Miracle-dz/UniFAR-FTUs huggingface dataset:
Distinct gene programs underpinning ‘disease tolerance’ and ‘resistance’ in influenza virus infection

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs – one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.
Methylene Blue Is a Nonspecific Protein–Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19

We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and used for other medical applications, as a small-molecule inhibitor of the protein-protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration-dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concerns such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1-5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63 – ACE2, hepatitis C virus E – CD81) as well as others (e.g., IL-2 – IL-2Rα) with similar potency. This non-specificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and it has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19.
Physoxia Influences Global and Gene-Specific Methylation in Pluripotent Stem Cells

Pluripotent stem cells (PSC) possess unlimited proliferation, self-renewal, and a differentiation capacity spanning all germ layers. Appropriate culture conditions are important for the maintenance of self-renewal, pluripotency, proliferation, differentiation, and epigenetic states. Oxygen concentrations vary across different human tissues depending on precise cell location and proximity to vascularisation. The bulk of PSC culture-based research is performed in a physiologically hyperoxic, air oxygen (21% O2) environment, with numerous reports now detailing the impact of physiologic normoxia (physoxia) low oxygen culture in the maintenance of stemness, survival, morphology, proliferation, differentiation potential, and epigenetic profiles. Epigenetic mechanisms affect multiple cellular characteristics including gene expression during development and cell fate determination in differentiated cells. We hypothesized that epigenetic marks are responsive to a reduced oxygen microenvironment in PSCs and their differentiation progeny. Here, we evaluated the role of physoxia in PSC culture, the regulation of DNA methylation (5mC and 5hmC), and expression of regulatory enzymes DNMTs and TETs. Physoxia enhanced the functional profile of PSC including proliferation, metabolic activity, and stemness attributes. PSCs cultured in physoxia revealed significant downregulation of DNMT3B, DNMT3L, TET1, and TET3 vs. air oxygen, accompanied by significantly reduced 5mC and 5hmC levels. Downregulation of DNMT3B was associated with an increase in its promoter methylation. Coupled to above we also noted decreased HIF1A but increased HIF2A expression in physoxia cultured PSCs, versus air oxygen. In conclusion, PSCs display oxygen-sensitive methylation patterns that correlate with transcriptional and translational regulation of the de novo methylase DNMT3B.
Minimal geodesics

Abstract Motivated by the close relation between Aubry-Mather theory and minimal geodesies on a 2-torus we study the existence and properties of minimal geodesics in compact Riemannian manifolds of dimension ≥3. We prove that there exist minimal geodesics with certain rotation vectors and that there are restrictions on the rotation vectors of arbitrary minimal geodesics. A detailed analysis of the minimal geodesics of the ‘Hedlund examples’ shows that – to a certain extent – our results are optimal.
A New Method to Predict the Settlement of Embankment

In the article summarised is the law of consolidation settlement according to the long term survey data of the HU NING highway.It is considered that the settlement curve is close to the parabola in the s lgt coordinate when the load is stable.On this basis,a simple method is proposed to predict the future settlement accurately.Based on the survey data,combined with the reverse analysis of displacement,through calculation of the coefficient of the equation the equation of settlement can be obtained.Engineering practice proves that the result predicted by the present method is more accurate than that by conventional methods.
Another plea for ‘best practice’ in molecular approaches to trematode systematics: Diplostomum sp. clade Q identified as Diplostomum baeri Dubois, 1937 in Europe

Abstract Abstract DNA sequence data became an integral part of species characterization and identification. Still, specimens associated with a particular DNA sequence must be identified by the use of traditional morphology-based analysis and correct linking of sequence and identification must be ensured. Only a small part of DNA sequences of the genus Diplostomum (Diplostomidae) is based on adult isolates which are essential for accurate identification. In this study, we provide species identification with an aid of morphological and molecular (cox1, ITS-5.8S-ITS2 and 28S) characterization of adults of Diplostomum baeri Dubois, 1937 from naturally infected Larus canus Linnaeus in Karelia, Russia. Furthermore, we reveal that the DNA sequences of our isolates of D. baeri are identical with those of the lineage Diplostomum sp. clade Q , while other sequences labelled as the ‘D. baeri’ complex do not represent lineages of D. baeri. Our new material of cercariae from Radix balthica (Linnaeus) in Ireland is also linked to Diplostomum sp. clade Q. We reveal that D. baeri is widely distributed in Europe; as first intermediate hosts lymnaeid snails (Radix auricularia (Linnaeus), R. balthica) are used; metacercariae occur in eye lens of cyprinid fishes. In light of the convoluted taxonomy of D. baeri and other Diplostomum spp. , we extend the recommendations of Blasco-Costa et al. (2016, Systematic Parasitology 93, 295–306) for the ‘best practice’ in molecular approaches to trematode systematics. The current study is another step in elucidating the species spectrum of Diplostomum based on integrative taxonomy with well-described morphology of adults linked to sequences.
Effect of Tratak (Yogic Ocular Exercises) on Intraocular Pressure in Glaucoma: An RCT

Introduction: In healthy subjects, the intraocular pressure (IOP) is maintained by a dynamic equilibrium between continuous production of aqueous humor by ciliary bodies and continuous outflow through the two drainage pathways: trabecular meshwork and uveoscleral outflow. Here, we hypothesized that yogic ocular exercises, including extraocular muscles exercise, and modified Tratak Kriya (mTK), might reduce the IOP as well as stress and improve quality of life (QoL) in patients with glaucoma. Methodology: A parallel two-arm randomized controlled trial (RCT) was conducted in glaucoma patients (Control group and Intervention group). Control group patients were on standard medical treatment and intervention group patients practiced a Yoga-based lifestyle intervention (YBLI) for 4 weeks as add-on therapy with their standard medical treatment. All Participants were assessed at baseline day 1, day 14 (D14), and day 28 (D28). A minimum of 30 patients were recruited in each group. Results: We did not observe any statistically significant different mean IOP of right (IOP-r) or, left eyes at any time point as well as cortisol level and QoL between the two groups. However, with in intervention group, there was a reduction in IOP-r at D14 (15.54 ± 2.81 mmHg) and D28 (15.24 ± 3.1 mmHg), P = 0.006 and 0.001, respectively, compared to their baseline IOP (16.26 ± 2.98). Conclusion: Based on the present RCT, yoga-based ocular exercises practiced here cannot be recommended for management of raised IOP in glaucoma patients. Further larger studies are warranted with yoga-based interventions in patients with glaucoma. Clinical Trial Registration Number CTRI/2016/03/006703
The retinal vascular growth rate in babies with retinopathy of prematurity could indicate treatment need

Purpose: To analyze the weekly rate of retinal vascular growth in treatment-naïve babies with various stages of retinopathy of prematurity (ROP) and validate if this could be a predictor of treatment need. Methods: Retrospective review of medical charts and retinal images of babies with various stages of ROP. The images were enhanced using red-green image enhancement software. Using the length of the horizontal disc diameter (DD) of each eye, the vessel growth was measured from the disc margin up to the vessel tip in fixed quadrants. The rate of vessel growth was the ratio of vessel length to the number of weeks it took to reach this length. The babies were divided into treatment warranting ROP (group 1), low-risk pre-threshold (type II) ROP (group 2,), and no-ROP (group 3) for analysis. The “no-ROP” group acted as normal control. Group 1 was further subdivided into 1A (threshold ROP), IB (aggressive posterior ROP), 1C (hybrid ROP), and ID (high-risk pre-threshold ROP). Results: Out of 436 eyes, groups 1, 2, and 3 had 238, 108, and 90 eyes, respectively. The mean rate of vascular outgrowth along with 95% confidence interval (CI) was 0.490 [0.487,0.520], 0.612 [0.599, 0.638], and 0.719 [0.703, 0.740] DD/week, respectively, for babies with “treatment warranting,” “low risk pre-threshold” and “no ROP” groups, respectively. In our estimate, more than 80% of eyes with a vessel growth rate of 0.54 DD/week or less required treatment. Conclusion: A rate of retinal vascular growth less than 0.54 DD/week can be used to determine treatment requirements in babies with ROP.
Comparison of corneal endothelial changes following phacoemulsification in diabetic and non-diabetic patients

Purpose: To study corneal endothelial changes post phacoemulsification in diabetic and non-diabetic patients. Methods: A comparative, prospective, observational study was conducted on 100 diabetic and 100 non-diabetics who underwent phacoemulsification. All patients were operated by the same surgeon by using the phaco chop technique to exclude any surgeon-related bias. Endothelial cell count, CCT, and coefficient of variance (CV) were measured with a specular microscope along with BCVA preoperatively and at 1 week, 4 weeks, and 3 months postoperatively. For statistical analysis, data were analyzed by using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA). Data were summarized as mean and standard deviation for numerical variables and count and percentages for categorical variables. Chi square test, independent sample T test, and paired T test were used to compare the data. P ≤ 0.05 was considered statistically significant. Results: Postoperatively at 1 week, 4-week, and 3 months follow-up intervals, the mean endothelial cell count and coefficient of variance were significantly higher, and the mean percentage of hexagonal cells was significantly lower in non diabetic as compared to the diabetic group. A significant difference in mean central corneal thickness of the two groups was observed at 1-week and 4-weeks postoperative intervals; at both these intervals, the mean value was significantly higher in non diabetic as compared to the non-diabetic group. However, at 3-months post-operative interval, the difference between the two groups was not significant statistically. Mean BCVA values were significantly higher in diabetic as compared to the diabetic group at all three follow-up intervals. Conclusion: The findings of the present study show that endothelial cell characteristics are adversely affected in diabetic eyes as compared to non-diabetic patients undergoing phacoemulsification; this might also have an effect on the visual outcomes.
Utilizing human intelligence in artificial intelligence for detecting glaucomatous fundus images using human-in-the-loop machine learning

Purpose: For diagnosing glaucomatous damage, we have employed a novel convolutional neural network (CNN) from TrueColor confocal fundus images to conquer the black box dilemma in artificial intelligence (AI). This neural network with CNN architecture with human-in-the-loop (HITL) data annotation helps not only in diagnosing glaucoma but also in predicting and locating detailed signs in the glaucomatous fundus, such as splinter hemorrhages, glaucomatous optic atrophy, vertical glaucomatous cupping, peripapillary atrophy, and retinal nerve fiber layer (RNFL) defect. Methods: The training was done on a well-curated private dataset of 1,400 high-resolution confocal fundus images, out of which 1,120 images (80%) were used exclusively for training and 280 images (20%) were used exclusively for testing. A custom trained You Only Look Once version 5 (YOLOv5)-based object detection methodology was used to identify the underlying conditions precisely. Twenty-six predefined medical conditions were annotated by a team of humans (comprising two glaucoma specialists and two optometrists) by using the Microsoft Visual Object Tagging Tool (VoTT) tool. The 280 testing images were split into three groups (90,100, and 90 images) for three test runs done once every 15 days. Results: Test results showed consistent increments in the accuracy, from 94.44% to 98.89%, in predicting the glaucoma diagnosis along with the detailed signs of the glaucomatous fundus. Conclusion: Utilizing human intelligence in AI for detecting glaucomatous fundus images by using HITL machine learning has never been reported in the literature before. This AI model not only has good sensitivity and specificity in accurate glaucoma predictions but is also an explainable AI, thus overcoming the black box dilemma.
Sub-fs electron bunch generation with sub-10-fs bunch arrival-time jitter via bunch slicing in a magnetic chicane

The generation of ultrashort electron bunches with ultrasmall bunch arrival-time jitter is of vital importance for laser-plasma wakefield acceleration with external injection. We study the production of 100-MeV electron bunches with bunch durations of subfemtosecond (fs) and bunch arrival-time jitters of less than 10 fs, in an S-band photoinjector by using a weak magnetic chicane with a slit collimator. The beam dynamics inside the chicane is simulated by using two codes with different self-force models. The first code separates the self-force into a three-dimensional (3D) quasistatic space-charge model and a one-dimensional coherent synchrotron radiation (CSR) model, while the other one starts from the first principle with a so-called 3D sub-bunch method. The simulations indicate that the CSR effect dominates the horizontal emittance growth and the 1D CSR model underestimates the final bunch duration and emittance because of the very large transverse-to-longitudinal aspect ratio of the sub-fs bunch. Particularly, the CSR effect is also strongly affected by the vertical bunch size. Due to the coupling between the horizontal and longitudinal phase spaces, the bunch duration at the entrance of the last dipole magnet of the chicane is still significantly longer than that at the exit of the chicane, which considerably mitigates the impact of space charge and CSR effects on the beam quality. Exploiting this effect, a bunch charge of up to 4.8 pC in a sub-fs bunch could be simulated. In addition, we analytically and numerically investigate the impact of different jitter sources on the bunch arrival-time jitter downstream of the chicane, and define the tolerance budgets assuming realistic values of the stability of the linac for different bunch charges and compression schemes.
Transepithelial phototherapeutic keratectomy for post-traumatic recurrent corneal erosions

Purpose: To evaluate the outcomes of transepithelial phototherapeutic keratectomy (transepithelial PTK) for treatment of posttraumatic recurrent corneal erosions. Methods: Twenty-four eyes of 22 patients with posttraumatic recurrent corneal erosions who were treated with transepithelial PTK from April 2018 to July 2020 were included in this retrospective study. The rates of recurrent erosions and complications were evaluated during the follow-up after surgery. Visual acuity and refraction were recorded preoperatively and 1 year after surgery. Total corneal astigmatism, total corneal irregular astigmatism, and total corneal spherical aberrations were recorded using corneal tomography preoperatively and 1 year after surgery. Results: Mean postoperative follow-up was 13 months (range: 12–32 months). None of the patients suffered from any complications or further erosions. Uncorrected distance visual acuity, best-corrected distance visual acuity, spherical equivalent, and cylinder remained stable at 1-year postoperatively compared with the baseline (P = 0.214, P = 0.461, P = 0.084, and P = 0.879, respectively). Moreover, there was no significant difference in total corneal astigmatism, total corneal irregular astigmatism, and total corneal spherical aberrations between baseline and 1-year postoperative visit (P = 0.938, P = 0.136, and P = 0.981, respectively). Conclusion: Transepithelial PTK was an effective treatment for patients with posttraumatic recurrent corneal erosions.
Patterns of Enrollment in Cancer Treatment Trials During the COVID-19 Pandemic at National Cancer Institute–Designated Cancer Centers

Abstract The COVID-19 pandemic posed unprecedented strain on enrollment to cancer clinical trials and their conduct. Here, we highlight an analysis using information from the National Cancer Institute (NCI) Clinical Trials Reporting Program database to describe enrollment patterns to interventional cancer treatment trials at NCI-Designated Cancer Centers during the pandemic. Enrollment to cancer treatment trials at NCI-Designated Cancer Centers decreased precipitously early in the pandemic and has not yet fully returned to the 2019 baseline as of mid-2021. We discuss possible reasons for this and how some of the changes in clinical trial conduct implemented during the pandemic may become part of the standard conduct of NCI-supported clinical trials and broaden access to trials.
Commentary: Impact of intraocular surgeries on corneal endothelial cells in patients with diabetes mellitus

Corneal endothelial cells are indispensable for maintaining corneal transparency. Endothelial cell dysfunction may place the cornea at a greater risk of developing endothelium decompensation and consequent bullous keratopathy. Endothelial cells are known to show a decline in both qualitative and quantitative features, especially with increasing age owing to amitotic characteristics. Thus, endothelial cell damage can be significant in elderly individuals postoperatively. Consequent to any damage to the endothelial cell layer, the remaining contiguous cells enlarge and reposition to restore the functional anatomy. This is reflected as an increase in the cell size and a decrease in the percentage of hexagonal cells. [1]
Optical coherence tomography features and correlation of functional and structural parameters in patients of idiopathic intracranial hypertension

Purpose: To determine the correlation between functional parameters and optical coherence tomography (OCT) features in patients of idiopathic intracranial hypertension (IIH). Methods: A prospective observational study in early and established cases of papilledema in IIH presenting from December 2017 to February 2019. Functional parameters (visual acuity, contrast sensitivity, mean deviation, VER, and MfERG) and structural parameters (RNFL, GCL-IPL, and optic disc height) were measured at baseline and every 6 weeks for 6 months. Results: At baseline, average RNFL had a moderate negative correlation with mean deviation (r = −0.45; P = 0.0007) and a positive correlation with logMAR visual acuity (r = 0.18; P = 0.17). On the contrary, baseline GCL and logMAR visual acuity had a negative correlation (r = −0.4, P = 0.02). Optic disc height (ODH) had a negative correlation with visual field mean deviation (r = −0.046; P = 0.0005). At 6 months, ODH and GCL-IPL complex had a statistically significant correlation with functional parameters. However, RNFL values did not show any significant correlation with any of the functional parameters. Baseline GCL-IPL and optic disc height values had a moderate and significant correlation with final functional parameters. However, RNFL did not show any correlation with final functional parameters. Correlation between GCL-IPL thickness at 6 weeks and final functional parameters were stronger than that with baseline GCL values. Conclusion: In the setting of severe papilledema, RNFL can misguide the prognosis. GCL-IPL can be a valuable tool for an objective evaluation of the integrity of the optic nerve in IIH and ODH may be used as an alternative or in combination with GCL-IPL in these cases.
Bolus versus continuous infusion of nitroglycerin for the treatment of acute hypertensive heart failure

Background: The use of intravenous nitroglycerin by intermittent bolus doses in hypertensive acute heart failure patients (AHF) is still unclear. Aim and Objectives: This study aimed to determine intermittent bolus nitroglycerin's effect on the use of resources, admissions to intensive care unit (ICU), hospital length of stay (LOS), and safety. Patients and Methods: This prospective, randomized, parallel, single-blind clinical study, which included patients diagnosed with hypertensive AHF, was conducted from May 2019 to October 2020 at Benha University Hospital. Two hundred patients were recruited and randomly allocated into two groups, each composed of 100 patients. Results: The prevalence of hypertension and chronic obstructive pulmonary disease patients was significantly higher in patients given intermittent boluses of nitroglycerin than in standard therapy (88.0 vs. 77.0%, P = 0.041) and (27.0 vs. 15.0%, P = 0.037), respectively. Dyslipidemia was significantly lower in patients on intermittent doses of nitroglycerin than those on standard infusion therapy (30 vs. 66%, P < 0.001). The median initial troponin was significantly higher in group I compared to group II (0.145 vs. 0.065 ng/ml, P < 0.001). Conclusion: Nitroglycerin intravenous boluses were associated with fewer ICU admissions and a shorter LOS in the hospital as opposed to ordinarily infusion therapy. In addition, the mean mechanical ventilation duration was slightly shorter. Finally, continuous nitroglycerin infusion use in AHF management is being questioned.