Repeated human leukocyte antigens eplets, importance of typing the partner.

INTRODUCTION: Antibody-mediated rejection (AMR) is the most common cause of immune-mediated allograft failure after kidney transplant and impacts allograft survival. Previous sensitization is a major risk factor for development of donor specific antibodies (DSA). AMR can have a wide range of clinical features such as impaired kidney function, proteinuria/hypertension or can be subclinical. HLA molecules have specific regions of antigens binding antibodies called epitopes and eplets are considered essential components responsible for immune recognition. We present a patient with subclinical AMR 1 week post transplantation. CASE REPORT: A 48-year-old, caucasian woman with end-stage kidney disease (ESKD) secondary to autosomal dominant polycystic kidney disease (ADPKD) on peritoneal dialysis was registered in deceased donor waitlist. She was a hypersensitized patient from 3 prior pregnancies with a calculated panel reactive antibody of 93,48%. She was transplanted through kidney paired exchange donation with no evidence of DSA pre transplantation. Surgery and post-op were unremarkable with excellent and immediate graft function. Per protocol DSA levels on the 5th day was DR1 of 3300 MFI, with an increase in MFI by day 13 with 7820 MFI and a new B41 1979MFI. Allograft kidney biopsy findings were diagnostic of AMR and she was treated with immunoglobulin and plasmapheresis. As early onset AMR post transplantation was observed an anamnestic response was hypothesized from a previous exposure to allo-HLA. We decided to type her husband, her son's father, which was presented with DSA. Mismatch eplet analysis revealed a shared 41 T and 67LQ eplets between the donor and husband, responsible for the reactivity and new HLA class I B41 and HLA class II DR1 DSA, respectively. DISCUSSION: Shared eplets between the patient husband and donor was responsible for the alloimmune response and early development of DSAs. This case highlights the importance of early monitoring DSA levels in highly sensitized patients after transplant in order to promptly address and lower inflammatory damage. Mismatch eplet analysis can provide a thorough and precise evaluation of immune compatibility providing a useful technique to immune risk stratification, donor selection and post-transplant immunosuppressive therapy and monitoring.

The bitter taste receptor (TAS2R) agonist denatonium promotes a strong relaxation of rat corpus cavernosum.

Bitter taste receptors (TAS2R) are found in numerous extra-oral tissues, including smooth muscle (SM) cells in both vascular and visceral tissues. Upon activation, TAS2R stimulate the relaxation of the SM. Nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway is involved in penile erection, and type 5 phosphodiesterase (PDE5) inhibitors, a cGMP-specific hydrolase are used as first-line treatments for erectile dysfunction (ED). Nevertheless, PDE5 inhibitors are ineffective in a considerable number of patients, prompting research into alternative pharmacological targets for ED. Since TAS2R agonists regulate SM contractility, this study investigates the role of TAS2Rs in rat corpus cavernosum (CC). We performed immunohistochemistry to detect TAS2R10, isometric force recordings for TAS2R agonists denatonium and chloroquine, the slow-release H2S donor GYY 4137, the NO donor SNAP, the ß-adrenoceptor agonist isoproterenol and electrical field stimulation (EFS), as well as measurement of endogenous hydrogen sulfide (H2S) production. The immunofluorescence staining indicated that TAS2R10 was broadly expressed in the CC SM and to some extent in the nerve fibers. Denatonium, chloroquine, SNAP, and isoproterenol cause potent dose-dependent SM relaxations. H2S production was decreased by NO and H2S synthase inhibitors, while it was enhanced by denatonium. In addition, denatonium increased the relaxations induced by GYY 4137 and SNAP but failed to modify EFS- and isoproterenol-induced responses. These results suggest neuronal and SM TAS2R10 expression in the rat CC, where denatonium induces a strong SM relaxation per se and promotes the H2S- and NO-mediated inhibitory gaseous neurotransmission. Thus, TAS2R10 might represent a valuable therapeutic target in ED.

Multi-objective evolutionary optimization for dimensionality reduction of texts represented by synsets.

Despite new developments in machine learning classification techniques, improving the accuracy of spam filtering is a difficult task due to linguistic phenomena that limit its effectiveness. In particular, we highlight polysemy, synonymy, the usage of hypernyms/hyponyms, and the presence of irrelevant/confusing words. These problems should be solved at the pre-processing stage to avoid using inconsistent information in the building of classification models. Previous studies have suggested that the use of synset-based representation strategies could be successfully used to solve synonymy and polysemy problems. Complementarily, it is possible to take advantage of hyponymy/hypernymy-based to implement dimensionality reduction strategies. These strategies could unify textual terms to model the intentions of the document without losing any information (e.g., bringing together the synsets "viagra", "ciallis", "levitra" and other representing similar drugs by using "virility drug" which is a hyponym for all of them). These feature reduction schemes are known as lossless strategies as the information is not removed but only generalised. However, in some types of text classification problems (such as spam filtering) it may not be worthwhile to keep all the information and let dimensionality reduction algorithms discard information that may be irrelevant or confusing. In this work, we are introducing the feature reduction as a multi-objective optimisation problem to be solved using a Multi-Objective Evolutionary Algorithm (MOEA). Our algorithm allows, with minor modifications, to implement lossless (using only semantic-based synset grouping), low-loss (discarding irrelevant information and using semantic-based synset grouping) or lossy (discarding only irrelevant information) strategies. The contribution of this study is two-fold: (i) to introduce different dimensionality reduction methods (lossless, low-loss and lossy) as an optimization problem that can be solved using MOEA and (ii) to provide an experimental comparison of lossless and low-loss schemes for text representation. The results obtained support the usefulness of the low-loss method to improve the efficiency of classifiers.

Cardiac System during the Aging Process.

The aging process is accompanied by a continuous decline of the cardiac system, disrupting the homeostatic regulation of cells, organs, and systems. Aging increases the prevalence of cardiovascular diseases, thus heart failure and mortality. Understanding the cardiac aging process is of pivotal importance once it allows us to design strategies to prevent age-related cardiac events and increasing the quality of live in the elderly. In this review we provide an overview of the cardiac aging process focus on the following topics: cardiac structural and functional modifications; cellular mechanisms of cardiac dysfunction in the aging; genetics and epigenetics in the development of cardiac diseases; and aging heart and response to the exercise.

High-Intensity Interval Training Minimizes the Deleterious Effects of Arterial Hypertension on the Urinary Bladder of Spontaneously Hypertensive Rats.

Arterial hypertension promotes urological complications by modifying the functional capacity of the urinary bladder. On the other hand, physical exercise has been suggested as a nonpharmacological tool to improve blood pressure regulation. High-intensity interval training (HIIT) can effectively increase peak oxygen consumption, body composition, physical fitness, and health-related characteristics of adults; however, its action on the urinary bladder is little discussed. In the present study, we verified the effect of HIIT on the modulation of the redox state, morphology, and inflammatory and apoptotic processes of the urinary bladder of hypertensive rats. Spontaneously hypertensive rats (SHR) were divided into two groups: SHR sedentary and SHR submitted to HIIT. Arterial hypertension promoted an increase in the plasma redox state, modified the volume of the urinary bladder, and increased collagen deposition in detrusor muscle. It was also possible to identify, in the sedentary SHR group, an increase in inflammatory markers such as IL-6 and TNF-α in the urinary bladder, as well as a reduction in BAX expression. However, in the HIIT group, reduced blood pressure levels were observed, together with an improvement in morphology, such as a decrease in collagen deposition. HIIT also regulated the proinflammatory response, promoting increases in IL-10 and BAX expressions and in the number of plasma antioxidant enzymes. The present work highlights the intracellular pathways involved with the oxidative and inflammatory capacity of the urinary bladder and the potential effect of HIIT on the regulation of the urothelium and detrusor muscle of hypertensive rats.

Terson Syndrome - Clinical Presentation, Management, and Visual Outcomes in a Tertiary Centre.

Purpose: The purpose of this study was to characterize the clinical presentation, management strategy and visual outcomes of patients diagnosed with Terson syndrome and followed in a tertiary centre in Portugal. Patients and Methods: A single-centre retrospective study was performed, based on the survey review of the medical records of every consecutive patient diagnosed with Terson syndrome and followed from January 2018 to August 2021. The change in best-corrected visual acuity (BCVA) from baseline to the final evaluation was the primary outcome. Results: Fifteen eyes from 8 patients (50% female) were included. The mean age at diagnosis was 55±7 years. The neurological event was traumatic brain injury in 37.5% (n=3) and subarachnoid haemorrhage in 62.5% of the patients (n=5). Bilateral intraocular haemorrhage occurred in 875% (n=7) of the patients. Vitreous and preretinal haemorrhages occurred each in 66.7% (n=10), intraretinal in 30% (n=3) and subretinal in 13.3% (n=2) of the eyes. In 40% of the eyes (n=6), spontaneous resolution of intraocular haemorrhage occurred, while PPV was performed in the remaining 60% (n=9). Ocular haemorrhage detection occurred 58.47 ± 40.94 days after the neurological event (range 11 to 121 days). Baseline BCVA was 1.11 ± 1.01 logMAR and improved to 0.32 ± 0.69 logMAR in the follow-up period (p=0.004). A positive correlation was found between initial and final BCVA (Spearman's rho = 0.643, p=0.01). Baseline BCVA of eyes undergoing PPV was lower than of those conservatively managed (1.84±0.72 vs 0.20±0.28 logMAR, p<0.001). However, there were no statistically significant differences in final BCVA after surgery or observation (0.56 ± 0.90 vs 0.04 ± 0.04 logMAR, p=0.149). Longer periods between the neurological and the ophthalmological diagnosis were correlated with worse final BCVA (Spearman's rho = 0.688, p=0.005). Conclusion: Terson syndrome is a potential cause of irreversible visual loss. Diagnosis delay may affect visual prognosis. PPV is indicated when intraocular haemorrhage is dense and does not resolve spontaneously or when visual acuity at presentation is low, allowing for good visual outcomes with minimal complications.

Intravitreal Fluocinolone Acetonide Implant (FAc, 0.19 mg, ILUVIEN®) in the Treatment of Patients with Recurrent Cystoid Macular Edema After Pars Plana Vitrectomy.

INTRODUCTION: Postoperative cystoid macular edema (PCME) is a complication of several ocular procedures, including pars plana vitrectomy (PPV), due to the activation of the inflammatory cascade. The purpose of this case series is to evaluate the effectiveness and safety of fluocinolone acetonide intravitreal implant (FAc, 0.2 µg/day; ILUVIEN®) in the treatment of refractory PCME after successful PPV. METHODS: This retrospective observational case series includes consecutive eyes of patients with recurrent PCME after PPV and treated with a single FAc implant at Centro Hospitalar Universitário de São João, Porto, Portugal. Previous treatments, best-corrected visual acuity (BCVA, ETDRS letters), central macular thickness (CMT, µm), intraocular pressure (IOP, mmHg), and IOP-lowering medication needed were recorded at baseline and during follow-up. Total macular edema resolution was defined as CMT less than 300 µm or a reduction of greater than 20%, and partial macular edema resolution was defined as a reduction of greater than 10%. RESULTS: Nine eyes from nine patients were included. Before FAc implant, all eyes received intravitreal short-action corticosteroids (triamcinolone and dexamethasone implant), with a good response but relapse 1-5 months later. At baseline, BCVA was 55.0 ± 10.6 letters, CMT was 514.9 ± 165.6 µm, and IOP was 15.4 ± 2.4 mmHg with four eyes under IOP-lowering medication. After FAc implant, all eyes achieved edema resolution (eight total and one partial) with a peak gain of 17.2 letters and a maximum decrease of 208.2 µm in CMT. During follow-up (44.0 ± 14.8 months), 66.7% of the eyes kept their macula dry and three showed recurrence after 11, 14, and 28 months, respectively. The maximum IOP registered was 17.0 ± 6.0 mmHg. IOP-lowering regimen was increased in one eye and two additional eyes started hypotensive drops. CONCLUSION: FAc implant can be considered a therapeutic alternative in PCME refractory to other therapies in vitrectomized eyes, reducing the need for repeated treatments.

Starting gastrointestinal endoscopy in a lower middle-income country in Africa: Training, creating an endoscopy facility and developing telemedicine.

Background and study aims The prevalence of digestive diseases seems to be high in African countries. Nonetheless, the human and material resources are scarce. The aim of the Portuguese volunteering project described in this report was to develop the specialty of digestive endoscopy in Sao Tome and Principe, a lower-middle-income country in Africa. Methods Beginning by assessing the local needs and available resources and managing immediate issues related to this field, we aimed to provide the tools necessary to improve gastroenterological and endoscopic care in the country. The first step included training of the local teams, through the development and accomplishment of an adapted curriculum for a 3-year medical gastroenterological fellowship and a short-term nursing fellowship, both in Portugal, and the organization of regular gastroenterological and endoscopic theoretical and practical sessions in Sao Tome and Principe. Second, the endoscopy facilities of the unit were significantly optimized. Third, a web platform was designed to provide telemedicine incorporating real-time endoscopic imaging available remotely. Results Through these sequential steps achieved in collaboration with Portuguese and local teams, this 5-year project provided the basis for gastroenterology care in this country. Conclusions At the present time, Sao Tome and Principe has an autonomous, efficient and skilled team and unit to provide care for patients with gastrointestinal diseases who need endoscopic procedures.

Coronal brain atlas in stereotaxic coordinates of the African spiny mouse, Acomys cahirinus.

The African spiny mouse (Acomys cahirinus) is an emerging model of mammalian epimorphic regeneration that has aroused the interest of the scientific community in the last decade. To date, studies on brain repair have been hindered by the lack of knowledge on the neuroanatomy of this species. Here, we present a coronal brain atlas in stereotaxic coordinates, which allows for three-dimensional identification and localization of the brain structures of this species. The brain of 12-week-old spiny mice was mapped in stereotaxic coordinates using cresyl violet-stained brain sections obtained from coronal cryosectioning of the brain after transcardial perfusion with fixative. The atlas is presented in 42 plates representing sections spaced 240 µm apart. Stereotaxic coordinates were validated using both a model of Parkinsonian lesion of the striatum with 6-hydroxydopamine and labeling of the corticospinal tract in the spiny mouse spinal cord using AAV1/2-GFP intracortical injections. This work presents a new tool in A. cahirinus neurobiology and opens new avenues of research for the investigation of the regenerative ability of A. cahirinus in models of brain disorders.

Experiences and mediating factors in nurses' responses to electronic device alarms: A phenomenological study.

AIM: This study aims to explore the experiences and mediating factors of nurses' responses to electronic device alarms in critical care units (CCUs). BACKGROUND: Alarm fatigue occasionally has adverse consequences for patient safety. METHODS: This qualitative study was designed and analysed following Giorgi's descriptive phenomenological approach. Seventeen nurses were theoretically sampled, reaching information saturation. Semistructured interviews were used to collect the data. RESULTS: Three central themes explained nurses' experiences: general perceptions about alarms (basic equipment of the CCU), strategies to reduce false alarms (training in the configuration of monitors, customization of the alarms to fit he patient's condition. teamwork and taking advantage of the development of technology) and key elements of the response to alarms (information about patient's condition, nurses' clinical experience, type of CCU, 'cry-wolf' phenomenon and nurse/patient ratio). CONCLUSIONS: To reduce false alarms, nurses need further postgraduate training, training on monitors and customizing alarms to fit the patient's health status. The complex process of deciding to respond to an alarm includes environmental, professional variables and patient status. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers should ensure that nurses have sufficient experience and training in the CCU, improve the nurse/patient ratio, promote teamwork and ensure that the devices are the latest generation.

Avaliação de resíduos de agrotóxicos em amostras de farinha de trigo por espectrometria de massas / Evaluation of pesticide residues in wheat flour by mass spectrometry

Os cereais são uma importante fonte alimentícia e econômica, dentre eles se destaca o trigo e sua farinha. Durante o cultivo, visando o controle de pragas, frequentemente são utilizados os agrotóxicos, porém seu uso abusivo pode acarretar danos à saúde humana e ao meio ambiente. O trabalho teve como objetivo avaliar a presença de resíduos de agrotóxicos em amostras de farinha de trigo comercializadas no estado de São Paulo, utilizando o método QuEChERS (Rápido, Fácil, Barato, Efetivo, Robusto e Seguro) modificado, seguido de análise por CG-EM/EM e CLUE-EMAR para identificação e quantificação. No total, 124 ingredientes ativos (i.a.) estavam dentro dos critérios de aceitação para linearidade, limites de detecção e quantificação, exatidão e precisão (intervalo de confiança de 95%; k = 2). Os resultados de 25 amostras indicaram a presença de bifentrina, fenitrotiona, clorpirifós, deltametrina, lambda-cialotrina e pirimifós-metílico em farinha de trigo comum e os quatro últimos i.a. também foram detectados em farinha de trigo orgânica. O pirimifósmetílico foi detectado em 92% das amostras. Os i.a. encontrados nas amostras estavam abaixo do Limite Máximo de Resíduos (LMR) estabelecidos pela Agência Nacional de Vigilância Sanitária (Anvisa) para farinha de trigo e as amostras foram consideradas próprias para o consumo (AU).

Cereals are an important economic factor and food source, which wheat and its flour stand out. Pesticides are often employed to control harmful organisms, but their abusive use can cause damage to human health and the environment. This study aimed to evaluate the presence of pesticide residues in wheat flour samples commercialized in the state of São Paulo ­ Brazil, using the modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method, followed by GC-MS/MS and UHPLC-HRMS analysis for identification and quantification. Thus, 124 active ingredients (a.i.) were within acceptable criteria for linearity, limits of detection and quantification, accuracy (trueness), and precision (95% confidence level; k = 2). The results for 25 wheat flour samples showed the presence of bifenthrin, fenitrothion, chlorpyrifos, deltamethrin, lambda-cyhalothrin, and pirimiphos-methyl, and the last four a.i. were also detected in organic wheat flour. Pirimiphos-methyl was detected in 92% of all samples. All compounds were found below the Maximum Residue Levels (MRL) established by Brazilian Health Regulatory Agency (Anvisa) for wheat flour and the samples were considered suitable for consumption (AU).

In vitro inhibition of phosphodiesterase type 4 enhances rat corpus cavernosum nerve-mediated relaxation induced by gasotransmitters.

AIMS: Nitric oxide (NO) and hydrogen sulfide (H2S) are involved in nerve-mediated corpus cavernosum (CC) relaxation. Expression of phosphodiesterase type 5 (PDE5) and type 4 (PDE4), cyclic guanosine monophosphate (cGMP)- and cyclic adenosine monophosphate (cAMP)-specific, respectively, has been described and PDE5- and PDE4-inhibitors induce cavernous smooth muscle relaxation. Whereas the NO/cGMP signaling pathway is well established in penile erection, the cAMP-mediated mechanism is not fully elucidated. The aim of this study is to investigate the localization and the functional significance of PDE4 in rat CC tone regulation. MAIN METHODS: We performed immunohistochemistry for the detection of the PDE4A isoenzyme. Isometric tension recordings for roflumilast and tadalafil, PDE4 and PDE5 inhibitors, respectively, electrical field stimulation (EFS) and ß-adrenoceptor agonist isoproterenol and endogenous H2S production measurement. KEY FINDINGS: A marked PDE4A expression was detected mainly localized in the nerve cells of the cavernous smooth muscle. Furthermore, roflumilast and tadalafil exhibited strong corpus cavernous relaxations. Endogenous H2S production was decreased by NO and H2S synthase inhibitors and increased by roflumilast. Isoproterenol- and EFS-induced relaxations were increased by roflumilast. SIGNIFICANCE: These results indicate that PDE4A is mainly expressed within the nerves cells of the rat CC, where roflumilast induces a potent corpus cavernous relaxation per se and potentiates the response induced by ß-adrenoceptor activation. The fact that roflumilast enhances H2S production, as well as EFS-elicited responses suggests that PDE4 inhibitors modulate, in a positive feedback fashion, nerve-mediated relaxation induced by gasotransmitters, thus indicating a key role for neuronal PDE4 in penile erection.

Rewired glycosylation activity promotes scarless regeneration and functional recovery in spiny mice after complete spinal cord transection.

Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury (SCI). Here, we show that the spiny mouse (Acomys) is an exception to other mammals, being capable of spontaneous and fast restoration of function after severe SCI, re-establishing hind limb coordination. Remarkably, Acomys assembles a scarless pro-regenerative tissue at the injury site, providing a unique structural continuity of the initial spinal cord geometry. The Acomys SCI site shows robust axon regeneration of multiple tracts, synapse formation, and electrophysiological signal propagation. Transcriptomic analysis of the spinal cord following transcriptome reconstruction revealed that Acomys rewires glycosylation biosynthetic pathways, culminating in a specific pro-regenerative proteoglycan signature at SCI site. Our work uncovers that a glycosylation switch is critical for axon regeneration after SCI and identifies ß3gnt7, a crucial enzyme of keratan sulfate biosynthesis, as an enhancer of axon growth.

Scleral Fixation of Akreos AO60 Intraocular Lens Using Gore-Tex Suture: An Eye on Visual Outcomes and Postoperative Complications.

PURPOSE: "In-the-bag" placement of an IOL is the Holy Grail for any cataract surgeon. However, in the absence of capsular integrity, alternative surgical options to place the IOL must be sought. We aim to report the clinical outcomes and safety profile of scleral-fixated Akreos AO60 intraocular lens implantation using Gore-Tex suture, combined with pars plana vitrectomy. METHODS: This is a single-center, retrospective case series descriptive study. Electronic clinical records of all patients subjected to scleral fixation of a Bausch and Lomb Akreos AO60 IOL combined with pars plana vitrectomy, between April 1, 2017, and August 1, 2021, were reviewed. Data concerning age, sex, laterality, past ophthalmological history, pre- and postoperative best-available visual acuity, surgical indication, and intra- and postoperative complications were collected. Measured outcomes were the differences in best-available visual acuity and frequency of postoperative complications. RESULTS: A total of 37 eyes (20 right eyes and 17 left eyes) from 36 patients (16 females and 20 males) were included in the statistical analysis. The mean age at time of surgery was 72.0 ± 12.4 years. The mean follow-up period was 548.9 days (range 39-1564 days). Globally, the mean best-available logMAR visual acuity improved from 1.61 preoperatively (0.025 decimal equivalent) to 0.57 postoperatively (0.3 decimal equivalent), this difference being statistically significant (P < 0.001). Indications for surgery included aphakia due to complicated cataract surgery (24.3%; n = 9); subluxated IOL due to closed trauma (21.6%; n = 8); PEX-related subluxated IOL (16.2%; n = 6); non-traumatic, non-PEX-related subluxated IOL (18.9%; n = 7); subluxated crystalline lens due to closed trauma (8.1%; n = 3); aphakia due to open-globe injury (5.4%; n = 2); silicone-induced IOL opacification (2.7%; n = 1); and aphakia post-endophthalmitis (2.7%; n = 1). Postoperative complications included transient ocular hypertension (27.0%; n = 10), transient corneal edema (18.9%; n = 7), cystoid macular edema (18.9%, n = 7), self-limited hypotension (5.4%, n = 2), self-limited vitreous hemorrhage (2.7%, n = 1), central retinal vein occlusion (2.7%, n = 1), late retinal detachment (2.7%, n = 1), and Akreos IOL opacification (2.7%, n = 1). No suture-related complications were observed. CONCLUSION: There was a statistically significant improvement in visual acuity after scleral fixation of Akreos AO60 intraocular lens using Gore-Tex suture, with no suture-related problems recorded. This procedure seems to be a valuable alternative for posterior chamber IOL placement when secondary IOL implantation is required.

Adhesion G protein-coupled receptor Gpr126/Adgrg6 is essential for placental development.

Mutations in the G protein­coupled receptor GPR126/ADGRG6 cause human diseases, including defective peripheral nervous system (PNS) myelination. To study GPR126 function, we generated new genetic mice and zebrafish models. Murine Gpr126 is expressed in developing heart endocardium, and global Gpr126 inactivation is embryonically lethal, with mutants having thin-walled ventricles but unaffected heart patterning or maturation. Endocardial-specific Gpr126 deletion does not affect heart development or function, and transgenic endocardial GPR126 expression fails to rescue lethality in Gpr126-null mice. Zebrafish gpr126 mutants display unaffected heart development. Gpr126 is also expressed in placental trophoblast giant cells. Gpr126-null mice with a heterozygous placenta survive but exhibit GPR126-defective PNS phenotype. In contrast, Gpr126-null embryos with homozygous mutant placenta die but are rescued by placental GPR126 expression. Gpr126-deficient placentas display down-regulation of preeclampsia markers Mmp9, Cts7, and Cts8. We propose that the placenta-heart axis accounts for heart abnormalities secondary to placental defects in Gpr126 mutants.

Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators.

Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising strategy is to investigate the regulatory mechanisms involved in sepsis progression, but there are few studies regarding gene regulation in sepsis. This work aimed to reconstruct the sepsis regulatory network and identify transcription factors (TFs) driving transcriptional states, which we refer to here as master regulators. We used public gene expression datasets to infer the co-expression network associated with sepsis in a retrospective study. We identified a set of 15 TFs as potential master regulators of pediatric sepsis, which were divided into two main clusters. The first cluster corresponded to TFs with decreased activity in pediatric sepsis, and GATA3 and RORA, as well as other TFs previously implicated in the context of inflammatory response. The second cluster corresponded to TFs with increased activity in pediatric sepsis and was composed of TRIM25, RFX2, and MEF2A, genes not previously described as acting in a coordinated way in pediatric sepsis. Altogether, these results show how a subset of master regulators TF can drive pathological transcriptional states, with implications for sepsis biology and treatment.

Host Stress Signals Stimulate Pneumococcal Transition from Colonization to Dissemination into the Lungs.

Streptococcus pneumoniae is an asymptomatic colonizer of the nasopharynx, but it is also one of the most important bacterial pathogens of humans, causing a wide range of mild to life-threatening diseases. The basis of the pneumococcal transition from a commensal to a parasitic lifestyle is not fully understood. We hypothesize that exposure to host catecholamine stress hormones is important for this transition. In this study, we demonstrated that pneumococci preexposed to a hormone released during stress, norepinephrine (NE), have an increased capacity to translocate from the nasopharynx into the lungs compared to untreated pneumococci. Examination of NE-treated pneumococci revealed major alterations in metabolic profiles, cell associations, capsule synthesis, and cell size. By systemically mutating all 12 two-component and 1 orphan regulatory systems, we also identified a unique genetic regulatory circuit involved in pneumococcal recognition and responsiveness to human stress hormones. IMPORTANCE Microbes acquire unique lifestyles under different environmental conditions. Although this is a widespread occurrence, our knowledge of the importance of various host signals and their impact on microbial behavior is not clear despite the therapeutic value of this knowledge. We discovered that catecholamine stress hormones are the host signals that trigger the passage of Streptococcus pneumoniae from a commensal to a parasitic state. We identify that stress hormone treatment of this microbe leads to reductions in cell size and capsule synthesis and renders it more able to migrate from the nasopharynx into the lungs in a mouse model of infection. The microbe requires the TCS09 protein for the recognition and processing of stress hormone signals. Our work has particular clinical significance as catecholamines are abundant in upper respiratory fluids as well as being administered therapeutically to reduce inflammation in ventilated patients, which may explain why intubation in the critically ill is a recognized risk factor for the development of pneumococcal pneumonia.

Ancestry analysis indicates two different sets of essential genes in eukaryotic model species.

Essential genes are so-called because they are crucial for organism perpetuation. Those genes are usually related to essential functions to cellular metabolism or multicellular homeostasis. Deleterious alterations on essential genes produce a spectrum of phenotypes in multicellular organisms. The effects range from the impairment of the fertilization process, disruption of fetal development, to loss of reproductive capacity. Essential genes are described as more evolutionarily conserved than non-essential genes. However, there is no consensus about the relationship between gene essentiality and gene age. Here, we identified essential genes in five model eukaryotic species (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster, Caenorhabditis elegans, and Mus musculus) and estimate their evolutionary ancestry and their network properties. We observed that essential genes, on average, are older than other genes in all species investigated. The relationship of network properties and gene essentiality convey with previous findings, showing essential genes as important nodes in biological networks. As expected, we also observed that essential orthologs shared by the five species evaluated here are old. However, all the species evaluated here have a specific set of young essential genes not shared among them. Additionally, these two groups of essential genes are involved with distinct biological functions, suggesting two sets of essential genes: (i) a set of old essential genes common to all the evaluated species, regulating basic cellular functions, and (ii) a set of young essential genes exclusive to each species, which perform specific essential functions in each species.

Electrochemical Installation of CFH2 -, CF2 H-, CF3 -, and Perfluoroalkyl Groups into Small Organic Molecules.

Electrosynthesis can be considered a powerful and sustainable methodology for the synthesis of small organic molecules. Due to its intrinsic ability to generate highly reactive species under mild conditions by anodic oxidation or cathodic reduction, electrosynthesis is particularly interesting for otherwise challenging transformations. One such challenge is the installation of fluorinated alkyl groups, which has gained significant attention in medicinal chemistry and material science due to their unique physicochemical features. Unsurprisingly, several electrochemical fluoroalkylation methods have been established. In this review, we survey recent developments and established methods in the field of electrochemical mono-, di-, and trifluoromethylation, and perfluoroalkylation of small organic molecules.