The relationship between female orgasmic disorder, attention-deficit/hyperactivity disorder, and depression in Dominican women.

BACKGROUND: Female orgasmic disorder is listed in the DSM-5 and is defined as the persistent or recurrent inability to have an orgasm. Many depressed women may experience sexual dysfunction, including female orgasmic disorder. AIM: The study sought to analyze the relationship between depressive disorders and attention-deficit/hyperactivity disorder (ADHD) and their influence on the development of female orgasmic disorder. METHODS: A total of 221 Dominican women participated in this case-control study. The case group consisted of 107 women diagnosed with female orgasmic disorder, while the control group consisted of 114 women without any sexual dysfunction. OUTCOMES: The diagnosis of ADHD was obtained from the participants' medical records, previously conducted using the DSM-5-TR criteria. The Beck Depression Inventory II was used to assess the severity of depressive symptoms in both groups. RESULTS: There was a significant relationship between female orgasmic disorder and ADHD and depression. The results of multiple logistic regression indicated that the highest risk of female orgasmic disorder was observed in women with ADHD (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.46-9.20; P < .001), women with severe depression (OR, 2.50; 95% CI, 1.08-6.96; P = .04), and women who had sexual intercourse that focused on penetration (OR, 2.02; 95% CI, 1.03-3.98; P = .04). CLINICAL IMPLICATIONS: These findings may have important implications for the prevention and treatment of sexual disorders in women. STRENGTHS AND LIMITATIONS: This design selected all diagnosed cases of female orgasmic disorder and did not select a specific subgroup. However, some limitations must be considered. This study was conducted in a single clinic, although it should be noted that it is the main clinic for the treatment of sexual dysfunction in the country. A further limitation could be that this type of study design does not allow for statements about causality to be made. CONCLUSION: There is an increased risk of female orgasmic disorder in women with ADHD, with severe depression, and who engage in penetrative sex.

The SAGES MASTERS program bariatric surgery pathway selects 10 seminal publications on adjustable gastric banding.

BACKGROUND: Bariatric surgery is one of the clinical pathways of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Masters Program, and laparoscopic adjustable gastric banding (LAGB) is one of the three anchoring bariatric procedures. To improve surgeon lifelong learning, the Masters Program seeks to identify sentinel articles of each of the 3 bariatric anchoring procedures. In this article, we present the top 10 articles on LAGB. METHODS: A systematic literature search of papers on LAGB was completed, and publications with the most citations and citation index were selected and shared with SAGES Metabolic and Bariatric Surgery Committee members for review. The individual committee members then ranked these papers, and the top 10 papers were chosen based on the composite ranking. RESULTS: The top 10 sentinel publications on LAGB contributed substantially to the body of literature related to the procedure, whether for surgical technique, novel information, or outcome analysis. A summary of each paper including expert appraisal and commentary is presented here. CONCLUSION: These seminal articles have had significant contribution to our understanding and appreciation of the LAGB procedure. Bariatric surgeons should use this resource to enhance their continual education and acquisition of specialized skills.

New spin coated multilayer lactate biosensor for acidosis monitoring in continuous flow assisted with an electrochemical pH probe.

A LOx-based electrochemical biosensor for high-level lactate determination was developed. For the construction of the biosensor, chitosan and Nafion layers were integrated by using a spin coating procedure, leading to less porous surfaces in comparison with those recorded after a drop casting procedure. The analytical performance of the resulting biosensor for lactate determination was evaluated in batch and flow regime, displaying satisfactory results in both modes ranging from 0.5 to 20 mM concentration range for assessing the lactic acidosis. Finally, the lactate levels in raw serum samples were estimated using the biosensor developed and verified with a blood gas analyzer. Based on these results, the biosensor developed is promising for its use in healthcare environment, after its proper miniaturization. A pH probe based on common polyaniline-based electrochemical sensor was also developed to assist the biosensor for the lactic acidosis monitoring, leading to excellent results in stock solutions ranging from 6.0 to 8.0 mM and raw plasma samples. The results were confirmed by using two different approaches, blood gas analyzer and pH-meter. Consequently, the lactic acidosis monitoring could be achieved in continuous flow regime using both (bio)sensors.

Isolation of Clavispora lusitaniae from the Oral Cavity of Immunocompetent Young Adults from the North of Mexico.

The human oral cavity is normally colonized by microorganisms including bacteria, fungi, archaea, viruses and protozoa. The aim of this study was to determine the frequency of Candida spp., in de oral cavity in a group of medical students from the north of Mexico. Oral sample were obtained from 240 healthy students. The specimens were analyzed by traditional microbiology cultures and DNA sequencing. Candida spp., grew in Sabouraud dextrose agar from 57 samples and subsequently were isolated and phenotyped. The definitive identification to the species level was done by sequence analysis. The yeasts were identified as follow: 28 Clavispora lusitaniae, 20 Candida albicans, 5 Pichia kudriavzevii and 4 Candida parapsilosis. Our findings revealed that 23.75% of the healthy population has a potential pathogen in their mouth. Surprisingly, C. albicans is not the predominant yeast; instead other non-Candida species are the colonizers of the oral cavity as normal microbiota. C. lusitaniae is considered an emerging opportunistic pathogen in immunosuppressive patients. This paper pretends to highlight the presence of this yeast in the oral cavity in immunocompetent young adults. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01145-x.

Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.

Inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are homologous cation channels that mediate release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) and thereby are involved in many physiological processes. In previous studies, we determined that when the D2594 residue, located at or near the gate of the IP3R type 1, was replaced by lysine (D2594K), a gain of function was obtained. This mutant phenotype was characterized by increased IP3 sensitivity. We hypothesized the IP3R1-D2594 determines the ligand sensitivity of the channel by electrostatically affecting the stability of the closed and open states. To test this possibility, the relationship between the D2594 site and IP3R1 regulation by IP3, cytosolic, and luminal Ca2+ was determined at the cellular, subcellular, and single-channel levels using fluorescence Ca2+ imaging and single-channel reconstitution. We found that in cells, D2594K mutation enhances the IP3 ligand sensitivity. Single-channel IP3R1 studies revealed that the conductance of IP3R1-WT and -D2594K channels is similar. However, IP3R1-D2594K channels exhibit higher IP3 sensitivity, with substantially greater efficacy. In addition, like its wild type (WT) counterpart, IP3R1-D2594K showed a bell-shape cytosolic Ca2+-dependency, but D2594K had greater activity at each tested cytosolic free Ca2+ concentration. The IP3R1-D2594K also had altered luminal Ca2+ sensitivity. Unlike IP3R1-WT, D2594K channel activity did not decrease at low luminal Ca2+ levels. Taken together, our functional studies indicate that the substitution of a negatively charged residue by a positive one at the channels' pore cytosolic exit affects the channel's gating behavior thereby explaining the enhanced ligand-channel's sensitivity.

Disparities in clinical trial participation in ovarian cancer: A real-world analysis.

BACKGROUND: Significant disparities exist in clinical trial participation in non-gynecologic cancers, but little is known about disparities in ovarian cancer trial participation. Our objective was to examine patient, sociodemographic (race/ethnicity, insurance), cancer, and health system factors associated with clinical trial participation in ovarian cancer. METHODS: We conducted a retrospective cohort study of patients with epithelial ovarian cancer diagnosed from 2011 to 2021, using a real-world electronic health record derived database, representing around 800 sites of care in US academic and community practices. We used multivariable Poisson regression modeling to analyze the association of ever participating in an ovarian cancer clinical drug trial with patient, sociodemographic, health system, and cancer factors. RESULTS: Of the 7540 patients with ovarian cancer, 5.0% (95% CI 4.5-5.5) ever participated in a clinical drug trial. Patients of Hispanic or Latino ethnicity were 71% less likely to participate in clinical trials (RR 0.29, 95% CI 0.13-0.61) than non-Hispanic patients, and patients whose race was unknown or other than Black or White were 40% less likely to participate in clinical trials (RR 0.68, 95% CI 0.52-0.89). Patients who had Medicaid insurance were 51% less likely (RR 0.49, 95% CI 0.28-0.87) and those with Medicare were 32% (RR 0.48-0.97) less likely to participate in clinical trials than privately-insured patients. CONCLUSION: In this national cohort study, only 5% of patients with ovarian cancer participated in clinical drug trials. Interventions are needed to decrease race, ethnicity, and insurance disparities in clinical trial participation.

Sleeve gastrectomy morphology and long-term weight-loss and gastroesophageal reflux disease outcomes.

BACKGROUND: The relationship between sleeve gastrectomy (SG) morphology and long-term weight-loss and gastroesophageal reflux disease (GERD) outcomes is unknown. METHODS: All patients (n = 268) undergoing SG performed by 3 surgeons at a single academic institution from January 1, 2010 to December 31, 2012 were included. Long-term weight-loss and GERD outcomes were available for 90 patients which were incorporated in analyses. SG morphology was determined from postoperative day 1 upper gastrointestinal series (UGIS) available from 50 patients. Images were independently categorized using previously published methodology as Dumbbell (38%), Lower Pouch (22%), Tubular (26%), or Upper Pouch (14%) by Radiologist and Surgeon. Radiologist categorization was used when disagreement occurred (8%). Univariable analyses were conducted to explore potential associations between SG morphology, weight loss, and GERD outcomes. RESULTS: Follow-up was 8.2 ± 0.9 years. Population characteristics included age of 45.1 ± 10.8 years, female sex in 83.3%, and hiatal hernia repair (HHR) performed at index SG in 17.8%. Surgeons did not preferentially achieve a specific SG morphology. Changes from preoperative obesity and associated diseases comprised body mass index (BMI) (49.5 ± 7.6 vs. 39.2 ± 9.4 kg/m2; p < 0.0001), diabetes mellitus (30.0 vs. 12.2%; p = 0.0006), hypertension (70.0 vs. 54.4%; p = 0.0028), hyperlipidemia (42.2 vs. 24.2%;p = 0.0017), obstructive sleep apnea (41.1 vs. 15.6%; p < 0.0001), osteoarthritis (48.9 vs. 13.3%; p < 0.0001), back pain (46.5 vs. 28.9%; p = 0.0035), and medications (4.8 ± 3.3 vs. 3.7 ± 3.5; p < 0.0001). Dumbbell SG morphology was associated with lesser reduction in BMI at follow-up (--6.8 ± 7.2 vs. -12.4 ± 8.3 kg/m2; p = 0.0196) while greater BMI change was appreciated with Lower Pouch SG shape (-16.9 ± 9.9 vs. -8.4 ± 6.8 kg/m2; p = 0.0017). GERD was more prevalent at follow-up than baseline (67.8 vs. 47.8%; p < 0.0001). GERD-specific outcomes included de novo (51.1%), persistent (27.9%), worsened (58.1%), and resolved (14.0%) disease. Ten patients underwent reoperation for refractory GERD with SG morphology corresponding to Dumbbell (n = 5) and Upper Pouch (n = 1) for those with available UGIS. Univariable analyses showed that patients with GERD experienced a larger reduction in BMI compared with patients without GERD (-11.8 ± 7.7 vs. -7.0 ± 5.1 kg/m2; p = 0.0007). Patient age, surgeon, morphology category, and whether a HHR was done at index SG were not associated with the presence of any, de novo, or worsened GERD. Female sex was associated with worsened GERD (96.0 vs. 4.0%; p = 0.0455). Type of calibration device, distance from staple line to pylorus, and whether staple line reinforcement was used were not associated with SG morphology classification. CONCLUSION: This is the first study assessing the impact of SG morphology on long-term weight loss and GERD. Our data suggest an association between SG morphology and long-term weight loss but not with GERD outcomes. Current technical standards may be limited in reproducing the same SG morphology. This information may help guide the technical optimization and standardization of SG. Surgeons did not favor a specific SG morphology (1). Our results signal to a relationship between radiographic assessment of SG morphology and long-term weight-loss outcomes with Dumbbell classification correlated with lesser reduction in BMI (2a) and Lower Pouch morphology associated with superior weight loss (2b). SG, sleeve gastrectomy; BMI, body mass index.

Putative intestinal permeability markers do not correlate with cardiometabolic health and gut microbiota in humans, except for peptides recognized by a widely used zonulin ELISA kit.

BACKGROUND AND AIMS: Cardiometabolic diseases refer to a group of interrelated conditions, sharing metabolic dysfunctions like insulin resistance, obesity, dyslipidemia, and hypertension. The gut microbiota has been associated with CMD and related conditions. Alterations in the intestinal epithelium permeability triggered by chronic stress and diet could bridge gut microbiota with inflammation and CMD development. Here, we assessed the relationship between intestinal permeability and circulating SCFAs with cardiometabolic health status (CMHS) and gut microbiota in a sample of 116 Colombian adults. METHODS AND RESULTS: Plasma levels of lipopolysaccharide-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP), claudin-3, and purported zonulin peptides (PZP) were measured by ELISA, whereas plasmatic levels of acetate, propionate, butyrate, isobutyrate, and valerate were measured by gas chromatography/mass spectrometry. In addition, for further statistical analysis, we took data previously published by us on this cohort, including gut microbiota and multiple CMD risk factors that served to categorize subjects as cardiometabolically healthy or cardiometabolically abnormal. From univariate and multivariate statistical analyses, we found the levels of I-FABP, LBP, and PZP increased in the plasma of cardiometabolically abnormal individuals, although only PZP reached statistical significance. CONCLUSIONS: Our results did not confirm the applicability of I-FABP, LBP, claudin-3, or SCFAs as biomarkers for associating intestinal permeability with the cardiometabolic health status in these subjects. On the other hand, the poorly characterized peptides detected with the ELISA kit branded as "zonulin" were inversely associated with cardiometabolic dysfunctions and gut microbiota. Further studies to confirm the true identity of these peptides are warranted.

Beyond S. cerevisiae for winemaking: Fermentation-related trait diversity in the genus Saccharomyces.

Saccharomyces cerevisiae is the yeast of choice for most inoculated wine fermentations worldwide. However, many other yeast species and genera display phenotypes of interest that may help address the environmental and commercial challenges the wine industry has been facing in recent years. This work aimed to provide, for the first time, a systematic phenotyping of all Saccharomyces species under winemaking conditions. For this purpose, we characterized the fermentative and metabolic properties of 92 Saccharomyces strains in synthetic grape must at two different temperatures. The fermentative potential of alternative yeasts was higher than expected, as nearly all strains were able to complete fermentation, in some cases more efficiently than commercial S. cerevisiae strains. Various species showed interesting metabolic traits, such as high glycerol, succinate and odour-active compound production, or low acetic acid production, compared to S. cerevisiae. Altogether, these results reveal that non-cerevisiae Saccharomyces yeasts are especially interesting for wine fermentation, as they may offer advantages over both S. cerevisiae and non-Saccharomyces strains. This study highlights the potential of alternative Saccharomyces species for winemaking, paving the way for further research and, potentially, for their industrial exploitation.

Sex Differences in Glomerular Lesions, in Atherosclerosis Progression, and in the Response to Angiotensin-Converting Enzyme Inhibitors in the ApoE-/- Mice Model.

This study analyzes sex-based differences in renal structure and the response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Eight weeks old ApoE-/- mice received enalapril (5 mg/kg/day, subcutaneous) or PBS (control) for an additional 14 weeks. Each group consisted of six males and six females. Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells, and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in the female group), and hypertrophy of the PECs in males. This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

Is generative artificial intelligence the next step toward a personalized hemodialysis?

Artificial intelligence (AI) generative models driven by the integration of AI and natural language processing technologies, such as OpenAI's chatbot generative pre-trained transformer large language model (LLM), are receiving much public attention and have the potential to transform personalized medicine. Dialysis patients are highly dependent on technology and their treatment generates a challenging large volume of data that has to be analyzed for knowledge extraction. We argue that, by integrating the data acquired from hemodialysis treatments with the powerful conversational capabilities of LLMs, nephrologists could personalize treatments adapted to patients' lifestyles and preferences. We also argue that this new conversational AI integrated with a personalized patient-computer interface will enhance patients' engagement and self-care by providing them with a more personalized experience. However, generative AI models require continuous and accurate updates of data, and expert supervision and must address potential biases and limitations. Dialysis patients can also benefit from other new emerging technologies such as Digital Twins with which patients' care can also be addressed from a personalized medicine perspective. In this paper, we will revise LLMs potential strengths in terms of their contribution to personalized medicine, and, in particular, their potential impact, and limitations in nephrology. Nephrologists' collaboration with AI academia and companies, to develop algorithms and models that are more transparent, understandable, and trustworthy, will be crucial for the next generation of dialysis patients. The combination of technology, patient-specific data, and AI should contribute to create a more personalized and interactive dialysis process, improving patients' quality of life.

Periodontitis is associated with higher subclinical atherosclerosis in patients with systemic lupus erythematosus.

AIM: To determine periodontitis prevalence in patients with systemic lupus erythematosus (SLE) and to assess whether periodontitis in SLE patients is associated with a greater subclinical atherosclerosis. METHODS: An observational case-control study was conducted in SLE (cases) and patients without any rheumatic diseases (controls), matched for sex. Sociodemographic and cardiometabolic variables were gathered, and SLE activity was assessed through several indexes. Periodontal examination registered probing pocket depth, clinical attachment level, bleeding on probing, plaque index, and tooth loss. Subclinical atherosclerosis was assessed by measuring the carotid-femoral pulse wave velocity (PWV) by Doppler velocimetry, homocysteine levels, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Bivariate analyses and logistic regression were used to assess the association of any of the studied variables with SLE. RESULTS: Seventy-one cases and 72 controls were included in the study. Thirty-nine SLE patients (54.9%) were diagnosed with periodontitis, compared with 16 controls (22.2%). High levels of PWV (≥7.7 m/s, 75th percentile) were shown by 44.3% of the cases vs. 22.4% of the controls (p = .011). Among SLE patients, those with periodontitis showed higher PWV values (8.1 ± 1.52 vs. 7.16 ± 1.11 m/s, p = .006) and higher homeostasis model assessment index (indicative of insulin resistance) (1.7 ± 0.73 vs. 2.92 ± 3.05, p = .028) compared to those with periodontal health. Logistic regression showed that waist circumference (OR 1.06, 95% CI 1.01-1.12, p = .015); ESR (OR 1.09, 95% CI 1.03-1.16, p = .003); and bleeding on probing (OR 1.1, 95% CI 1.01-1.19, p = .018) were associated with the risk of SLE. CONCLUSION: Systemic lupus erythematosus patients showed a higher periodontitis percentage than controls. Higher PWV values were found in SLE patients with periodontitis, indicating a higher prevalence of subclinical atherosclerosis. Patients with higher gingival bleeding showed a higher risk of SLE.

A potent virucidal activity of functionalized TiO2 nanoparticles adsorbed with flavonoids against SARS-CoV-2.

The coronavirus SARS-CoV-2 has caused a pandemic with > 550 millions of cases and > 6 millions of deaths worldwide. Medical management of COVID-19 relies on supportive care as no specific targeted therapies are available yet. Given its devastating effects on the economy and mental health, it is imperative to develop novel antivirals. An ideal candidate will be an agent that blocks the early events of viral attachment and cell entry, thereby preventing viral infection and spread. This work reports functionalized titanium dioxide (TiO2)-based nanoparticles adsorbed with flavonoids that block SARS-CoV-2 entry and fusion. Using molecular docking analysis, two flavonoids were chosen for their specific binding to critical regions of the SARS-CoV-2 spike glycoprotein that interacts with the host cell angiotensin-converting enzyme-2 (ACE-2) receptor. These flavonoids were adsorbed onto TiO2 functionalized nanoparticles (FTNP). This new nanoparticulate compound was assayed in vitro against two different coronaviruses; HCoV 229E and SARS-CoV-2, in both cases a clear antiviral effect was observed. Furthermore, using a reporter-based cell culture model, a potent antiviral activity is demonstrated. The adsorption of flavonoids to functionalized TiO2 nanoparticles induces a ~ threefold increase of that activity. These studies also indicate that FTNP interferes with the SARS-CoV-2 spike, impairing the cell fusion mechanism. KEY POINTS/HIGHLIGHTS: • Unique TiO2 nanoparticles displaying flavonoid showed potent anti-SARS-CoV-2 activity. • The nanoparticles precisely targeting SARS-CoV-2 were quantitatively verified by cell infectivity in vitro. • Flavonoids on nanoparticles impair the interactions between the spike glycoprotein and ACE-2 receptor.

Cardio-renal benefits of sacubitril/valsartan in patients with advanced chronic kidney disease: experience in daily clinical practice.

BACKGROUND: The association between cardiac complications, such as heart failure (HF), and chronic kidney disease (CKD) is well known. In this study, we examined the effectiveness and safety of treatment with neprilysin inhibition in patients with advanced chronic kidney disease (stage 3b-4). METHODS: This single-centre, longitudinal, retrospective study of 31 months duration involved consecutive patients with CKD and HF with a reduced ejection fraction (HFrEF) who started treatment with sacubitril/valsartan. Glomerular filtration rate (GFR), cardiovascular risk factors, proteinuria, potassium, echocardiographic parameters and admissions for heart failure were analysed. RESULTS: The study comprised 25 patients with a median age of 73.2 ± 5.9 years. The most frequent aetiology of heart failure was ischemic heart disease. The median GFR was 29.4 ± 8.3 ml/min/1.73 m2 and the left ventricular ejection fraction (LVEF) 36.4 ± 8.9%. The GFR improved after initiating the treatment (F = 3.396, p = 0.019), as did the LVEF at one year of follow-up (p = 0.018). The number of visits to the emergency department for heart failure was also reduced. No patients needed to start renal replacement therapy. CONCLUSIONS: This study shows that sacubitril/valsartan may play a beneficial role in patients who have advanced CKD and HFrEF, with a satisfactory safety profile.

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer's Disease and Other Neurodegenerative Diseases.

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

Gestational long-term hypoxia induces metabolomic reprogramming and phenotypic transformations in fetal sheep pulmonary arteries.

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3,801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals were presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g., eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxy docosapentaenoic acid) and higher levels of some omega-6 metabolites (P < 0.02) including 15-keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.

Short-term effects of increased CO2, nitrate and temperature on photosynthetic activity in Ulva rigida (Chlorophyta) estimated by different pulse amplitude modulated fluorometers and oxygen evolution.

Short-term effects of pCO2 (700-380 ppm; High carbon (HC) and Low carbon (LC), respectively) and nitrate content (50-5 µM; High nitrogen (HN) and Low nitrogen (LN), respectively on photosynthesis were investigated in Ulva rigida (Chlorophyta) under solar radiation (in-situ) and in the laboratory under artificial light (ex-situ). After six days of incubation at ambient temperature (AT), algae were subjected to a 4 °C temperature increase (AT+4 °C) for 3 d. Both in-situ and ex-situ maximal electron transport rate (ETRmax) and in situ gross photosynthesis (GP), measured by O2 evolution, presented highest values under HCHN, and lowest under HCLN, across all measuring systems. Maximal quantum yield (Fv/Fm), and ETRmax of photosystem (PS) II [ETR(II)max] and PSI [ETR(I)max], decreased under HCLN at AT+4 °C. Ex situ ETR was higher than in situ ETR. At noon, Fv/Fm decreased (indicating photoinhibition), whereas ETR(II)max and maximal non-photochemical quenching (NPQmax) increased. ETR(II)max decreased under AT+ 4 °C in contrast to Fv/Fm, photosynthetic efficiency (α ETR) and saturated irradiance (EK). Thus, U. rigida exhibited a decrease in photosynthesis under acidification, changing LN, and AT+4 °C. These results emphasize the importance of studying the interaction between environmental parameters using in-situ versus ex-situ conditions, when aiming to evaluate the impact of global change on marine macroalgae.

New thermostable endoglucanase from Spirochaeta thermophila and its mutants with altered substrate preferences.

Endoglucanases are key elements in several industrial applications, such as cellulosic biomass hydrolysis, cellulose fiber modification for the production paper and composite materials, and in nanocellulose production. In all of these applications, the desired function of the endoglucanase is to create nicks in the amorphous regions of the cellulose. However, endoglucanase can be diverted from its activity on the fibers by other substrates-soluble oligosaccharides. This issue was addressed in the current study using enzyme engineering and an enzyme evolution approach. To this end, a hypothetical endoglucanase from a thermostable bacterium Spirochaeta thermophila was for the first time cloned and characterized. The wild-type enzyme was used as a starting point for mutagenesis and molecular evolution toward a preference for the higher molecular weight substrates. The best of the evolved enzymes was more active than the wild-type enzyme toward high molecular weight substrate at temperatures below 45 °C (3-fold more active at 30 °C) and showed little or no activity with low molecular weight substrates. These findings can be instrumental in bioeconomy sectors, such as second-generation biofuels and biomaterials from lignocellulosic biomass. KEY POINTS: • A new thermostable endoglucanase was characterized. • The substrate specificity of this endoglucanase was changed by means of genetic engineering. • A mutant with a preference for long molecular weight substrate was obtained and proposed to be beneficial for cellulose fiber modification.

The Unconventional Role for Gastric Volume in the Response to Bariatric Surgery for Both Weight Loss and Glucose Lowering.

OBJECTIVE: To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance. BACKGROUND DATA: Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention. METHODS: A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained. RESULTS: All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested. CONCLUSIONS: The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.

The McCAVE Trial: Vanucizumab plus mFOLFOX-6 Versus Bevacizumab plus mFOLFOX-6 in Patients with Previously Untreated Metastatic Colorectal Carcinoma (mCRC).

BACKGROUND: Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC. PATIENTS AND METHODS: All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS. RESULTS: One hundred eighty-nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64-1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. CONCLUSION: Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC. IMPLICATIONS FOR PRACTICE: This randomized phase II study demonstrates that additional angiopoietin-2 (Ang-2) inhibition does not result in superior benefit over anti-VEGF-A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang-2 is not a relevant therapeutic target in the clinical setting of treatment-naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF-A and Ang-2 inhibitor vanucizumab was discontinued.