Miracle-dz/UniFAR-FTUs huggingface dataset:
The effects of vasopressors with and without dobutamine on haemodynamics, metabolism and gut injury during endotoxic shock in rabbits. A controlled study

Background Vasopressors increase arterial pressure but they may have deleterious effects on mesenteric blood flow. We aimed to evaluate the response of gut biomarkers and superior mesenteric blood flow to different vasopressors with and without dobutamine. Methods Thirty New Zealand rabbits were included and randomly allocated to 5 groups: group A – sham group; group B – norepinephrine; group C – norepinephrine plus dobutamine; group D – vasopressin; and group E – vasopressin plus dobutamine. Mean arterial pressure (MAP) target was greater than 60 mmHg. Endotoxic shock was induced by intra-venous injection of lipopolysaccharide (LPS) in four of the five groups. Aortic blood flow (Qao), superior mesenteric artery flow (QSMA) and lactate were measured after LPS injection. Enterocyte damage was evaluated by measurements of serum citrulline and intestinal fatty acid-binding protein (I-FABP) after 4 h. Results The largest reduction in Qao occurred in group D (64 ± 17.3 to 38 ± 7.5 mL min–1;P = 0.04). QSMA also declined significantly in groups D and E and remained lower than in the other groups over 4 h (group D – baseline: 65 ± 31; 1 h: 37 ± 10; 2 h: 38 ± 10; 3 h: 46 ± 26; and 4 h: 48 ± 15 mL min–1; P < 0.005; group E – baseline: 73 ± 14; 1 h: 28 ± 4.0; 2 h: 37 ± 6.4; 3 h: 40 ± 11; and 4 h: 48 ± 11; P < 0.005; all in mL min–1). Serum citrulline was significantly lower in groups D (P = 0.014) and E (P = 0.019) in comparison to group A. The fluid administration regimen was similar in all groups. Conclusions Vasopressin seems to negatively impact gut enterocyte function during endotoxic shock despite the association of an inodilator and adequate fluid replacement.
Identification of AL proteins from 10 λ-AL amyloidosis patients by mass spectrometry extracted from abdominal fat and heart tissue

Abstract Background Systemic AL amyloidosis arises from the misfolding of patient-specific immunoglobulin light chains (LCs). Potential drivers of LC amyloid formation are mutational changes and post-translational modifications (PTMs). However, little information is available on the exact primary structure of the AL proteins and their precursor LCs. Objective We analyse the exact primary structure of AL proteins extracted from 10 λ AL amyloidosis patients and their corresponding precursor LCs. Materials and Methods By cDNA sequencing of the precursor LC genes in combination with mass spectrometry of the AL proteins, the exact primary structure and PTMs were determined. This information was used to analyse their biochemical properties. Results All AL proteins comprise the VL and a small part of the CL with a common C-terminal truncation region. While all AL proteins retain the conserved native disulphide bond of the VL, we found no evidence for presence of other common PTMs. The analysis of the biochemical properties revealed that the isoelectric point of the VL is significantly increased due to introduced mutations. Conclusion Our data imply that mutational changes influence the surface charge properties of the VL and that common proteolytic processes are involved in the generation of the cleavage sites of AL proteins.
Multi-residue methodology for quantification of antiparasitics in hen eggs by LC-MS/MS: development, validation and application to 348 samples from Brazil

Abstract Analytical methodology for quantification of 15 antiparasitic drugs and their respective metabolites in laying hen eggs was optimized and validated. The method uses acetonitrile as solvent extraction, sodium chloride for salting-out, low-temperature purification and analysis by LC-MS/MS. A total of 348 egg samples were collected in 11 states of Brazil and 50% of the total samples presented antiparasitic residues, which were albendazole, fipronil, fenbendazole, ivermectin, oxibendazole and mebendazole. A total of 12.4% of the samples were considered non-compliant, and residues quantified in these samples were albendazole, fipronil, and mebendazole. Albendazole was always identified as albendazole sulfone. Only one sample presented fipronil and fipronil sulfone; all others exclusively the sulfone metabolite. Fenbendazole was characterized by the presence of both metabolites: sulfone and sulfoxide. Maximum limits adopted are based on the Normative Instruction 51/2019 of the Brazilian Health Regulatory Agency (ANVISA), but albendazole, fipronil, oxibendazole, ivermectin, and mebendazole do not have their maximum residue level established. In addition, metabolites of albendazole, fipronil and fenbendazole in eggs are not considered in this Instruction.
Reply re: single-stage orbital decompression, strabismus and eyelid surgery in moderate to severe thyroid associated orbitopathy

To the Editor: We quite agree with the observations by Dr. Sonam and Sumita. Preoperative imaging is essential to assess radiological disease activity of dysthyroid patients, and all the patients of our series were submitted to orbital and maxillofacial CT scan prior to surgery. MRI was also performed in patients with active disease as it helps to differentiate active and inactive orbitopathy. All patients had a complete preand postoperative orthoptic evaluation (corneal light reflex test in primary position, examination of ductions and versions in all gaze positions, determination of the vergences, cover and coveruncover tests, binocular single vision field) – data available in our records. Forced duction test was performed intraoperatively. The increased contractile force of the medial rectus may be responsible for strabismus changes after orbital decompression surgery, and the management of residual diplopia in our patients has been thoroughly described. Patients with either residual esotropia or new onset esotropia following decompression had medial rectus recession performed at a second stage. Two patients were submitted to lateral rectus resection to obtain eye alignment. Press-on prisms can be used temporarily both in horizontal and vertical diplopia to restore single binocular vision in primary and/or reading position, and may be definitive in dysthyroid patients with residual small-angle strabismus. One patient with persisting diplopia in the group with one-stage treatment, and two patients with residual diplopia in primary position submitted to staged decompression and vertical strabismus surgery were prescribed Fresnel prisms. Our combined surgical approach with endoscopic decompression of the medial wall resolved dysthyroid optic neuropathy (DON) in seven patients who had previous intravenous steroid therapy but did not respond to medical treatment; in all cases with active disease, surgical orbital decompression resulted in stabilization and improvement in vision. Orbital decompression surgery usually reverses DON, but it may be followed by a progressive orbitopathy that reduces the amount of expanded orbital volume, with recurrent optic nerve compression. In our series, only one patient had recurrent DON 11 months following prior orbital decompression combined with muscle surgery, and was successfully treated with systemic glucocorticoids with no further relapse.
Trehalose‐6‐phosphate synthase influences polysaccharide synthesis and cell wall components in Ganoderma lucidum

Trehalose‐6‐phosphate synthase (TPS) is a key enzyme that participates in trehalose metabolism, which can synthesize trehalose in a two‐step pathway with trehalose phosphatase, but its role in fungi is rarely studied, especially in large basidiomycetes. In this study, the tps gene of Ganoderma lucidum was cloned and named as gltps. And gltps‐silenced strains were constructed by RNA interference. In this study, it is found that the extracellular polysaccharide content increased 1.6–2‐fold, but there was no significant change on intracellular polysaccharide content in gltps‐silenced strains compared with the wild‐type (WT) strain. Furthermore, the cell wall compositions of the gltps‐silenced strains were also altered, which showed that the chitin and β‐1,3‐glucan contents were significantly decreased. Compared with WT, the concentration of chitin decreased by 20%–50% and that of β‐1, 3‐glucan decreased by 15%–30%. The study found that the cells of gltps‐silenced strains were more sensitive to cell wall stress, which might be due to changes in the compounds and structure of the cell wall. These results showed that gltps had an important effect on carbohydrate metabolism of G. lucidum cells.
Isolation and Characterization of Engineered Nucleoside Deoxyribosyltransferase with Enhanced Activity Toward 2’-Fluoro-2’-Deoxynucleoside

Nucleoside deoxyribosyltransferase (NDT) is an enzyme that replaces the purine or pyrimidine base of 2′-deoxyribonucleoside. This enzyme is generally used in the nucleotide salvage pathway in vivo and synthesizes many nucleoside analogs in vitro for various biotechnological purposes. Since NDT is known to exhibit relatively low reactivity toward nucleoside analogs such as 2’-fluoro-2’-deoxynucleoside, it is necessary to develop an enhanced NDT mutant enzyme suitable for nucleoside analogs. In this study, molecular evolution strategy via error-prone PCR was performed with ndt gene derived from Lactobacillus leichmannii as a template to obtain an engineered NDT with higher substrate specificity to 2FDU (2′-fluoro-2′-deoxyuridine). A mutant library of 214 ndt genes with different sequences was obtained and performed for the conversion of 2FDU to 2FDA (2′-fluoro-2′-deoxyadenosine). The E. coli containing a mutant NDT, named NDTL59Q, showed 1.7-fold (at 40°C) and 4.4-fold (at 50°C) higher 2FDU-to-2FDA conversions compared to the NDTWT, respectively. Subsequently, both NDTWT and NDTL59Q enzymes were over-expressed and purified using a His-tag system in E. coli. Characterization and enzyme kinetics revealed that the NDTL59Q mutant enzyme containing a single point mutation of leucine to glutamine at the 59th position exhibited superior thermal stability with enhanced substrate specificity to 2FDU.
Transcriptomic landscape of GC‐2spd(ts) cell in response to the downregulation of piR‐1207/2107

Spermatogenesis is a highly orchestrated dynamic developmental process, during which piRNAs play an indispensable role. Our previous studies have confirmed that the levels of piR‐1207 and piR‐2107 were significantly decreased in spermatozoa and seminal plasma of patients with asthenozoospermia, compared with the fertile controls. In order to explore the function of piR‐1207 and piR‐2107 in human spermatogenesis and their potential regulatory downstream genes, we examined the transcriptomic landscape in mouse spermatocyte cell line GC‐2spd(ts) transfected with anti‐piR‐1207 and anti‐piR‐2107 by RNA sequencing. The result showed that 86 and 75 differential expression genes (DEGs) in anti‐piR‐1207 and anti‐piR‐2107 group, respectively. Among the DEGs, three genes including Pbp2, Pde3a and Cage1 were identified as potential key genes playing important roles in mediating sperm motility and morphology in anti‐piR‐1207 or anti‐piR‐2107 transfected transcriptomic response. Next, the expression levels of Pbp2, Pde3a and Cage1 were confirmed by qRT‐PCR. These results showed that Pbp2, Pde3a and Cage1 may serve as the potential regulatory genes of piR‐1207 or piR‐2107. In summary, piR‐1207 and piR‐2107 might have an implication in modulating the process of spermatogenesis through regulating the expression of potential genes.
Lanthionine Ketimine Ethyl Ester Accelerates Remyelination in a Mouse Model of Multiple Sclerosis

Although over 20 disease modifying therapies are approved to treat Multiple Sclerosis (MS), these do not increase remyelination of demyelinated axons or mitigate axon damage. Previous studies showed that lanthionine ketenamine ethyl ester (LKE) reduces clinical signs in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and increased maturation of oligodendrocyte (OL) progenitor cells (OPCs) in vitro. In the current study, we used the cuprizone (CPZ) demyelination model of MS to test if LKE could increase remyelination. The corpus callosum (CC) and somatosensory cortex was examined by immunohistochemistry (IHC), electron microscopy and for mRNA expression changes in mice provided 5 weeks of CPZ diet followed by 2 weeks of normal diet in the presence of LKE or vehicle. A significant increase in the number of myelinated axons, and increased myelin thickness was observed in the CC of LKE-treated groups compared to vehicle-treated groups. LKE also increased myelin basic protein and proteolipid protein expression in the CC and cortex, and increased the number of mature OLs in the cortex. In contrast, LKE did not increase the percentage of proliferating OPCs suggesting effects on OPC survival and differentiation but not proliferation. The effects of LKE on OL maturation and remyelination were supported by similar changes in their relative mRNA levels. Interestingly, LKE did not have significant effects on GFAP or Iba1 immunostaining or mRNA levels. These findings suggest that remyelinating actions of LKE can potentially be formulated to induce remyelination in neurological diseases associated with demyelination including MS.
Improved anti‐solid tumor response by humanized anti‐podoplanin chimeric antigen receptor transduced human cytotoxic T cells in an animal model

Recently, research has been conducted with chimeric antigen receptor (CAR)‐T cells to improve efficacy against solid tumors. Humanized CAR improved the long‐term survival of CAR‐T cells in patients' peripheral blood, resulting in increased therapeutic efficacy. Therefore, the humanization of the CAR‐gene sequence is considered an effective method. Podoplanin (PDPN) is a glycosylated transmembrane protein that is highly expressed in solid tumors and is associated with poor prognosis in patients with cancer. Therefore, PDPN is considered a biomarker and good target for cancer treatment with CAR‐T cells. Previously, an anti‐PDPN CAR was generated from a conventional nonhumanized antibody—NZ‐1, the only anti‐PDPN antibody for which a CAR was produced. In this study, we investigated other anti‐PDPN CARs from the antibody NZ‐27, or humanized NZ‐1, to enhance the therapeutic potential of CAR‐T cells. The CAR signal intensity was enhanced by the efficient expression of CAR proteins on the T‐cell surface of NZ‐27 CAR‐T cells, which show tumor‐specific cytotoxicity, proinflammatory cytokine production, and anti‐tumor activity against PDPN‐expressing tumor xenografts in mice that were significantly better than those in nonhumanized NZ‐1 CAR‐T cells.
Optimised adaptive procedures and analysis methods for conducting speech-in-noise tests

Abstract Objective Speech-in-noise testing is a valuable part of audiological test batteries. Test standardisation using precise methods is desirable for ease of administration. This study investigated the accuracy and reliability of different Bayesian and non-Bayesian adaptive procedures and analysis methods for conducting speech-in-noise testing. Design Matrix sentence tests using different numbers of sentences (10, 20, 30 and 50) and target intelligibilities (50 and 75%) were simulated for modelled listeners with various characteristics. The accuracy and reliability of seven different measurement procedures and three different data analysis methods were assessed. Results The estimation of 50% intelligibility was accurate and showed excellent reliability across the majority of methods tested, even with relatively few stimuli. Estimating 75% intelligibility resulted in decreased accuracy. For this target, more stimuli were required for sufficient accuracy and selected Bayesian procedures surpassed the performance of others. Some Bayesian procedures were also superior in the estimation of psychometric function width. Conclusions A single standardised procedure could improve the consistency of the matrix sentence test across a range of target intelligibilities. Candidate adaptive procedures and analysis methods are discussed. These could also be applicable for other speech materials. Further testing with human participants is required.
Vitamin D3 for reducing mortality from cancer and other outcomes before, during and beyond the COVID‐19 pandemic: A plea for harvesting low‐hanging fruit

Vitamin D3, also known as cholecalciferol, is a fat-soluble secosteroid whose key role in calcium and phosphate homeostasis and bone health has been recognized for long. In recent years, evidence has accumulated on multiple other biological effects, such as immunomodulatory and anti-inflammatory effects. The main source of vitamin D for humans is its production in the skin under sunlight exposure, which is often insufficient to ensure adequate vitamin D supply, particularly at high latitudes during fall, winter and spring. This editorial aims to draw attention to the underused potential of enhancing vitamin D3 supply for reducing cancer mortality and other adverse health outcomes, which might be a most valuable low-hanging fruit before, during and after the Coronavirus Disease 2019 (COVID-19) pandemic.
Comparison of the association of masked hypertension defined by the 2017 ACC/AHA BP guideline versus the JNC7 guideline with left ventricular hypertrophy

Background: Compared with the Seventh Report of the Joint National Committee (JNC7), the 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guideline uses lower BP thresholds to define hypertension and BP control. Methods: We pooled data from five US-based studies to compare the association of masked hypertension (MHT) and masked uncontrolled hypertension, defined using the 2017 ACC/AHA guideline (n = 1653 without high office BP; <130/80 mmHg) versus the JNC7 guideline (n = 2451 without high office BP; <140/90 mmHg), with left ventricular hypertrophy (LVH). MHT and masked uncontrolled hypertension were defined using office BP and awake BP alone and awake, asleep, or 24-h BP. LVH was assessed by echocardiography. Results: Among participants without high office BP not taking antihypertensive medication, the prevalence of MHT defined by the JNC7 guideline and the 2017 ACC/AHA BP guideline was 25.0 and 33.5% using awake BP only and 37.1 and 52.0% when using awake, asleep, or 24-h BP. The adjusted prevalence ratios for LVH associated with MHT versus sustained normotension defined by the JNC7 and 2017 ACC/AHA BP guidelines were 1.72 [95% confidence interval (CI): 1.12–2.64] and 1.56 (95% CI: 0.97–2.51), respectively, when using awake BP only and 2.16 (95% CI: 1.36–3.44) and 1.03 (95% CI: 0.58–1.82), respectively, when using awake, asleep or 24-h BP. There was no evidence that masked uncontrolled hypertension was associated with LVH when defined using the BP thresholds in either the JNC7 or the 2017 ACC/AHA BP guideline. Conclusion: The association of MHT with LVH may depend on the BP thresholds used.
Extensive light profile fitting of galaxy-scale strong lenses. Towards an automated lens detection method

Aims. We investigate the merits of a massive forward-modeling of ground-based optical imaging as a diagnostic for the strong lensing nature of early-type galaxies, in the light of which blurred and faint Einstein rings can hide. Methods. We simulated several thousand mock strong lenses under ground- and space-based conditions as arising from the deflection of an exponential disk by a foreground de Vaucouleurs light profile whose lensing potential is described by a singular isothermal ellipsoid. We then fitted for the lensed light distribution with sl_fit after subtracting the foreground light emission (ideal case) and also after fitting the deflector light with galfit. By setting thresholds in the output parameter space, we can determine the lensed or unlensed status of each system. We finally applied our strategy to a sample of 517 lens candidates in the CFHTLS data to test the consistency of our selection approach. Results. The e ciency of the fast modeling method at recovering the main lens parameters such as Einstein radius, total magnification, or total lensed flux is quite similar under CFHT and HST conditions when the deflector is perfectly subtracted (only possible in simulations), fostering a sharp distinction between good and poor candidates. Conversely, a substantial fraction of the lensed light is absorbed into the deflector model for a more realistic subtraction, which biases the subsequent fitting of the rings and then disturbs the selection process. We quantify completeness and purity of the lens-finding method in both cases. Conclusions. This suggests that the main limitation currently resides in the subtraction of the foreground light. Provided further enhancement of the latter, the direct forward-modeling of large numbers of galaxy-galaxy strong lenses thus appears tractable and might constitute a competitive lens finder in the next generation of wide-field imaging surveys.
A report on a series of nanophthalmos with histopathology and immunohistochemistry analyses using light microscopy

We aimed to study the histopathological and immunohistochemistry features in clinically diagnosed cases of nanophthalmos using light microscopy. This was an observational comparative study. We enrolled four eyes of four consecutive patients with nanophthalmos and visually significant cataract, who underwent cataract surgery with prophylactic posterior sclerostomy. Histological analysis of the excised scleral tissue was done and compared with age-matched cadaver controls between January 2021 and October 2021. Hematoxylin and Eosin (H&E) stains were used for histological analysis, and was further supplemented with immunohistochemistry (IHC) and immunofluorescence (IF) analyses using a simple light microscope. The immunostained sections were analyzed using confocal microscope for the fibronectin expression level. The main outcome measure was demonstration of histological changes of sclera in nanophthalmic eyes undergoing cataract surgery. Light microscopic features of nanophthalmos revealed thick fibers with fraying and lightly stained cores, irregular serrated edges, and randomly interspersed fibroblasts compared to regular arrangement of collagen fibers seen in cadaver controls. Immunohistochemistry analysis with anti-fibronectin antibody showed strong positivity in clustered fibers in nanophthalmos, and less intense diffuse staining in cadaver tissue. Histoclinical correlation was observed in one nanophthalmic scleral tissue with axial length less than 17 mm showing severe disorganization with diffuse collagenization, loss of fibrillary architecture compared to another specimen with axial length more than 17 mm. Simple, cost-effective light microscopy using basic stains was effective in identifying the characteristic histopathological features in nanophthalmic eyes, and this was further highlighted by immunohistochemistry and immunofluorescence analyses.