Frequency of Gene Polymorphisms in Admixed Venezuelan Women with Recurrent Pregnancy Loss: Microsomal Epoxy Hydroxylase (rs1051740) and Enos (rs1799983).

Recurrent pregnancy loss (RPL) affects around 2% of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene single nucleotide polymorphisms (SNPs) have been associated with RPL. The frequency of some SNPs is increased in women suffering from RLP from Asian or Caucasian races; however, in admixed populations, the information on possible genetic links is scarce and contradictory. This study aimed to assess the frequency of two SNPs present in two different enzymes involved in medical conditions observed during pregnancy. It is a case-control study. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics, is present in the ovaries, and is hormonally regulated. The endothelial nitric oxide synthase (NOS3) that forms nitric is involved in vascular tone. Two SNPs, rs1051740 (mEPH) and rs1799983 (NOS3), were assessed. The study included 50 controls and 63 primary RPL patients. The frequency of mutated alleles in both SNPs was significantly higher in patients (p < 0.05). Double-mutated homozygotes were encountered only in RPL patients (p < 0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

BACKGROUND: Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. METHODS AND FINDINGS: This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. CONCLUSIONS: MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT04431674.

Temporal summation of second pain is affected by cognitive load.

This work attempted to clarify the interaction of cognition and pain sensitization during a paradigm of Temporal Summation of Second Pain (TSSP). We analyzed pain ratings and electroencephalographic (EEG) activity obtained from 21 healthy participants during the presentation of four experimental conditions that differed in the manipulation of attention to painful stimuli or working memory load (Attention to hand & TSSP; 0-back & TSSP (low cognitive load); 2-back & TSSP (high cognitive load); 2-back (without pain)). We found that the TSSP was reduced when the attention was diverted and the cognitive load increased, and this reduction was accompanied by higher midfrontal theta activity and lower posterior alpha and central beta activity. Although it is well established that TSSP is a phenomenon that occurs at the spinal level, here we show that it is also affected by supraspinal attentional mechanisms. Delivery of painful repeated stimuli did not affect the performance of the 2-back task but was associated with smaller amplitudes of attentional event-related potentials (ERPs) after standard stimuli (not the target). The study of brain activity during TSSP allowed to clarify the role of top-down attentional modulation in pain sensitization processes. Results contribute to a better understanding of cognitive dysfunction in pain conditions and reinforce the use of therapeutic strategies based on distracting attention away from pain.

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Telemental Health Use Is Associated With Lower Health Care Spending Among Medicare Beneficiaries With Major Depression.

BACKGROUND: Some policymakers are concerned that expanding telehealth coverage may increase Medicare expenditures. However, there is limited evidence on the association of telehealth use with utilization and spending among Medicare beneficiaries with major depression. OBJECTIVE: To examine the differences in spending and utilization among telemental health users and non-telemental health users with major depression. METHODS: We examined 2014-2019 traditional Medicare claims data for beneficiaries aged ≥50 years with major depression in Texas. Multivariable generalized linear models were used to assess the relationships between telemental health use and Medicare spending and utilization while adjusting for patient demographics and programmatic and clinical factors. RESULTS: In each of the years between 2014 and 2019, an average of 4.6% Medicare beneficiaries with major depression had at least 1 telemental health visit. Compared with beneficiaries without a telemental health visit, those who had a telemental health visit were significantly more likely to be enrolled in Medicaid, be Medicare eligible due to a disability, live in a lower income area or in a rural area, and have a higher comorbidity index. Beneficiaries utilizing telemental health services incurred higher unadjusted Medicare spending than those not receiving telemental health services. However, this difference appeared due to beneficiary and programmatic characteristics rather than telemental health use. Adjusting for model covariates, the telemental health group had lower overall per member per year predicted spending, inpatient admissions, and emergency department visits than non-telemental health users. CONCLUSION: Our findings suggest that telemental health care use may improve access to mental health care without increasing Medicare spending among telemental health users in Texas.

Functional and oncological outcomes after right hemisphere glioma resection in awake versus asleep patients: a systematic review and meta-analysis.

The right hemisphere has been underestimated by being considered as the non-dominant hemisphere. However, it is involved in many functions, including movement, language, cognition, and emotion. Therefore, because lesions on this side are usually not resected under awake mapping, there is a risk of unfavorable neurological outcomes. The goal of this study is to compare the functional and oncological outcomes of awake surgery (AwS) versus surgery under general anesthesia (GA) in supratentorial right-sided gliomas. A systematic review of the literature according to PRISMA guidelines was performed up to March 2023. Four databases were screened. Primary outcome to assess was return to work (RTW). Secondary outcomes included the rate of postoperative neurological deficit, postoperative Karnofsky Performance Status (KPS) score and the extent of resection (EOR). A total of 32 articles were included with 543 patients who underwent right hemisphere tumor resection under awake surgery and 294 under general anesthesia. There were no significant differences between groups regarding age, gender, handedness, perioperative KPS, tumor location or preoperative seizures. Preoperative and long-term postoperative neurological deficits were statistically lower after AwS (p = 0.03 and p < 0.01, respectively), even though no difference was found regarding early postoperative course (p = 0.32). A subsequent analysis regarding type of postoperative impairment was performed. Severe postoperative language deficits were not different (p = 0.74), but there were fewer long-term mild motor and high-order cognitive deficits (p < 0.05) in AwS group. A higher rate of RTW (p < 0.05) was documented after AwS. The EOR was similar in both groups. Glioma resection of the right hemisphere under awake mapping is a safer procedure with a better preservation of high-order cognitive functions and a higher rate of RTW than resection under general anesthesia, despite similar EOR.

Did the organization of primary care practices during the COVID-19 pandemic influence quality and safety? - an international survey.

BACKGROUND: Changes in demographics with an older population, the illness panorama with increasing prevalence of non-communicable diseases, and the shift from hospital care to home-based care place demand on primary health care, which requires multiprofessional collaboration and team-based organization of work. The COVID-19 pandemic affected health care in various ways, such as heightened infection control measures, changing work practices, and increased workload. OBJECTIVES: This study aimed to investigate the association between primary care practices' organization, and quality and safety changes during the COVID-19 pandemic. DESIGN: Data were collected from 38 countries in a large online survey, the PRICOV-19 study. For this paper, the participating practices were categorized as "Only GPs", comprising practices with solely general practitioners (GPs) and/or GP trainees, without any other health care professionals (n = 1,544), and "Multiprofessional," comprising practices with at least one GP or GP trainee and one or more other health professionals (n = 3,936). RESULTS: Both categories of practices improved in infection control routines when compared before and during the COVID-19 pandemic. A larger proportion of the multiprofessional practices changed their routines to protect vulnerable patients. Telephone triage was used in more "Multiprofessional" practices, whereas "Only GPs" were more likely to perform video consultations as an alternative to physical visits. Both types of practices reported that the time to review new guidelines and scientific literature decreased during the pandemic. However, both had more meetings to discuss directives than before the pandemic. CONCLUSIONS: Multiprofessional teams were keener to introduce changes to the care organization to protect vulnerable patients. However, practices with only GPs were found to be more aligned with video consultations, perhaps reflecting the close patient-doctor relationship. In contrast, telephone triage was used more in multiprofessional teams.

A contemporary analysis of surgical ligation versus endovascular embolization in patients with intracranial dural arteriovenous fistulas: a propensity score-matched and mixed-effects model study.

OBJECTIVE: Intracranial dural arteriovenous fistulas (dAVFs) are rare vascular lesions that can be asymptomatic or can lead to devastating hemorrhage based on the dAVF's aggressiveness. Several approaches can be taken to treat dAVFs, such as endovascular embolization and surgical ligation. However, very few studies have evaluated the influence of surgery compared to endovascular approaches on patient outcomes. This study was performed to analyze the clinical characteristics and outcomes of patients who underwent treatment for intracranial dAVF in which either endovascular embolization or microsurgical ligation was used. METHODS: The Nationwide Readmissions Database was reviewed for all patients who underwent treatment for dAVFs (n = 18,152) between 2016 and 2019. Patients who received only surgical ligation or endovascular embolization (i.e., not both) were included. Variables regarding demographics, clinical outcomes, and healthcare utilization were queried. Primary outcome measures were nonroutine discharge, 1-year readmission, top quartile length of stay (LOS), and top quartile of inpatient all-payer cost. Propensity score matching was performed to evaluate the influence of either surgery or embolization on patient outcomes. Receiver operating characteristic (ROC) curves were created for each outcome measure. The area under the curve (AUC) of each ROC was used to estimate mixed-effects model performance. RESULTS: Following propensity score matching, 127 and 113 patients made up the surgical ligation and endovascular embolization cohort, respectively. There were no differences found in age (p = 0.16), sex (p = 0.57), or average Elixhauser Comorbidity Index (p = 0.32). Patients receiving surgical ligation had lower odds of readmission (OR 0.37, p = 0.028) and greater odds of nonroutine discharge (OR 2.21, p = 0.03) compared to patients who underwent endovascular embolization. The authors found no differences in the top quartile of LOS (p = 0.84), top quartile of cost (p = 0.38), or mortality (p > 0.99) between cohorts. ROC curves revealed that the mixed-effects models inclusive of approach outperformed models agnostic to approach with respect to nonroutine discharge (AUC with approach, 0.871; AUC without approach, 0.850; p = 0.018) and readmission (AUC with approach, 0.686; AUC without approach, 0.651; p = 0.019), but no differences were observed regarding top quartile of LOS (p = 0.17) and top quartile of cost (p = 0.40). CONCLUSIONS: Surgical approach may influence perioperative outcomes in patients treated for intracranial dAVF-most significantly discharge disposition and 1-year readmission. Future longitudinal prospective studies with more clinical detail will be required to fully capture the predictive utility of surgical approach in patients treated for intracranial dAVF, particularly for various dAVF subtypes.

Medical deserts in Spain-Insights from an international project.

INTRODUCTION: Medical deserts are a growing phenomenon across many European countries. They are usually defined as (i) rural areas, (ii) underserved areas or (iii) by applying a measure of distance/time to a facility or a combination of the three characteristics. The objective was to define medical deserts in Spain as well as map their driving factors and approaches to mitigate them. METHODS: A mixed methods approach was applied following the project "A Roadmap out of medical deserts into supportive health workforce initiatives and policies" work plan. It included the following elements: (i) a scoping literature review; (ii) a questionnaire survey; (iii) national stakeholders' workshop; (iv) a descriptive case study on medical deserts in Spain. RESULTS: Medical deserts in Spain exist in the form of mostly rural areas with limited access to health care. The main challenge in their identification and monitoring is local data availability. Diversity of both factors contributing to medical deserts and solutions applied to eliminate or mitigate them can be identified in Spain. They can be related to demand for or supply of health care services. More national data, analyses and/or initiatives seem to be focused on the health care supply dimension. CONCLUSIONS: Addressing medical deserts in Spain requires a comprehensive and multidimensional approach. Effective policies are needed to address both the medical staff education and planning system, working conditions, as well as more intersectoral approach to the population health management.

Assessing Telemental Health Uptake and Associated Health Care Resource Implications among Mississippi Medicaid Enrollees with Major Depression.

Objective: Investigate the association between Telemental Health (TMH) uptake and sociodemographic characteristics, and how TMH uptake relates to health care resource utilization and Medicaid expenditures among Mississippi Medicaid enrollees with major depression. Methods: A retrospective cohort study was conducted (2019-2020), comparing those who utilized TMH and those who did not. Results: Among the 21,239 identified enrollees, 806 (3.79%) utilized TMH. The TMH cohort was more likely to be of older age, non-Hispanic White, comprehensive managed care organization enrollees, rural residents, and from areas with a higher area deprivation index, and have higher Charlson comorbidity index scores. The TMH cohort also exhibited higher mental health-related and all-cause outpatient and emergency department utilization, along with higher Medicaid expenditures. Conclusion: As the first study investigating telehealth utilization among Mississippi Medicaid enrollees, this study highlights sociodemographic disparities in telehealth adoption. Addressing barriers hindering telehealth adoption among vulnerable populations and ensuring the availability of quality data are vital for future research.

Telemental Health Services Usage and Association with Health Care Utilization and Expenditures Among Vulnerable Medicare Beneficiaries in 2019: A Comparative Study Using Propensity Score Matching.

Background: Telemental health (TMH) offers a promising approach to managing major depressive disorder (MDD). The objective of our work was to evaluate TMH usage among a vulnerable population of MDD Medicare beneficiaries and its association with health care utilization and expenditures. Methods: This cohort study analyzed 2019 Mississippi Medicare fee-for-service data for adult beneficiaries with MDD. Subjects were matched by the use of TMH following 1:1 propensity score matching. Comparisons between TMH and non-TMH cohorts were made on health care utilization and expenditure outcomes, adjusting for provider types postmatching. Results: Among 7,673 identified beneficiaries, 551 used TMH and 7,122 did not. Prematching, TMH cohort showed greater proportions of dual beneficiaries, rural residents, subjects with income below $40,000, those with disability entitlement, and higher Charlson comorbidity index scores, compared to the non-TMH cohort (all p < 0.001). Moreover, the TMH cohort had fewer outpatient visits, but more inpatient admissions, emergency department (ED) visits, and higher medical, pharmacy, and total expenditures (all p < 0.001). Postmatching, TMH was associated with a 25% reduction in outpatient visits (p < 0.001) and a 20% reduction in pharmacy expenditures (p = 0.01), with no significant effect on inpatient admissions, ED visits, medical expenditures, or total expenditures. Conclusions: These results underscore the potential of TMH in enhancing accessible health care services for vulnerable populations and affordable services for Medicare. Our results provide a robust baseline for future policy discussions concerning TMH. Future studies should consider identifying barriers to TMH use among vulnerable populations and ensuring equitable and high-quality patient care.

Polyvalent Bacterial Lysate with Potential Use to Treatment and Control of Recurrent Urinary Tract Infections.

Overuse of antimicrobials has greatly contributed to the increase in the emergence of multidrug-resistant bacteria, a situation that hinders the control and treatment of infectious diseases. This is the case with urinary tract infections (UTIs), which represent a substantial percentage of worldwide public health problems, thus the need to look for alternatives for their control and treatment. Previous studies have shown the usefulness of autologous bacterial lysates as an alternative for the treatment and control of UTIs. However, a limitation is the high cost of producing individual immunogens. At the same time, an important aspect of vaccines is their immunogenic amplitude, which is the reason why they must be constituted of diverse antigenic components. In the case of UTIs, the etiology of the disease is associated with different bacteria, and even Escherichia coli, the main causal agent of the disease, is made up of several antigenic variants. In this work, we present results on the study of a bacterial lysate composed of 10 serotypes of Escherichia coli and by Klebsiella pneumoniae, Klebsiella aerogenes, Enterococcus faecalis, Proteus mirabilis, Citrobacter freundii, and Staphylococcus haemolyticus. The safety of the compound was tested on cells in culture and in an animal model, and its immunogenic capacity by analysing in vitro human and murine macrophages (cell line J774 A1). The results show that the polyvalent lysate did not cause damage to the cells in culture or alterations in the animal model used. The immunostimulatory activity assay showed that it activates the secretion of TNF-α and IL-6 in human macrophages and TNF-α in murine cells. The obtained results suggest that the polyvalent lysate evaluated can be an alternative for the treatment and control of chronic urinary tract infections, which will reduce the use of antimicrobials.

Naturalization of treated wastewater by a constructed wetland in a water-scarce Mediterranean region.

The effluents from conventional wastewater treatment plants (WWTP), even if accomplishing quality regulations, substantially differ in their characteristics with those of waters in natural environments. Constructed wetlands (CWs) serve as transitional ecosystems within WWTPs, mitigating these differences and restoring natural features before water is poured into the natural environment. Our study focused on an experimental surface-flow CW naturalizing the WWTP effluent in a semiarid area in Eastern Spain. Despite relatively low pollutant concentrations entering the CW, it effectively further reduced settled organic matter and nitrogen. Dissolved organic matter (DOM) reaching the CW was mainly protein-like, yet optical property changes in the DOM indicated increased humification, aromaticity, and stabilization as it flowed through the CW. Flow cytometry analysis revealed that the CW released less abundant but more active bacterial populations than those received. MiSeq Illumina sequencing highlighted changes in the prokaryotic community composition, with phyla Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria dominating the CW outflow. Functional prediction tools (FaproTax and PICRUSt2) demonstrated a shift towards microbial guilds aligned with those of the natural aquatic environments, increased aerobic chemoheterotrophs, photoautotrophs, and metabolic reactions at higher redox potentials. Enhanced capabilities for degrading plant material correlated well with changes in the DOM pool. Our findings emphasize the role of CWs in releasing biochemically stable DOM and functionally suited microbial populations for natural receiving environments. Consequently, we propose CWs as a naturalization nature-based solution (NBS) in water-scarce regions like the Mediterranean, where reclaimed discharged water can significantly contribute to ecosystem's water resources compared to natural flows.

Use of Residual Malt from an Artisanal Beer Brewing Process in the Biosynthesis of Silver Nanoparticles Mediated by Nucleating and Structure-Directing Agents.

Biosynthesized silver nanoparticles (AgNPs) are widely used in varied applications, which are morphology dependent. Consequently, a morphology-controlled synthesis is mandatory. Although there are several studies focused on the plant extract-based biosynthesis of metallic nanoparticles, the use of extracts obtained from agro-wastes is scant. Furthermore, information regarding morphology modification through the use of additional agents is even more scarce. Thus, in this study, AgNPs were synthesized using a malt extract (ME) obtained from an artisanal beer brewing process residue. Additionally, sodium chloride (NaCl), gum arabic (GA), and talc (T) were used in an attempt to modify the morphology of AgNPs. XRD, DLS, SEM, and TEM results demonstrate that stable AgNPs of different sizes and shapes were synthesized. FTIR, HPLC analysis, and the quantification of total proteins, free amino acids, reducing sugars, and total polyphenols before and after AgNPs synthesis showed that ME biomolecules allowed them to act as a source of reducing and stabilizing agents. Therefore, this study provides evidence that ME can be successfully used to biosynthesize AgNPs. Additionally, the antibacterial activity of AgNPs against Gram-negative and Gram-positive bacteria was evaluated. Results indicate that AgNPs show a higher antibacterial activity against Gram-positive bacteria.

Production of a bacterial secretome highly efficient for the deconstruction of xylans.

Bacteria within the Paenibacillus genus are known to secrete a diverse array of enzymes capable of breaking down plant cell wall polysaccharides. We studied the extracellular xylanolytic activity of Paenibacillus xylanivorans and examined the complete range of secreted proteins when grown on carbohydrate-based carbon sources of increasing complexity, including wheat bran, sugar cane straw, beechwood xylan and sucrose, as control. Our data showed that the relative abundances of secreted proteins varied depending on the carbon source used. Extracellular enzymatic extracts from wheat bran (WB) or sugar cane straw (SCR) cultures had the highest xylanolytic activity, coincidently with the largest representation of carbohydrate active enzymes (CAZymes). Scaling-up to a benchtop bioreactor using WB resulted in a significant enhancement in productivity and in the overall volumetric extracellular xylanase activity, that was further concentrated by freeze-drying. The enzymatic extract was efficient in the deconstruction of xylans from different sources as well as sugar cane straw pretreated by alkali extrusion (SCRe), resulting in xylobiose and xylose, as primary products. The overall yield of xylose released from SCRe was improved by supplementing the enzymatic extract with a recombinant GH43 ß-xylosidase (EcXyl43) and a GH62 α-L-arabinofuranosidase (CsAbf62A), two activities that were under-represented. Overall, we showed that the extracellular enzymatic extract from P. xylanivorans, supplemented with specific enzymatic activities, is an effective approach for targeting xylan within lignocellulosic biomass.

Biochemical and Genetic Analysis Identify CSLD3 as a beta-1,4-Glucan Synthase That Functions during Plant Cell Wall Synthesis.

In plants, changes in cell size and shape during development fundamentally depend on the ability to synthesize and modify cell wall polysaccharides. The main classes of cell wall polysaccharides produced by terrestrial plants are cellulose, hemicelluloses, and pectins. Members of the cellulose synthase (CESA) and cellulose synthase-like (CSL) families encode glycosyltransferases that synthesize the ß-1,4-linked glycan backbones of cellulose and most hemicellulosic polysaccharides that comprise plant cell walls. Cellulose microfibrils are the major load-bearing component in plant cell walls and are assembled from individual ß-1,4-glucan polymers synthesized by CESA proteins that are organized into multimeric complexes called CESA complexes, in the plant plasma membrane. During distinct modes of polarized cell wall deposition, such as in the tip growth that occurs during the formation of root hairs and pollen tubes or de novo formation of cell plates during plant cytokinesis, newly synthesized cell wall polysaccharides are deposited in a restricted region of the cell. These processes require the activity of members of the CESA-like D subfamily. However, while these CSLD polysaccharide synthases are essential, the nature of the polysaccharides they synthesize has remained elusive. Here, we use a combination of genetic rescue experiments with CSLD-CESA chimeric proteins, in vitro biochemical reconstitution, and supporting computational modeling and simulation, to demonstrate that Arabidopsis (Arabidopsis thaliana) CSLD3 is a UDP-glucose-dependent ß-1,4-glucan synthase that forms protein complexes displaying similar ultrastructural features to those formed by CESA6.

Molecular Mechanism of Polysaccharide Acetylation by the Arabidopsis Xylan O-acetyltransferase XOAT1.

Xylans are a major component of plant cell walls. O-Acetyl moieties are the dominant backbone substituents of glucuronoxylan in dicots and play a major role in the polymer-polymer interactions that are crucial for wall architecture and normal plant development. Here, we describe the biochemical, structural, and mechanistic characterization of Arabidopsis (Arabidopsis thaliana) xylan O-acetyltransferase 1 (XOAT1), a member of the plant-specific Trichome Birefringence Like (TBL) family. Detailed characterization of XOAT1-catalyzed reactions by real-time NMR confirms that it exclusively catalyzes the 2-O-acetylation of xylan, followed by nonenzymatic acetyl migration to the O-3 position, resulting in products that are monoacetylated at both O-2 and O-3 positions. In addition, we report the crystal structure of the catalytic domain of XOAT1, which adopts a unique conformation that bears some similarities to the α/ß/α topology of members of the GDSL-like lipase/acylhydrolase family. Finally, we use a combination of biochemical analyses, mutagenesis, and molecular simulations to show that XOAT1 catalyzes xylan acetylation through formation of an acyl-enzyme intermediate, Ac-Ser-216, by a double displacement bi-bi mechanism involving a Ser-His-Asp catalytic triad and unconventionally uses an Arg residue in the formation of an oxyanion hole.

Liquid biopsy in the setting of leptomeningeal metastases: a systematic review and meta-analysis.

PURPOSE: The blood-brain barrier can prevent circulating tumor DNA (ctDNA) derived from the central nervous system from entering the blood making it challenging to evaluate molecular features of leptomeningeal metastasis (LM). Accordingly, we sought to systematically compare the diagnostic power or significance of ctDNA derived from cerebrospinal fluid (CSF) compared to plasma ctDNA in patients with LM. METHODS: A systematic review and meta-analysis was performed under the PRISMA guideline. We used PubMed, EMBASE, and the EuroPMC to search the literature using combinations of the following terms: circulating tumor DNA, ctDNA, circulating tumor cell, brain metastasis, leptomeningeal metastasis, outcome(s), and prognosis. We included all available English language studies that compared the diagnostic significance of CSF derived and serum ctDNA. All eligible studies level of bias was assessed using the New Castle Ottawa Scale (NOS). RESULTS: Our meta-analysis from 6 included studies (n = 226) that confirmed the diagnostic power of liquid biopsies in detecting genomic alteration is better when taking a CSF-derived samples than from the plasma (RR 1.46 [0.93; 2.29]; I2 = 92%; p-value < 0.01). CONCLUSION: CSF ctDNA is better at describing molecular landscape for LM; such an understanding may ultimately help inform patient treatment and responses to therapy.

Flexible joint modeling of mean and dispersion for the directional tuning of neuronal spike counts.

The study of how the number of spikes in a middle temporal visual area (MT/V5) neuron is tuned to the direction of a visual stimulus has attracted considerable attention over the years, but recent studies suggest that the variability of the number of spikes might also be influenced by the directional stimulus. This entails that Poisson regression models are not adequate for this type of data, as the observations usually present over/underdispersion (or both) with respect to the Poisson distribution. This paper makes use of the double exponential family and presents a flexible model to estimate, jointly, the mean and dispersion functions, accounting for the effect of a circular covariate. The empirical performance of the proposal is explored via simulations and an application to a neurological data set is shown.

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.