055-2064, and 2090-2099) aiming to develop effective adaptation and mitigation strategies. Four General Circulation Models (GCMs), chosen based on distinct Representative Concentration Pathways (RCPs) determined by the annual mean temperature gradient, are employed. These models generate daily maximum (Tmax) and minimum (Tmin) temperatures along with precipitation data. Subsequently, these variables are integrated into the Soil and Water Assessment Tool (SWAT) model to analyze river flow alterations for each decadal timeframe. Comparison between future projections and observed climate data reveals a gradual decline in precipitation and Tmax, coupled with a substantial increase in Tmin. The average precipitation diminishes from 0.77 mm in the period 1985-1994 to a range of 0.42-0.28 mm in 2090-2099. The simulated flow at the basin outlet highlights that the GCM with the highest annual mean temperature gradient yields the lowest streamflow, while conversely, the model with the lowest gradient generates the highest. Consequently, streamflow experiences a decline from 52 m3/s in 1985-1994 to a range of 41-20 m3/s in 2090-2099.