Search

Background Corticosteroid injection is an effective treatment for trigger digits but the pain during the injection is an ever-present side effect. Since the palmar skin has a high density of sensitive receptors, injecting through dorsal skin could be less painful. Our aim was to assess whether a dorsal technique through the dorsal web is safe for extra-sheath injection of trigger fingers and thumb. Material and method This is an anatomical study in sixteen cadaveric hands. An injection through the dorsal web was performed on each digit. After careful resection of the palmar skin, the distance between the needle and the main anatomical structures was measured. The risk of major injury was considered high when the mean distance from the needle to the neurovascular bundle was below one millimeter. Results The mean distance from the needle to the neurovascular bundle was 1.77 mm. Two neurovascular injuries in 112 injections were observed, one nerve and one artery. The safest digit was the thumb while the most dangerous was the index finger. At the ring finger, the technique was safer when it was carried out from the dorso-radial. Conclusions A subcutaneous injection near the flexor tendon sheath can be carried out through the dorsal web with a low, but present, risk of neurovascular injury. It could be useful for injection in the treatment of trigger finger and trigger thumb but it should be assessed in a clinical study.

The researchers designed and conducted this study using the predictive analytics to determine the different science performance predictors of the first batch of K to 12 curriculum in Valencia District, Valencia, Negros Oriental. The researchers had chosen three kinds of predictors namely; student-related predictors, teacher-related predictors, and school-related predictors. For the student-related predictors, parents’ educational attainment, parents’ occupation, family income, IQ level, learning styles and previous grade level science performance. The teacher-related predictors include teachers’ educational qualifications, length of science teaching experience, relevant science trainings and seminars attended, and exposure to access internet connection. On the other hand, the school-related predictors include the type of school, class size, ratio of science books to number of students and conformity of science laboratory equipment and apparatus to K to 12 standards. The researchers had randomly chosen 311 student-respondents and 8 teacher-respondents coming from four public and two private secondary schools of Valencia District. Questionnaires that were tested on its reliability and validity were used in this study. The collected data were then interpreted and analysed using appropriate statistical tools. Students’ previous science performance, parents’ educational attainment, parents’ occupation, intelligence quotient (IQ), teachers’ educational qualification, number of years in science teaching experience, levels and numbers of seminars and trainings attended and teachers’ internet access significantly predict the level of students’ performance in science; thus, they are considered as predictors. However, learning styles, class size, parents’ occupation, type of school, student-book ratio, and conformity of science equipment and apparatus cannot predict students’ level of performance.

Contains fulltext : 225281.pdf (Publisher’s version ) (Closed access) Contains fulltext : 225281pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple biliary cysts. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. We hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. METHODS: ER stress was analysed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy, TEM) and functional (proteasome activity) levels in different PLD models. The effect of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or activators [tunicamycin (TM)] was tested in polycystic (PCK) rats and cystic cholangiocytes in vitro. RESULTS: The expression levels of unfolded protein response (UPR) components were upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (ie synthesis, folding, trafficking and degradation of proteins), marked enlargement of the ER lumen (by TEM) and hyperactivation of the proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline conditions or after TM administration compared to controls. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized proteomic profiles related to protein synthesis, folding, trafficking and degradation and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. CONCLUSIONS: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel therapeutic strategy.

Given the importance of the management of sedation, analgesia and delirium in Intensive Care Units, and in order to update the previously published guidelines, a new clinical practice guide is presented, addressing the most relevant management and intervention aspects based on the recent literature. A group of 24 intensivists from 9 countries of the Pan-American and Iberian Federation of Societies of Critical Medicine and Intensive Therapy met to develop the guidelines. Assessment of evidence quality and recommendations was made according to the Grading of Recommendations Assessment, Development and Evaluation Working Group. A systematic search of the literature was carried out using MEDLINE, Cochrane Library databases such as the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database and the database of Latin American and Caribbean Literature in Health Sciences (LILACS). A total of 438 references were selected. After consensus, 47 strong recommendations with high and moderate quality evidence, 14 conditional recommendations with moderate quality evidence, and 65 conditional recommendations with low quality evidence were established. Finally, the importance of initial and multimodal pain management was underscored. Emphasis was placed on decreasing sedation levels and the use of deep sedation only in specific cases. The evidence and recommendations for the use of drugs such as dexmedetomidine, remifentanil, ketamine and others were incremented.

We provide a continuous-time “risk-centric” representation of the New Keynesian model, which we use to analyze the interactions between asset prices, financial speculation, and macroeconomic outcomes when output is determined by aggregate demand. In principle, interest rate policy is highly effective in dealing with shocks to asset valuations. However, in practice monetary policy faces a wide range of constraints. If these constraints are severe, a decline in risky asset valuations generates a demand recession. This reduces earnings and generates a negative feedback loop between asset prices and aggregate demand. In the recession phase, average beliefs matter because they not only affect asset valuations but also determine the strength of the amplification mechanism. In the ex ante boom phase, belief disagreements (or heterogeneous asset valuations) matter because they induce investors to speculate. This speculation exacerbates the crash by reducing high-valuation investors’ wealth when the economy transitions to recession, which depresses (wealth-weighted) average beliefs. Macroprudential policy that restricts speculation in the boom can Pareto improve welfare by increasing asset prices and aggregate demand in the recession.

Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cysts (more than ten), which constitute the main cause of morbidity and markedly affect the quality of life. Liver cysts arise in patients with autosomal dominant PLD (ADPLD) or in co-occurrence with renal cysts in patients with autosomal dominant or autosomal recessive polycystic kidney disease (ADPKD and ARPKD, respectively). Hepatic cystogenesis is a heterogeneous process, with several risk factors increasing the odds of developing larger cysts. Depending on the causative gene, PLDs can arise exclusively in the liver or in parallel with renal cysts. Current therapeutic strategies, mainly based on surgical procedures and/or chronic administration of somatostatin analogues, show modest benefits, with liver transplantation as the only potentially curative option. Increasing research has shed light on the genetic landscape of PLDs and consequent cholangiocyte abnormalities, which can pave the way for discovering new targets for therapy and the design of novel potential treatments for patients. Herein, we provide a critical and comprehensive overview of the latest advances in the field of PLDs, mainly focusing on genetics, pathobiology, risk factors and next-generation therapeutic strategies, highlighting future directions in basic, translational and clinical research.

RESUMEN Se determinó el efecto de dos protocolos de antisepsia del campo operatorio sobre la reducción del número de bacterias de la piel en bovinos sometidos a cirugías reproductivas a campo. Se tomaron muestras antes (M1), luego de la antisepsia (M2) y al finalizar el procedimiento quirúrgico (M3) en 12 bovinos mestizos de 18 a 24 meses de edad. Se realizó la tricotomía del campo operatorio previo a los dos protocolos de antisepsia: Iodopovidona al 7.5% y Gluconato de Clorhexidina al 2% (ambos con 3 min de contacto y aclaramiento con alcohol isopropílico de 2 min de contacto) y posterior embrocado con iodopovidona solución al 1% y clorhexidina solución al 0.5%, respectivamente. Los hisopados de piel fueron procesadas por la técnica de recuento de unidades formadoras de colonias (UFC/ml). La carga bacteriana de los dos protocolos fue analizada con el test de Mann-Whitney-Wilcoxon para muestras independientes, sin encontrar diferencias significativas entre protocolos por momento de evaluación (p>0.05). El test de Friedman indicó una reducción significativa entre M1 con M2 y M3 (p0.05). ABSTRACT The effect of two surgical field antisepsis protocols on the reduction of the number of skin bacteria in bovines subjected to field reproductive surgeries was determined. Samples were taken before (M1), and after antisepsis (M2) and at the end of the surgical procedure (M3) in 12 crossbred bovines aged 18 to 24 months. Trichotomy of the operating field was performed prior to the two antisepsis protocols: 7.5% povidone-iodine and 2% Chlorhexidine Gluconate (both with 3-min contact time and 2-min contact clearance with isopropyl alcohol) and later embrocation with 1% povidone-iodine solution and 0.5% chlorhexidine solution, respectively. The skin swabs were processed by the count technique of colony forming units (CFU/ml). The bacterial load of the two protocols was analysed with the Mann-Whitney-Wilcoxon test for independent samples, without finding significant differences between protocols by evaluation time (p>0.05). The Friedman test indicated a significant reduction between M1 with M2 and M3 (p0.05).

Aedes albopictus is a species of mosquito, originally from Southeast Asia, that belongs to the Culicidae family and the Dipteran insect order. The distribution of this vector has rapidly changed over the past decade, making most of the temperate territories in the world vulnerable to important human vector-borne diseases such as dengue, yellow fever, zika or chikungunya. Bacillus thuringiensis var. israeliensis (Bti)-based insecticides represent a realistic alternative to the most common synthetic insecticides for the control of mosquito larvae. However, several studies have revealed emerging resistances to the major Bti Crystal proteins such as Cry4Aa, Cry4Ba and Cry11Aa, making the finding of new toxins necessary to diminish the exposure to the same toxicity factors overtime. Here, we characterized the individual activity of Cyt1Aa, Cry4Aa, Cry4Ba and Cry11Aa against A. albopictus and found a new protein, Cyt1A-like, that increases the activity of Cry11Aa more than 20-fold. Additionally, we demonstrated that Cyt1A-like facilitates the activity three new Bti toxins: Cry53-like, Cry56A-like and Tpp36-like. All in all, these results provide alternatives to the currently available Bti products for the control of mosquito populations and position Cyt proteins as enablers of activity for otherwise non-active crystal proteins.

Item does not contain fulltext Polycystic liver diseases (PLDs) are inherited genetic disorders characterized by progressive development of intrahepatic, fluid-filled biliary cysts (more than ten), which constitute the main cause of morbidity and markedly affect the quality of life. Liver cysts arise in patients with autosomal dominant PLD (ADPLD) or in co-occurrence with renal cysts in patients with autosomal dominant or autosomal recessive polycystic kidney disease (ADPKD and ARPKD, respectively). Hepatic cystogenesis is a heterogeneous process, with several risk factors increasing the odds of developing larger cysts. Depending on the causative gene, PLDs can arise exclusively in the liver or in parallel with renal cysts. Current therapeutic strategies, mainly based on surgical procedures and/or chronic administration of somatostatin analogues, show modest benefits, with liver transplantation as the only potentially curative option. Increasing research has shed light on the genetic landscape of PLDs and consequent cholangiocyte abnormalities, which can pave the way for discovering new targets for therapy and the design of novel potential treatments for patients. Herein, we provide a critical and comprehensive overview of the latest advances in the field of PLDs, mainly focusing on genetics, pathobiology, risk factors and next-generation therapeutic strategies, highlighting future directions in basic, translational and clinical research. 01 september 2022

Bacterial genomes are pervasively transcribed, generating a wide variety of antisense RNAs (asRNAs). Many of them originate from transcriptional read-through events (TREs) during the transcription termination process. Previous transcriptome analyses revealed that the lexA gene from Staphylococcus aureus, which encodes the main SOS response regulator, is affected by the presence of an asRNA. Here, we show that the lexA antisense RNA (lexA-asRNA) is generated by a TRE on the intrinsic terminator (TTsbrB) of the sbrB gene, which is located downstream of lexA, in the opposite strand. Transcriptional read-through occurs by a natural mutation that destabilizes the TTsbrB structure and modifies the efficiency of the intrinsic terminator. Restoring the mispairing mutation in the hairpin of TTsbrB prevented lexA-asRNA transcription. The level of lexA-asRNA directly correlated with cellular stress since the expressions of sbrB and lexA-asRNA depend on the stress transcription factor SigB. Comparative analyses revealed strain-specific nucleotide polymorphisms within TTsbrB, suggesting that this TT could be prone to accumulating natural mutations. A genome-wide analysis of TREs suggested that mispairings in TT hairpins might provide wider transcriptional connections with downstream genes and, ultimately, transcriptomic variability among S. aureus strains., This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant No. 646869 to A.T.-A.) and by the Spanish Ministry of Science and Innovation grants (BIO2017-83035-R to I.L. and PID2019-105216GBI00 to A.T.-A.). Funding for open access charge was provided by the CSIC Open Access Publication Support Initiative, Unit of Information Resources for Research (URICI).

Objective: Studies evaluating the association of metals with subclinical atherosclerosis are mostly limited to carotid arteries. We assessed individual and joint associations of nonessential metals exposure with subclinical atherosclerosis in 3 vascular territories. Approach and Results: One thousand eight hundred seventy-three Aragon Workers Health Study participants had urinary determinations of inorganic arsenic species, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten. Plaque presence in carotid and femoral arteries was determined by ultrasound. Coronary Agatston calcium score ≥1 was determined by computed tomography scan. Median arsenic, barium, cadmium, chromium, antimony, titanium, uranium, vanadium, and tungsten levels were 1.83, 1.98, 0.27, 1.18, 0.05, 9.8, 0.03, 0.66, and 0.23 μg/g creatinine, respectively. The adjusted odds ratio (95% CI) for subclinical atherosclerosis presence in at least one territory was 1.25 (1.03–1.51) for arsenic, 1.67 (1.22–2.29) for cadmium, and 1.26 (1.04–1.52) for titanium. These associations were driven by arsenic and cadmium in carotid, cadmium and titanium in femoral, and titanium in coronary territories and mostly remained after additional adjustment for the other relevant metals. Titanium, cadmium, and antimony also showed positive associations with alternative definitions of increased coronary calcium. Bayesian Kernel Machine Regression analysis simultaneously evaluating metal associations suggested an interaction between arsenic and the joint cadmium-titanium exposure. Conclusions: Our results support arsenic and cadmium and identify titanium and potentially antimony as atherosclerosis risk factors. Exposure reduction and mitigation interventions of these metals may decrease cardiovascular risk in individuals without clinical disease.

Background Selective dry cow therapy (SDCT) is widely promoted in dairy farming as a method to reduce antimicrobial usage. New legislation introduced by the European Union will restrict and regulate the prophylactic and metaphylactic use of antibiotics from January 2022. Blanket dry cow therapy continues to be a practice engaged in by many farmers in Ireland and for many of these farmers, moving towards SDCT would require a significant infrastructural, behavioural and/or cultural change on their farm. Existing research has reported the important need to understand farmers’ motivations to initiate any substantial behaviour change. However, it is currently unknown what farmers know, think and believe about SDCT in Ireland. The aim of this study was to use qualitative methods to explore what barriers and facilitators farmers perceived to exist with SDCT and explore if they had chosen to implement SDCT after voluntarily participating in a funded dry cow consult with a trained veterinarian, with the objective of maximising the dry period udder health performance and moving safely to SDCT. Results In this study, 19 farmers were contacted, and telephone interviews were conducted regarding farmers’ beliefs about the consequences of SDCT. Audio recordings were professionally transcribed verbatim and analysed qualitatively using an inductive thematic analysis. The analysis identified 6 barriers and 6 facilitators to implementing SDCT. A significant fear of increasing mastitis incidence was evident that caused reluctance towards SDCT and reliance on antibiotics. Mixed perceptions on SDCT, infrastructure limitations, a perceived lack of preventive advice as well as peer influence were presented as barriers to SDCT. Farmers can build confidence when a graded approach to SDCT is implemented, which could help overcome the fear of SDCT and reliance on antibiotics. Regulatory pressure, high standards of farm hygiene and use of targeted veterinary consults were found to facilitate SDCT. Education was suggested to motivate farmers in the future uptake of SDCT. Despite cited negative influences, peer influence can be utilised to encourage the farming community. Conclusions This study prioritises areas to facilitate the major behaviour change required as a dairy industry in order to move from blanket dry cow therapy to SDCT.

In this paper, we present a sufficient condition for the uniqueness of solutions to a nonlocal fractional boundaryvalue problem which can be considered as the fractional version to the thermostat model. As application of ourresult, we study the eigenvalues problem associated and, moreover, we get a Lyapunov-type inequality.

In this paper, by using a recent fixed point theorem, we study the existence and uniqueness of positive solutions for the following m-point fractional boundary value problem on an infinite interval $$\begin{aligned} \left\{ \begin{array}{ll} D_{0^{+}}^{\alpha }x(t)+f(t,x(t))=0,&{}\quad 0

Two moderately halophilic and psychrotolerant new Mycoplasma species were isolated from common cephalopods. Three strains were isolated in pure culture from two individual European flying squid (Todarodes sagittatus), and two individual octopuses (Octopus vulgaris). The strains showed optimal growth at 25 °C and a salinity of 3% (w/v) NaCl. Molecular analyses revealed that the isolates belonged to two new, but phylogenetically related species, divergent from all previously described Mollicutes, representing the first marine isolates of the class, and also the first Mycoplasma strains for which NaCl requirement has been demonstrated. A genome search against all available marine metagenomes and 16S rRNA gene databases indicated that these two species represent a novel non-free-living marine lineage of Mollicutes, specifically associated with marine animals. Morphology and physiology were compatible with other members of this group, and genomic and phenotypic analyses demonstrated that these organisms represent two novel species of the genus Mycoplasma, for which the names Mycoplasma marinum sp. nov. and Mycoplasma todarodis sp. nov. are proposed; the type strains are PET (DSM 105487T, CIP 111404T) and 5HT (DSM 105,488T, CIP 111405T), respectively., RRM acknowledges the Spanish Ministry of Economy project CLG2015_66686-C3-1-P also supported with European Regional Development Fund (FEDER) funds. ASR acknowledges the Gobierno de Canarias (Spain) project P2007/046. RRM acknowledges the financial support of the sabbatical stay at Georgia Institute of Technology supported by the grant PRX18/00048 of the Ministry of Sciences, Innovation and Universities. KTK’s research was supported, in part, by the U.S. National Science Foundation (Award No. 1,759,831).

Systemic granulomatosis has already been reported in meagre larvae with an adequate feeding protocol and enrichment media preventing its appearance in the first weeks of life. Afterwards, the control of this disease could be prevented through nutritional components of the inert food, being the antioxidants the key to success. For this reason, in the present study, meagre larvae were reared from 30 days post hatching (dph) with five isonitrogenous and isolipidic experimental microdiets with different levels of vitamin E and C: C– (40 mg kg−1 E, 100 mg kg−1C), C+ (400 mg kg−1 E, 1000 mg kg−1C), Krill (400 mg kg−1 E, 1000 mg kg−1C and substitution of fish oil by krill oil), EC (200 mg kg−1 E, 500 mg kg−1C) and EECC (800 mg kg−1 E, 2000 mg kg−1C). Prior to this, larvae were co-fed with rotifers and Artemia following a protocol which prevented the appearance of granulomas, as previously demonstrated. The substitution of fish oil by krill oil significantly increased levels of eicosapentaenoic acid (EPA, 16.6%) and docosahexaenoic acid (DHA, 17.6%) in meagre, consequently increasing the peroxidation index, which in turn translated into a higher incidence of granulomas. Although even low levels of vitamin E and C (40 mg kg−1 E, 100 mg kg−1C; C-) allowed the adequate growth of larvae, these levels were not enough to prevent the appearance of granulomas, requiring superior levels of both antioxidant vitamins (800 mg kg−1 E and 2000 mg kg−1C) to mitigate systemic granulomatosis. This mitigation was simultaneous with the reduction of thiobarbituric acid reactive substances TBARs content in larvae, which were highly correlated with the appearance of granulomas (R2 = 0.892, y = 0.0446× + 0.0756). A strong negative correlation was observed between the dietary levels of vitamin E (y = −0.0098× + 11.174, R2 = 0.8766, p value = .019, r = −0.93) and vitamin C (y = −0.0022× + 6.4777, R2 = 0.9278, p value = .003, r = −0.96) and the percentage of larvae with granulomas. The results showed that the occurrence of systemic granulomatosis seems to be associated to the larvae peroxidation status, so that high dietary levels of vitamin E and C (800 and 2000 mg kg−1, respectively; Diet EECC), reduced lipid peroxidation and completely prevented the appearance of granulomas in meagre larvae at 44 dph.

Objective To know the real clinical practice of Spanish ICUs in relation to analgesia, sedation and delirium, with a view to assessing adherence to current recommendations. Design A descriptive cross-sectional study was carried out based on a national survey on analgesia, sedation and delirium practices in patients admitted to intensive care on 16 November, 2013 and 16 October, 2014. An on-line questionnaire was sent with the endorsement of the SEMICYUC. Setting Spanish ICUs in public and private hospitals. Results A total of 166 ICUs participated, with the inclusion of 1567 patients. The results showed that 61.4% of the ICUs had a sedation protocol, and 75% regularly monitored sedation and agitation – the RASS being the most frequently used scale. Pain was monitored in about half of the ICUs, but the behavioral scales were very little used. Delirium monitoring was implemented in few ICUs. Among the patients on mechanical ventilation, midazolam remained a very commonly used agent. Conclusions This survey is the first conducted in Spain on the practices of analgesia, sedation and delirium. We identified specific targets for quality improvement, particularly concerning the management of sedation and the assessment of delirium.

Resumen Objetivo Conocer la practica clinica real de las UCI espanolas en relacion con la analgosedacion y delirium, y valorar como se ajusta a las recomendaciones actuales. Diseno Estudio transversal descriptivo elaborado mediante encuesta nacional sobre practicas de analgosedacion y delirium de los pacientes ingresados en UCI los dias 16 de noviembre de 2013 y 16 de octubre de 2014. Se envio un cuestionario a traves de Internet con el aval de la SEMICYUC. Ambito UCI tanto publicas como privadas de todo el territorio nacional. Resultados Se incluyeron un total de 166 UCI y a 1.567 pacientes. El 61,4% de las UCI contaban con un protocolo de sedacion. El 75% de las UCI monitorizaban la sedacion y agitacion, con RASS como la escala empleada con mayor frecuencia. El dolor se monitorizaba en algo mas de la mitad de las UCI, pero las escalas conductuales eran de muy baja implantacion. El delirium tambien presentaba un bajo nivel diagnostico. Entre los pacientes en ventilacion mecanica el midazolam continuaba siendo un sedante de muy amplio uso. Conclusiones Esta encuesta es la primera realizada en Espana sobre analgosedacion y delirium y nos muestra una fotografia sobre estas practicas, senala algunos aspectos como los relacionados con la monitorizacion y usos de escalas, junto con el manejo del delirium, en los que los resultados del estudio animan a desarrollar proyectos docentes que acerquen la practica clinica real a las recomendaciones nacionales e internacionales.

Aunque la causa más común de embolia coronaria es la fibrilación auricular, no debemos olvidar que existen otras afecciones que, a pesar de su baja frecuencia, se deben descartar para establecer un tratamiento definitivo. Entre ellas se encuentran las malformaciones arteriovenosas, como en el caso que se presenta a continuación. Una mujer de 36 años, con un síndrome de Rendu-Osler-Weber con epistaxis espontáneas recurrentes como único antecedente personal, acudió a urgencias por dolor centrotorácico opresivo, irradiado al miembro superior izquierdo y la espalda, acompañado de cortejo vegetativo. En el electrocardiograma se apreció una lesión subepicárdica en V2-3 que asociaba cifras de troponina ultrasensible con un pico máximo de 9.148 pg/ml.

This is a comprehensive review of the literature focusing on the use of prolotherapy in the treatment of osteoarthritis of the knee. It covers the background, efficacy, and advantages of prolotherapy in the management of osteoarthritis symptoms and then covers the existing evidence of the use of prolotherapy for this purpose. Current treatments for osteoarthritis of the knee are numerous, yet patients continue to endorse chronic pain and poor quality of life. Prolotherapy is a treatment that has been inadequately studied with poor sample sizes and lack of standardization between trials. However, in recent years the literature on prolotherapy in the treatment of knee osteoarthritis has grown. Although there is still a lack of homogeneity, trials have shown that dextrose prolotherapy, autologous conditioned serum, hyaluronic injections, and normal saline administered either intra- or peri-articularly are comparable in reducing pain scores to other primary treatment options. The mechanism of action for prolotherapy is still unclear, but researchers have found that prolotherapy plays some role in cartilage growth or chondrogenesis and has been shown to have improved radiographic outcomes. Prolotherapy appears to be a safe treatment alternative that has been shown to improve stiffness, pain, function, and quality of life in osteoarthritis of the knee. Knee osteoarthritis is remarkably prevalent in the United States and is one of the most common causes of disability in the elderly population. Although there are many treatment options, patients continue to live with chronic pain which can incur high costs for patients. A safe, long-term, and effective solution has not yet been identified. Prolotherapy has been shown to be a safe option for improving pain, function, and quality of life as effectively as other treatment options.

In this paper, we study the existence of positive solutions for the following nonlinear fractional boundary value problem: $$\begin{aligned} \left. \begin{array}{ll}D^{\alpha }_{0^+} u(t)+f(t,u(t),(Hu)(t))=0,&{} 0

Thermoregulation of virulence genes in bacterial pathogens is essential for environment-to-host transition. However, the mechanisms governing cold adaptation when outside the host remain poorly understood. Here, we found that the production of cold shock proteins CspB and CspC from Staphylococcus aureus is controlled by two paralogous RNA thermoswitches. Through in silico prediction, enzymatic probing and site-directed mutagenesis, we demonstrated that cspB and cspC 5′UTRs adopt alternative RNA structures that shift from one another upon temperature shifts. The open (O) conformation that facilitates mRNA translation is favoured at ambient temperatures (22°C). Conversely, the alternative locked (L) conformation, where the ribosome binding site (RBS) is sequestered in a double-stranded RNA structure, is folded at host-related temperatures (37°C). These structural rearrangements depend on a long RNA hairpin found in the O conformation that sequesters the anti-RBS sequence. Notably, the remaining S. aureus CSP, CspA, may interact with a UUUGUUU motif located in the loop of this long hairpin and favour the folding of the L conformation. This folding represses CspB and CspC production at 37°C. Simultaneous deletion of the cspB/cspC genes or their RNA thermoswitches significantly decreases S. aureus growth rate at ambient temperatures, highlighting the importance of CspB/CspC thermoregulation when S. aureus transitions from the host to the environment., A.T.-A. was supported by the European Research Council under the European Union's Horizon 2020 research and innovation program [ERC-CoG-2014-646869]; and the Spanish Ministry of Science and Innovation [PID2019-105216GB-I00] grants. I.C. was supported by Centre National de la Recherche Scientifique (CNRS) through an International Project of Scientific Cooperation between CNRS and CSIC [PICS07507]; and by the framework of the labEx Net RNA, French National Research Agency [ANR-10-LABX-0036 and IMCBio ANR-17-EURE-0023]. Funding for open access charge: CSIC Open Access Publication Support Initiative, Unit of Information Resources for Research (URICI).

In this paper, we present a result about the existence and uniqueness of positive solutions for a class of singular fractional differential equations with infinite-point boundary value conditions. The main tool used in the proof of the results is a fixed point theorem.

Background Polycystic liver diseases (PLDs) are genetic inherited disorders characterized by the progressive growth of numerous intrahepatic biliary cysts, which are the main cause of morbidity. Previous studies revealed that cystic cholangiocytes are characterized by endoplasmic reticulum stress and aberrant posttranslational modification (PTM) of proteins, in particular hyper-SUMOylation, that promote PLD pathobiology. Protein NEDDylation is a newly characterized PTM that modulates a plethora of biological processes and its dysregulation is associated with the development and progression of several human diseases. However, the role of NEDDylation in PLD remains elusive. Objective To explore the role of protein NEDDylation in PLD and its potential therapeutic regulatory value. Methods Levels and functional effects of NEDDylation, including response to Pevonedistat (first-in-class selective inhibitor of the NEDDylation E1 enzyme NAE), were assessed in vitro, in vivo, and/or in patients with PLD. NEDDylated protein levels in normal and cystic human cholangiocytes were assessed by immunoprecipitation, and the proteomic profile was further analyzed by mass spectrometry. Results and Conclusion The genes involved in the NEDDylation pathway were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture, compared to controls. Elevated levels of NEDDylated proteins were further confirmed in cystic cholangiocytes in vitro, which diminished under Pevonedistat incubation. Pevonedistat promoted apoptotic cell death and reduced proliferation in cystic cholangiocytes in vitro. Comparative proteomic profiling of NEDD8-immunoprecipitated proteins between normal and cystic cholangiocytes in culture reported candidate proteins involved in cystogenesis, mostly associated with protein biogenesis and quality control. All these data indicate that cystic cholangiocytes display increased protein NEDDylation, contributing to cell survival and proliferation, ultimately supporting hepatic cystogenesis. Targeting of protein hyper-NEDDylation in cystic cholangiocytes inhibits cystogenesis in experimental models, representing a novel therapeutic opportunity in PLD. Spanish Carlos III Health Institute (ISCIII), Grant/Award Numbers: CON14/00129, CPII19/00008, FIS PI12/00380, FIS PI14/ 00399, FIS PI15/01132, FIS PI17/00022, FIS PI18/01075, FIS PI20/00186, Sara Borrell CD19/00254; Diputacion Foral de Gipuzkoa, Grant/Award Numbers: DFG15/010, DFG16/004; Department of Health of the Basque Country, Grant/Award Numbers: 2015111100, 2017111010, 2019111024; Euskadi RIS3, Grant/Award Numbers: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010; Department of Industry of the Basque Country, Grant/Award Number: KK-2020/00008; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: RYC-2015-17755; Ministerio de Ciencia, Innovacion y Universidades, Grant/ Award Number: SAF2017-87301-R; Ayudas para apoyar grupos de investigacion del Sistema Universitario Vasco, Grant/Award Number: IT971-16; Universita Politecnica delle Marche, Grant/Award Number: PSA2017_UNIVPM; European Association for the Study of the Liver, Grant/Award Number: Sheila Sherlock Award 2017; Spanish Ministry of Science and Innovation, Grant/Award Number: BES-2014-069148; Basque Government, Grant/Award Number: PRE_2016_1_0269; Basque Foundation for Innovation and Health Research, Grant/Award Number: BIO15/CA/016/BD; Fundacion Cientifica de la Asociacion Espanola Contra el Cancer; La Caixa Scientific Foundation, Grant/ Award Number: HR17-00601; CIBERehd; Fondo Europeo de Desarrollo Regional Document

Background & Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods: Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results: Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdhl-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUM01-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis. Conclusions: Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy., Lay summary: Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients., Graphical Abstract

This is part 3.1 of the "Fluorescent Molecular Beacons Mimicking RNA Secondary Structures to Study RNA Chaperone Activity" collection of protocols. Collection Abstract: Molecular beacons (MBs) are oligonucleotide probes with a hairpin-like structure that are typically labelled at the 5' and 3' ends with a fluorophore and a quencher dye, respectively. The conformation of the MB acts as a switch for fluorescence emission. When the fluorophore is in close proximity to the quencher, fluorescence emission cannot be detected, meaning that the switch is in an OFF state. However, if the MB structure is modified, separating the fluorophore from the quencher, the switch turns ON allowing fluorescence emission. This property has been extensively used for a wide variety of applications including real-time PCR reactions, study of protein-DNA interactions, and identification of conformational changes in RNA structures. Here, we describe a protocol based on the MB technology to measure the RNA unfolding capacities of the CspA RNA chaperone from Staphylococcus aureus. This method, with slight variations, may also be applied for testing the activity of other RNA chaperones, RNA helicases, or ribonucleases.

Molecular beacons (MBs) are oligonucleotide probes with a hairpin-like structure that are typically labelled at the 5' and 3' ends with a fluorophore and a quencher dye, respectively. The conformation of the MB acts as a switch for fluorescence emission. When the fluorophore is in close proximity to the quencher, fluorescence emission cannot be detected, meaning that the switch is in an OFF state. However, if the MB structure is modified, separating the fluorophore from the quencher, the switch turns ON allowing fluorescence emission. This property has been extensively used for a wide variety of applications including real-time PCR reactions, study of protein-DNA interactions, and identification of conformational changes in RNA structures. Here, we describe a protocol based on the MB technology to measure the RNA unfolding capacities of the CspA RNA chaperone from Staphylococcus aureus. This method, with slight variations, may also be applied for testing the activity of other RNA chaperones, RNA helicases, or ribonucleases.

This is part 3.2 of the "Fluorescent Molecular Beacons Mimicking RNA Secondary Structures to Study RNA Chaperone Activity" collection of protocols. Collection Abstract: Molecular beacons (MBs) are oligonucleotide probes with a hairpin-like structure that are typically labelled at the 5' and 3' ends with a fluorophore and a quencher dye, respectively. The conformation of the MB acts as a switch for fluorescence emission. When the fluorophore is in close proximity to the quencher, fluorescence emission cannot be detected, meaning that the switch is in an OFF state. However, if the MB structure is modified, separating the fluorophore from the quencher, the switch turns ON allowing fluorescence emission. This property has been extensively used for a wide variety of applications including real-time PCR reactions, study of protein-DNA interactions, and identification of conformational changes in RNA structures. Here, we describe a protocol based on the MB technology to measure the RNA unfolding capacities of the CspA RNA chaperone from Staphylococcus aureus. This method, with slight variations, may also be applied for testing the activity of other RNA chaperones, RNA helicases, or ribonucleases.

Background & aims:polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Here, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting. Methods:levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry. Results:most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered the proteasome hyperactivity in cystic cholangiocytes, leading to the activation the unfolded protein response (UPR) and stress-related apoptosis. Conclusions:cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy. Keywords:Hepatic cystogenesis; S-adenosylmethionine (SAMe); SUMOylation; post-translational modifications; therapy.

A Brain-Computer Interface (BCI) System captures the neural activity of the Central Nervous System (CNS) and delivers an output which replaces the natural output of the CNS [1]. That helps who have lost their ability to speak, spelling words in a monitor or helps to recover the movements for people who have suffered some amputation of their limbs or a motor paralysis of their body. The main objective of the project is to control an upper limb using a Myohand twin Ottobock prosthesis ref 8E38 = 7 [2] using EEG silent speech signals. On this research, we will focus on a novel methodology that attempts to classify imagined speech based on vowels, which uses as the primary technique for artifact removal the Adaptive-Projection Intrinsically Transformed Multivariate Empirical Mode Decomposition (APIT-MEMD) [3], and for the feature generation stage the Singular Value Decomposition (SVD) [4]. For the classification stage, two classifiers where tested, the Extremely Randomized Trees classifier (ET) [5], and the Adaboost (ADB) [6]. The overall accuracy achieved per subject and per vowels’ pairwise classification, was 91.54% using ET. For a multiclass classifier, the overall accuracy over the eighteen subjects of the database was 79.06%.

We analyze optimal monetary policy when asset prices influence aggregate demand with a lag. In this environment, when there is a current or anticipated output gap, the central bank optimally overshoots asset prices (i.e., significantly reduces discount rates to increase asset prices). Asset price overshooting leads to a temporary disconnect between the performance of financial markets and the real economy, but it also accelerates the recovery. A more intense overshooting policy weakens the relationship between inflation and the output gap (i.e., it flattens the Phillips curve). We quantify the policy-induced overshooting through risk-free rates in the Covid-19 recession and find that actual overshooting significantly exceeded the overshooting implied by a Taylor rule benchmark. Our calibrated model suggests this additional overshooting substantially accelerated the recovery. Finally, we show that policy-induced overshooting, along with monetary policy constraints, can shed light on the cyclical variation in the response of asset prices to macroeconomic news.

The continuous sea level rising affects all those built heritage elements located near the seacoasts and oceans all over the world. Some of the most affected sites are the found Roman coastal fish tanks which were scattered along the coast of the Mediterranean Sea and had the purpose of breeding and keeping the fish in captivity. This study will analyze the current consequences of this phenomenon in these sites, mainly on those located in Spain. It will also analyze the effects in structures because of their submergence, the effects of erosion, the different reasons for coast line variations, the risks of sea storms and floods. Estimations are also made and they are based on the forecasts of sea-level rises in order of what it is being published in scientific fields. Finally, the pernicious effects that these types of infrastructures and their associated elements will suffer in a short or medium term will be studied.

RESUMEN Se reusaron efluentes textiles provenientes de teñidos negros reactivos, decolorados por el método de oxidación avanzada Fenton en procesos de blanqueo de fibra celulósica por agotamiento. Se recolectaron efluentes textiles provenientes de dos teñidos reactivos negros: Corafix Black SD y Corazol Black B 133 %, simulados y reales, para ser decolorados con el tratamiento Fenton. Se monitoreó la decoloración usando espectrofotometría UV-visible, se determinaron las proporciones óptimas de reactivo Fenton (sal de Fe (II) (g)/H2O2 (mL)): 0,0156 g/mL y 0,0251 g/mL con un tiempo de reacción de 90 minutos y pH óptimos de tratamiento de 3,70 y 3,88 para los efluentes textiles provenientes de teñido con colorantes Corafix Black SD y Corazol Black B 133%, respectivamente. Los efluentes tratados se caracterizaron, adecuaron y usaron en el blanqueo de tejidos celulósicos. Se obtuvo textiles con un grado de blancura de 74,73 °Be y 73,41 °Be, similares al sustrato blanqueado con agua blanda (76,61°Berger). Se compararon: las curvas de reflectancia con el espectrofotómetro Datacolor SF550, hidrofilidad y capilaridad según métodos normalizados. Finalmente se concluyó que el tratamiento Fenton es viable para este tipo de efluentes negros reactivos, pues se obtuvieron sustratos blanqueados con propiedades similares al blanqueo con agua blanda. ABSTRACT Textile effluents from reactive black dyes, decolorized using the advanced Fenton oxidation method, were reused in cellulosic fiber exhaustion bleaching processes. Textile black reactive effluents were collected, provided from two recipes of reactive blacks; Corafix Black SD (Black SD) and Corazol Black B 133 % (Black 5), simulated and real, due to being decolored by the Fenton treatment. The discoloration was monitored using UV- visible spectrophotometry, the optimal proportions of Fenton reagent (Fe (II) salt (g) / H2O2 (mL)) were determined: 0,0156 g / mL and 0,0251 g / mL with 90 minutes of reaction time, and optimal treatment pH of 3,70 and 3,88 for textile effluents from dyeing with Corafix Black SD and Corazol Black B 133 % dyestuffs respectively. The discolored effluents were characterized, adequated, and used in bleaching of cellulosic fabrics. Textiles with a degree of whiteness of 74,73 °Be and 73,41 °Be were obtained, similar to the substrate bleached with soft water (76,61 °Be). The reflectance curves were compared with the Datacolor SF550 spectrophotometer, hydrophilicity and capillarity according to standardized methods. Finally, it was concluded that the Fenton treatment is viable for this type of reactive black effluent since bleached substrates with properties similar to bleaching with soft water were obtained.

Characteristics of sheep milk are of great interest for the dairy industry, as almost the totality of production is intended for cheesemaking. However, the existing relationships between these variables are complex. This study assessed composition, hygienic quality, coagulation properties, and curd yield of 1,200 individual Manchega sheep milk samples. The aim was to compare the effect of composition and hygienic quality on coagulation and curdling, and to evaluate the relationship between curd yields and the coagulation process and the effect of other features by using path analysis methodologies. Outcomes proved path analysis to be a useful and effective tool to assess these relationships through direct and indirect paths within the same model. Results showed that the factors that had a direct influence on milk coagulation were lactose concentration, casein content, and initial pH of milk. Contrastingly, somatic cells did not seem to have any effect (direct or indirect) on the coagulation process. Factors that directly affected curd yield were fat content, lactose concentration, casein content, and curd moisture. However, technological parameters showed little effect over curd yield.

Central banks (the Fed) and markets (the market) often disagree about the path of interest rates. We develop a model where these different views stem from disagreements between the Fed and the market about future aggregate demand. We then study the implications of these disagreements for monetary policy, the term structure of interest rates, and economic activity. In our model, agents learn from the data but not from each other—they are opinionated. In this context, the market perceives monetary policy “mistakes” and the Fed partially accommodates the market’s view to mitigate the impact of perceived “mistakes” on output and inflation. The Fed plans to implement its own view gradually, as it expects the market to receive more information and move closer to the Fed’s belief. Disagreements about future demand translate into disagreements about future interest rates. Disagreements also provide a microfoundation for monetary policy shocks: after a surprise policy announcement, the market (partially) learns the Fed’s belief and the extent of future “mistaken” interest rate changes. We categorize these shocks into three groups: Fed belief shocks, market reaction shocks, and tantrum shocks. Tantrum shocks are the most damaging, as they arise when the Fed fails to forecast the forward rates’ reaction. These shocks motivate gradualism and communication policies that reveal the Fed’s belief, not to persuade the market (which is opinionated) but to prevent the market from misinterpreting the Fed’s belief. Finally, we also find that disagreements affect inflation and create a policy trade-off between output and inflation stabilization akin to “cost-push” shocks. Institutional subscribers to the NBER working paper series, and residents of developing countries may download this paper without additional charge at www.nber.org.