Seroprevalence and molecular detection of Brucella infection in livestock in the United Arab Emirates.

Small ruminants and camels are important livestock species in the United Arab Emirates (UAE), although Brucella infection can limit their productivity. This study aimed to investigate the seroprevalence of Brucella infection and its associated risk factors in small ruminants and camels in the Emirate of Abu Dhabi. Additionally, seropositive animals were tested for the DNA of Brucella. Multispecies competitive enzyme-linked immunosorbent assay (c-ELISA) and multispecies indirect (i-ELISA) were used to test 3,086 animals from 2022 to 2023. Brucella cell surface 31 kDa protein (bcsp31) gene-based real-time polymerase chain reaction (q-PCR) was used to detect Brucella DNA. Multivariate logistic regression was used to assess the association between seroprevalence and potential risk factors. The overall seroprevalences of Brucella infection were 1.7% (95% confidence interval [CI], 1.2%-2.2%) and 5.8% (95% CI, 5.0%-6.7%) based on serial and parallel testing, respectively. The DNA of Brucella was detected in 13 of the 51 seropositive animals. The overall seroprevalence of Brucella infection was associated with the region, type of animal holding, species, and age of the animals. In conclusion, this study documented Brucella infection in small ruminants and camels in the Emirate of Abu Dhabi, warranting necessary intervention strategies to eliminate Brucella infections in livestock populations.

Alternative isoform expression of key thermogenic genes in human beige adipocytes.

Background: The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes. Methods: We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing. Results: We find 777 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 562 genes. Importantly, only 10% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte differentiation. Functional classification of alternative isoforms points to a gain of function for key thermogenic transcription factors such as PPARG and CITED1, and enzymes such as PEMT, or LPIN1. We find that a large majority of the splice variants arise from differential TSS usage, with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT. Discussion: These results suggest that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification.

Complicated anorectal sepsis: Validation of scoring system for predicting anorectal sepsis severity.

Anorectal sepsis is a common and potentially serious medical condition characterized by infection and inflammation of the anal canal and surrounding tissues. However, the lack of standardized and comprehensive scoring systems specifically tailored for predicting the severity of anorectal sepsis poses challenges in clinical practice. This study aimed to develop and validate a scoring system for predicting the severity of anorectal sepsis by incorporating relevant patient factors. A retrospective cohort study was conducted at Mansoura University Hospital, a tertiary care center, over a period of 5 years. The study population consisted of 330 patients diagnosed with anorectal sepsis during the study period. A scoring system was developed using multiple variables, with each variable assigned a specific score based on its clinical significance and weight in predicting disease severity. The developed scoring system's predictive performance was evaluated using receiver operating characteristic (ROC) analysis, calculating the area under the ROC curve to assess discriminative ability. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population. Chi-square tests or t tests were performed to assess differences between non-severe and severe anal sepsis groups. The scoring system consisted of 12 variables, with a maximum total score of 18. The logistic regression analysis revealed significant associations between localized swelling, presentation within 72 hours, multiple drainage sessions, and severe anorectal sepsis. The ROC analysis showed an area under the curve of 0.85, indicating good discriminative ability of the scoring system. The scoring system was developed and validated in a single center, which may limit its generalizability to other settings. The scoring system demonstrated good predictive performance and can be a valuable tool for clinicians in assessing disease severity, guiding treatment decisions, and identifying high-risk patients.

Examining the Applicability of Surgical Coaching Rules for Resident Autonomy in Non-teaching Hospitals.

INTRODUCTION: This retrospective study aims to analyze the impact of standardized rules for teaching in university hospitals on surgical resident autonomy and patient safety, as measured by patient outcomes, and also examines the learning curves for residents and their impact on patient outcomes in a non-teaching hospital. METHODS: The data for the study was collected retrospectively from medical records of 2000 adult patients who went through surgical procedures from January 2020 to December 2022. Participants were categorized into two groups based on the supervision level provided by attending surgeons and residents. Appropriate statistical methods were used to analyze the data. RESULTS: It was observed that operative times of cases handled by both attending and resident surgeons were less than those handled by residents alone. On the other hand, the former group had a significantly higher burden of comorbidities and higher rate of perioperative complications than the latter. These results have important implications for the training of medical residents and the overall delivery of healthcare services in university hospitals. CONCLUSION: The findings will also help towards better understanding of the effectiveness of these rules and their potential for improving the quality of care provided by residents in these settings.

Multi-level 3D genome organization deteriorates during breast cancer progression.

Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) remain largely stable, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion leads to the formation of de novo enhancer contacts and activation of the oncogene, illustrating how structural variants can interact with the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the degradation of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes.

PML modulates epigenetic composition of chromatin to regulate expression of pro-metastatic genes in triple-negative breast cancer.

The promyelocytic leukemia (PML) protein organizes nuclear aggregates known as PML nuclear bodies (PML-NBs), where many transcription factors localize to be regulated. In addition, associations of PML and PML-NBs with chromatin are described in various cell types, further implicating PML in transcriptional regulation. However, a complete understanding of the functional consequences of PML association to DNA in cellular contexts where it promotes relevant phenotypes is still lacking. We examined PML chromatin association in triple-negative breast cancer (TNBC) cell lines, where it exerts important oncogenic functions. We find that PML associates discontinuously with large heterochromatic PML-associated domains (PADs) that contain discrete gene-rich euchromatic sub-domains locally depleted of PML. PML promotes heterochromatic organization in PADs and expression of pro-metastatic genes embedded in these sub-domains. Importantly, this occurs outside PML-NBs, suggesting that nucleoplasmic PML exerts a relevant gene regulatory function. We also find that PML plays indirect regulatory roles in TNBC cells by promoting the expression of pro-metastatic genes outside PADs. Our findings suggest that PML is an important transcriptional regulator of pro-oncogenic metagenes in TNBC cells, via transcriptional regulation and epigenetic organization of heterochromatin domains that embed regions of local transcriptional activity.

Cellular and Genomic Features of Muscle Differentiation from Isogenic Fibroblasts and Myoblasts.

The ability to recapitulate muscle differentiation in vitro enables the exploration of mechanisms underlying myogenesis and muscle diseases. However, obtaining myoblasts from patients with neuromuscular diseases or from healthy subjects poses ethical and procedural challenges that limit such investigations. An alternative consists in converting skin fibroblasts into myogenic cells by forcing the expression of the myogenic regulator MYOD. Here, we directly compared cellular phenotype, transcriptome, and nuclear lamina-associated domains (LADs) in myo-converted human fibroblasts and myotubes differentiated from myoblasts. We used isogenic cells from a 16-year-old donor, ruling out, for the first time to our knowledge, genetic factors as a source of variations between the two myogenic models. We show that myo-conversion of fibroblasts upregulates genes controlling myogenic pathways leading to multinucleated cells expressing muscle cell markers. However, myotubes are more advanced in myogenesis than myo-converted fibroblasts at the phenotypic and transcriptomic levels. While most LADs are shared between the two cell types, each also displays unique domains of lamin A/C interactions. Furthermore, myotube-specific LADs are more gene-rich and less heterochromatic than shared LADs or LADs unique to myo-converted fibroblasts, and they uniquely sequester developmental genes. Thus, myo-converted fibroblasts and myotubes retain cell type-specific features of radial and functional genome organization. Our results favor a view of myo-converted fibroblasts as a practical model to investigate the phenotypic and genomic properties of muscle cell differentiation in normal and pathological contexts, but also highlight current limitations in using fibroblasts as a source of myogenic cells.

Extended Pedicled Perforator Plus Submental Flap for Large Cheek Defect Reconstruction.

The submental flap is an alternative repair technique in the maxillo-facial region when microsurgical reconstruction is not required or is difficult to apply. The purpose of this study was to illustrate the benefits of restoring the cheeks with an extended pedicled submental flap. Method: Eight patients aged 58 to 81 years with cheek cancer presented to the surgery department at the Benha University Hospital in Egypt, from May 2019 to October 2021 for the removal of their tumors and reconstruction of the resulting defects, using the extended submental perforator plus pedicled artery flap. Results: The average blood loss was 250 cm3 (range: 50-400 cm3). The average operation took 3 hours to complete, including excision and rebuilding (a range of 2.5 to 3.5 hours). The length of the postoperative hospital stay was 2 to 4 days. Fortunately, there was no complete flap loss; nonetheless, distal flap necrosis in one case left a raw area, which was allowed to heal naturally, and hemorrhages in two cases were conservatively handled. Conclusions: For the reconstruction of cheek abnormalities, the submental flap is a viable alternative, particularly in older patients or patients whose overall health has declined and who need less severe therapies and quicker surgery. The submental flap, which conceals the donor site, provides a dependable supply of skin for facial resurfacing with excellent color, shape, and texture matching. The flap is quick, and easy to raise.

Fabrication of hierarchical flower-like WO3 nanoparticles for effective metal ions sensing and catalytic degradation of organic dyes.

In this work, we report on the synthesis of flower-like tungsten oxide nanoparticles (WO3 NPs) using a simple precipitation method. This paper reports a simple method for synthesizing flower-like WO3 NPs, which can be used for environmentally treating hazardous organic pollutants. The photocatalytic degradation of model artificial Orange II and Congo red was assessed under natural sunlight irradiation. The surface morphologies, crystallinity, and binding energy of the synthesized WO3 NPs were determined. The synthesized WO3 NPs exhibited good photodegradation percentages of approximately Orange II (97.6%) and Congo red dye (98.2%) after 120 min of irradiation. Furthermore, the WO3 NPs maintained their degradation ability for up to three cycles. In addition, WO3 NPs were examined in different metal ions sensing (Hg2+, Fe2+, Cu2+, Ni2+, and Cd2+) in an aqueous solution. The results showed that the WO3 NPs exhibited excellent Cd2+ ion sensing. Based on the investigations, WO3 NPs proved to be an efficient photocatalyst and hold promise as the best material for future applications in preventing water pollution.

Multicenter trans-Atlantic experience with fenestrated-branched endovascular aortic repair of chronic post-dissection thoracoabdominal aortic aneurysms.

OBJECTIVE: This multicenter international study aimed to describe outcomes of fenestrated-branched endovascular aortic repairs (FB-EVAR) in a cohort of patients treated for chronic post-dissection thoracoabdominal aortic aneurysms (PD-TAAAs). METHODS: We reviewed the clinical data of all consecutive patients treated by FB-EVAR for repair of extent I to III PD-TAAAs in 16 centers from the United States and Europe (2008-2021). Data were extracted from institutional prospectively maintained databases and electronic patient records. All patients received off-the-shelf or patient-specific manufactured fenestrated-branched stent grafts. Endpoints were any cause mortality and major adverse events at 30 days, technical success, target artery (TA) patency, freedom from TA instability, minor (endovascular with <12 Fr sheath) and major (open or ≥12 Fr sheath) secondary interventions, patient survival, and freedom from aortic-related mortality (ARM). RESULTS: A total of 246 patients (76% male; median age, 67 years [interquartile range, 61-73 years]) were treated for extent I (7%), extent II (55%), and extent III (35%) PD-TAAAs by FB-EVAR. The median aneurysm diameter was 65 mm (interquartile range, 59-73 mm). Eighteen patients (7%) were octogenarians, 212 (86%) were American Society of Anesthesiologists class ≥3, and 21 (9%) presented with contained ruptured or symptomatic aneurysms. There were 917 renal-mesenteric vessels targeted by 581 fenestrations (63%) and 336 directional branches (37%), with a mean of 3.7 vessels per patient. Technical success was 96%. Mortality and rate of major adverse events at 30 days was 3% and 28%, including disabling complications such as new onset dialysis in 1%, major stroke in 1%, and permanent paraplegia in 2%. Mean follow-up was 24 months. Kaplan-Meier (KM) estimated patient survival at 3 and 5 years was 79% ± 6% and 65% ± 10%. KM estimated freedom from ARM was 95% ± 3% and 93% ± 5% at the same intervals. Unplanned secondary interventions were needed in 94 patients (38%), including minor procedures in 64 (25%) and major procedures in 30 (12%). There was one conversion to open surgical repair (<1%). KM estimated freedom from any secondary intervention was 44% ± 9% at 5 years. KM estimated primary and secondary TA patency were 93% ± 2% and 96% ± 1% at 5 years, respectively. CONCLUSIONS: FB-EVAR for chronic PD-TAAAs was associated with high technical success and a low rate of mortality (3%) and disabling complications at 30 days. Although the procedure is effective in the prevention of ARM, patient survival was low at 5 years (65%), likely due to the significant comorbidities in this cohort of patients. Freedom from secondary interventions at 5 years was 44%, although most procedures were minor. The significant rate of reinterventions highlights the need for continued patient surveillance.

Editor's Choice - Estimated Radiation Dose to the Operator During Endovascular Aneurysm Repair.

OBJECTIVE: To estimate operator organ doses from fluoroscopically guided infrarenal endovascular aneurysm repair (EVAR) procedures, using the detailed exposure information contained in radiation dose structured reports. METHODS: Conversion factors relating kerma area product (PKA) to primary operator organ doses were calculated using Monte Carlo methods for 91 beam angles and seven x-ray spectra typical of clinical practice. A computer program was written, which selects the appropriate conversion factor for each exposure listed in a structured report and multiplies it by the respective PKA. This system was used to estimate operator doses for 81 EVAR procedures for which structured reports were available. The impact of different shielding scenarios and variations in operator position was also investigated. RESULTS: Without any shielding, the median estimated effective dose was 113 µSv (interquartile range [IQR] 71, 252 µSv). The highest median organ doses were for the colon (154 µSv, IQR 81, 343) and stomach (133 µSv, IQR 76, 307). These dose estimates represent all exposures, including fluoroscopy and non-fluoroscopic digital acquisitions. With minimal shielding provided by 0.25 mm of Pb covering the torso and upper legs, the effective dose was reduced by a factor of around 6. With additional shielding from ceiling and table shields, a 25 to 50 fold reduction in dose is achievable. Estimated doses were highest where the primary beam was pointed directly away from the operator. CONCLUSION: The models suggest that with optimal use of shielding, operator doses can be reduced to levels equivalent to one to two days of natural background exposure and well below statutory dose limits.

Development of luminescence carbon quantum dots for metal ions detection and photocatalytic degradation of organic dyes from aqueous media.

In the present study, fish scale waste was used for the organic synthesis of luminescence CQDs by the hydrothermal method. The impact of CQDs on improved photocatalytic degradation of organic dyes and metal ions detection is examined in this study. The synthesized CQDs had a variety of characteristics that were detected, such as crystallinity, morphology, functional groups, and binding energies. The luminescence CQDs showed outstanding photocatalytic effectiveness for the destruction of methylene blue (96.5%) and reactive red 120 dye (97.8%), respectively after 120 min exposure to visible light (420 nm). The high electron transport properties of the CQDs edges, which make it possible to efficiently separate electron-hole pairs, are attributed to the enhanced photocatalytic activity of the CQDs. These degradation results prove that the CQDs are the outcome of a synergistic interaction between visible light (adsorption); a potential mechanism is also suggested, and the kinetics is analyzed to use a pseudo-first-order model. Additionally, the metal ions detection of CQDs was studied by various metal ions (Hg2+, Fe2+, Cu2+, Ni2+, and Cd2+) in an aqueous solution and results revealed that the PL intensity of CQDs in presence of cadmium ions decreased. Studies show that the organic fabrication of CQDs are effective photocatalyst and may one day serve as the ideal material to reduce water pollution.

Effects of Antioxidant Combinations on the Renal Toxicity Induced Rats by Gold Nanoparticles.

This study investigated some possible mechanisms underlying the nephrotoxic effect of gold nanoparticles (AuNPs) in rats and compared the protective effects of selected known antioxidants-namely, melanin, quercetin (QUR), and α-lipoic acid (α-LA). Rats were divided into five treatment groups (eight rats per group): control, AuNPs (50 nm), AuNPs + melanin (100 mg/kg), AuNPs + QUR (200 mg/kg), and AuNPs + α-LA (200 mg/kg). All treatments were administered i.p., daily, for 30 days. AuNPs promoted renal glomerular and tubular damage and impaired kidney function, as indicated by the higher serum levels of creatinine (Cr), urinary flow, and urea and albumin/Cr ratio. They also induced oxidative stress by promoting mitochondrial permeability transition pore (mtPTP) opening, the expression of NOX4, increasing levels of malondialdehyde (MDA), and suppressing glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). In addition, AuNPs induced renal inflammation and apoptosis, as evidenced by the increase in the total mRNA and the cytoplasmic and nuclear levels of NF-κB, mRNA levels of Bax and caspase-3, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Treatment with melanin, QUR, and α-lipoic acid (α-LA) prevented the majority of these renal damage effects of AuNPs and improved kidney structure and function, with QUR being the most powerful. In conclusion, in rats, AuNPs impair kidney function by provoking oxidative stress, inflammation, and apoptosis by suppressing antioxidants, promoting mitochondrial uncoupling, activating NF-κB, and upregulating NOX4. However, QUR remains the most powerful drug to alleviate this toxicity by reversing all of these mechanisms.

Gene Regulatory Interactions at Lamina-Associated Domains.

The nuclear lamina provides a repressive chromatin environment at the nuclear periphery. However, whereas most genes in lamina-associated domains (LADs) are inactive, over ten percent reside in local euchromatic contexts and are expressed. How these genes are regulated and whether they are able to interact with regulatory elements remain unclear. Here, we integrate publicly available enhancer-capture Hi-C data with our own chromatin state and transcriptomic datasets to show that inferred enhancers of active genes in LADs are able to form connections with other enhancers within LADs and outside LADs. Fluorescence in situ hybridization analyses show proximity changes between differentially expressed genes in LADs and distant enhancers upon the induction of adipogenic differentiation. We also provide evidence of involvement of lamin A/C, but not lamin B1, in repressing genes at the border of an in-LAD active region within a topological domain. Our data favor a model where the spatial topology of chromatin at the nuclear lamina is compatible with gene expression in this dynamic nuclear compartment.

Concomitant Sub-Chronic Administration of Small-Size Gold Nanoparticles Aggravates Doxorubicin-Induced Liver Oxidative and Inflammatory Damage, Hyperlipidemia, and Hepatic Steatosis.

This study examined the effect of gold nanoparticles (AuNPs) on doxorubicin (DOX)-induced liver damage and steatosis in rats and tested its effect mechanism. Wistar male rats were divided into four groups (each of eight rats) as control, AuNPs (50 µL of 10 nm), DOX (15 mg/kg; 3 mg/kg/week), and DOX + AuNPs-treated rats. DOX is known to induce fasting hyperglycemia and hyperinsulinemia in treated rats. Individual treatment of both DOX and AuNPs also promoted liver damage, increased circulatory levels of ALT and AST, and stimulated serum and liver levels of TGs, CHOL, LDL-c, and FFAs. They also stimulated MDA, TNF-α, and IL-6, reduced GSH, SOD, HO-1, and CAT, upregulated mRNA levels of Bax and caspases-3 and -8 and downregulated mRNA levels of Bcl2 in the livers of rats. However, while DOX alone reduced hepatic levels of PPARα, both AuNPs and DOX stimulated mRNA levels of SREBP1, reduced the mRNA, cytoplasmic and nuclear levels of Nrf2, and increased mRNA, cytoplasmic, and nuclear levels of NF-κB. The liver damage and the alterations in all these parameters were significantly more profound when both AuNPs and DOX were administered together. In conclusion, AuNPs exaggerate liver damage, hyperlipidemia, and hepatic steatosis in DOX-treated rats by activating SREBP1 and NF-κB and suppressing the Nrf2/antioxidant axis.

Versatility of unilateral propeller groin flap for coverage of large scrotal defects and its impact on testicular function.

Background: There are many options for scrotal reconstruction, each having its own benefits and drawbacks. In the last years, the introduction of the propeller flaps gained great popularity, while the use of groin flap as propeller in scrotal reconstruction remains anecdotal, with only a few cases reported in the literature. Objectives: In this research, we study the versatility of unilateral propeller groin flaps in the reconstruction of large scrotal defects. Patients and Methods: This study was done on 10 patients with scrotal defects who were admitted to the plastic unit of the general surgery department at Benha University Hospital from 2019 to 2021 for scrotal reconstruction. Results: All surgeries were successful with a mean operative time of 103.5 min, ranging from 90 to 130 min. All flaps survived well with no flap necrosis, and only one case showed flap congestion. Donor site healed well with the scar hidden in a natural crease, with no affection on the testicular functions. Conclusions: The use of groin flap as a propeller allows for free movement and rotation of the flap, which allows for better coverage of a large scrotal defect with good vascularity, lesser complications, no need for further operations to separate the pedicle, and the lowest donor site morbidity. Level of evidence: Level IV, therapeutic study.

The Protective Effect of α-Lipoic Acid against Gold Nanoparticles (AuNPs)-Mediated Liver Damage Is Associated with Upregulating Nrf2 and Suppressing NF-κB.

This study examined if regulating the keap-1? Nrf2 antioxidant pathway mediated gold nanoparticles (AuNPs) induced liver damage, and examined the protective effect of co-supplement of α-lipoic acid (α-LA). Rats were separated into 4 groups (n = 8/each) as control, α-LA (200 mg/kg), AuNPs (5 µg/2.85 × 1011), and AuNPs (5 µg/2.85 × 1011) + α-LA (200 mg/kg). After 7 days, AuNPs induced severe degeneration in the livers of rats with the appearance of some fatty changes. In addition, it increased serum levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (É£-GTT), and aspartate aminotransferase (AST), as well as liver levels of malondialdehyde (MDA). Concomitantly, AuNPs significantly depleted hepatic levels of total glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) but increased hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). It also reduced mRNA levels of B-cell lymphoma 2 (Bcl2) and heme oxygenase-1 (HO-1) but significantly increased those of Bax and cleaved caspase-3, as well as the ratio of Bax/Bcl2. In addition, AuNPs enhanced the total and nuclear levels of NF-κB p65 but reduced the mRNA and total and nuclear protein levels of Nrf2. Of note, AuNPs did not affect the mRNA levels of keap-1. All these events were reversed by α-LA in the AuNPs-treated rats. In conclusion, α-LA attenuated AuNPs-mediated liver damage in rats by suppressing oxidative stress and inflammation, effects that are associated with upregulation/activation of Nrf2.

Local euchromatin enrichment in lamina-associated domains anticipates their repositioning in the adipogenic lineage.

BACKGROUND: Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confer structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains, however, elusive. RESULTS: We examined changes in the association of lamin B1 with the genome in the first 72 h of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. Lastly, we link differentially expressed genes in LADs to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation. CONCLUSIONS: We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment.

The impact of omeprazole on mycophenolate pharmacokinetics in kidney transplant recipients.

BACKGROUND: The absorption rates of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) may be influenced by the concomitant use of omeprazole. METHODS: One hundred kidney transplant patients were recruited during their outpatient visits, including 50 on MMF and 50 on EC-MPS. At the clinic, a predose mycophenolic acid (MPA) sample (C0) was collected; subsequently, the participants received the proton-pump inhibitor omeprazole along with either MMF or EC-MPS. Two more blood samples were collected at 1.5 and 3.5 hours and used to estimate an area under the curve (AUC) from zero to 12 hours [AUC (0-12)]. RESULTS: The mean number of months after transplant was 92 months. The median AUC (0-12) and C0 results were 62.2 mg·h/L and 2.0 mg/L for the MMF group and 71.9 mg·h/L and 1.8 mg/L for the EC-MPS group (P = 0.160 and 0.225, respectively). Interestingly, 54% of the MMF group and 62% of the EC-MPS group showed AUCs above the target values. The correlation between MPA C0 and the predicted AUC was poor in both groups. CONCLUSION: Omeprazole can be safely co-administered with either MMF or EC-MPS, as it did not compromise the MPA exposure. Unexpectedly, however, a high percentage of patients presented MPA AUCs exceeding the target value, highlighting the importance of periodically assessing MPA level.