Miracle-dz/UniFAR-FTUs huggingface dataset:
Nanopore sensors for single molecular protein detection: Research progress based on computer simulations

Abstract As biological macromolecules, proteins are involved in important cellular functions ranging from DNA replication and biosynthesis to metabolic signalling and environmental sensing. Protein sequencing can help understand the relationship between protein function and structure, and provide key information for disease diagnosis and new drug design. Nanopore sensors are a novel technology to achieve the goal of label‐free and high‐throughput protein sequencing. In recent years, nanopore‐based biosensors have been widely used in the detection and analysis of biomolecules such as DNA, RNA, and proteins. At the same time, computer simulations can describe the transport of proteins through nanopores at the atomic level. This paper reviews the applications of nanopore sensors in protein sequencing over the past decade and the solutions to key problems from a computer simulation perspective, with the aim of pointing the way to the future of nanopore protein sequencing.
Two cyanobacterial response regulators with diguanylate cyclase activity, Rre2 and Rre8, participate in biofilm formation

Phototrophic bacteria face diurnal variations of environmental conditions such as light and osmolarity that affect their carbon metabolism and ability to generate organic compounds. The model cyanobacterium, Synechocystis sp. PCC 6803 forms a biofilm when it encounters extreme conditions like high salt stress, but the molecular mechanisms involved in perception of environmental changes that lead to biofilm formation are unknown. Here, we studied two two‐component regulatory systems (TCSs) that contain diguanylate cyclases (DGCs), which produce the second messenger c‐di‐GMP, as potential components of the biofilm‐inducing signaling pathway in Synechocystis. Analysis of single mutants provided evidence for involvement of the response regulators, Rre2 and Rre8 in biofilm formation. A bacterial two‐hybrid assay showed that Rre2 and Rre8 each formed a TCS with a specific histidine kinase, Hik12 and Hik14, respectively. The in vitro assay showed that Rre2 had DGC activity regardless of its de/phosphorylation status, whereas Rre8 required phosphorylation for DGC activity. Hik14‐Rre8 likely functioned as an inducible sensing system in response to environmental change. Biofilm assays with Synechocystis mutants suggested that pairs of hik12‐rre2 and hik14‐rre8 responded to high salinity‐induced biofilm formation. Inactivation of hik12‐rre2 and hik14‐rre8 did not affect the performance of the light reactions of photosynthesis. These data suggest that Hik12‐Rre2 and Hik14‐Rre8 participate in biofilm formation in Synechocystis by regulating c‐di‐GMP production via the DGC activity of Rre2 and Rre8.
Feasibility and first results of the ‘Trials-within-Cohorts’ (TwiCs) design in patients undergoing radiotherapy for lung cancer

Abstract Background: ‘Trials-within-Cohorts’ (TwiCs), previously known as ‘cohort multiple randomized controlled trials’ is a pragmatic trial design, supporting an efficient and representative recruitment of patients for (future) trials. To our knowledge, the ‘COhort for Lung cancer Outcome Reporting and trial inclusion’ (COLOR) is the first TwiCs in lung cancer patients. In this study we aimed to assess the feasibility and first year results of COLOR. Material and Methods: All patients diagnosed with lung cancer referred to the Radiotherapy department were eligible to participate in the ongoing prospective COLOR study. At inclusion, written informed consent was requested for use of patient data, participation in patient-reported outcomes (PROs), and willingness to participate in (future) trials. Feasibility was studied by assessing participation and comparing baseline PROs to EORTC reference values. First-year results of PROs at baseline and 3 months after inclusion were evaluated separately for stereotactic body radiotherapy (SBRT) and conventional radiotherapy patients. Results: Of the 338 eligible patients between July 2020 and July 2021, 169 (50%) participated. Among these, 127 (75%) gave informed consent to PROs participation and 110 (65%) were willing to participate in (future) trials. The inclusion percentage dropped from 77% to 33% when the information procedure was switched from in-person to by phone (due to COVID-19 pandemic measures). Baseline PROs for physical and cognitive functioning were comparable in COLOR patients compared to the EORTC reference values. No significant changes in PROs were observed 3 months after inclusion, except for a slight increase in pain scores in the SBRT group (n = 97). Conclusions: The TwiCs-design appears feasible in lung cancer patients with fair participation rates (although negatively impacted by the COVID-19 pandemic). With a planned expansion to other centers, the COLOR-study is expected to enable multiple (randomized) evaluations of experimental interventions with important advantages for recruitment, generalizability, and long-term outcome data collection.
Photographic stellar photometry with the PDS microdensitometer

A technique for photographic stellar photometry with the PDS microdensitometer is described. It employs a least-squares fit to a model density profile to derive an instrumental magnitude index, an image-abnormality index, and the local value of the background density for each image. The instrumental magnitude index is calibrated in terms of true magnitude by the same methods as for iris photometry. A preliminary test of the method using plates of the open cluster NGC 188 indicates that a precision comparable to or slightly better than that of conventional iris photometry or other methods of PDS reduction may easily be attained. Possibilities for the future elaboration of the technique are mentioned.
Existence and Estimates of Solutions for Singular Nonlinear Elliptic Problems

for both bounded and unbounded domain in R d ≥ 3 , with smooth boundary ∂ . The function φ × 0 ∞ → 0 ∞ is measurable and satisfies some appropriate hypotheses detailed below. The problem (1) has been studied extensively for the special nonlinearity φ x t = p x t−γ γ > 0 . Indeed, in [7], Edelson proved the existence of a positive solution u ∈ C2+α loc R decaying as x 2−n as x → ∞, provided that p ∈ C loc R 0 0, for x > 0 and satisfying the growth condition ∫ ∞
Validation of MELD 3.0 scoring system in East Asian patients with cirrhosis awaiting liver transplantation

Recently, a new predictive model that jointly considers the Model of End-stage Liver Disease (MELD) 3.0 and albumin has been proposed. This study investigated the performance of the MELD 3.0 score in predicting the 3-month survival of East Asian patients with cirrhosis compared with the other MELD-based scores. Validation was performed with the retrospective data of 2153 patients in South Korea who were listed for liver transplantation (LT). Discrimination and calibration analyses were performed using the MELD-based scores as an independent variable. On average, patients had the original MELD score of 18.70 ± 9.65. Alcohol (39.99%) and chronic HBV (38.55%) were the 2 main etiologies. The MELD 3.0 with albumin showed slightly better discrimination [c-index = 0.738, incremental AUC (iAUC) = 0.719] compared with the MELD 3.0 without albumin (c-index = 0.737, iAUC = 0.715), MELD-Na (c-index = 0.730, iAUC = 0.707), or the original MELD (c-index = 0.718, iAUC = 0.687) for predicting 3-month survival but not significantly different compared with prior models. Likewise, in the stratified analysis according to the strata of MELD, although the performance of MELD 3.0 was better throughout all the MELD strata than MELD original, there was no statistical difference in performance. The MELD 3.0 with albumin reclassified 22.61% of cases classified by the original MELD to higher MELD score categories, and there was no significant difference in the reclassification rate between males and females. The predictive power of the MELD-based system is lower in Asian populations than in western countries. Nonetheless, the MELD 3.0 score with albumin was significantly better in predicting the short-term prognosis of East Asian patients on the LT waitlist than the current allocation system, original MELD.
Synchronously Manipulating Absorption and Extinction Coefficient of Semiconducting Polymers via Precise Dual-Acceptor Engineering for NIR-II Excited Photothermal Theranostics.

Integrating all of the ultralong excitation wavelength, high extinction coefficient, and prominent photothermal conversion ability into a single photothermal agent is an appealing yet significantly challenging task. Herein, a precise dual-acceptor engineering strategy is exploited for this attempt based on donor-acceptor (D-A) type semiconductor polymers by subtly regulating the molar proportions of the two employed electron acceptor moieties featured with different electronic affinity and π-conjugation degrees, and taking full use of the active intramolecular motion-induced photothermal effect. The optimal polymer SP4, synchronously shows desirable second near-infrared (NIR-II) absorption, extremely high extinction coefficient, and satisfactory photothermal conversion behavior. Consequently, the unprecedented performance of SP4 NPs on 1064 nm laser-excited photoacoustic imaging (PAI)-guided photothermal therapy (PTT) is demonstrated by the precise tumor diagnosis and complete tumor elimination outcomes.
Structural analyses of strained SiGe wires formed by hydrogen thermal etching and Ge-condensation processes

Strained SiGe-wire structures formed by a thermal oxidation of SiGe-on-insulator (SGOI) fins after an anisotropic gas etching in atmospheric hydrogen are investigated in terms of morphology, strain, and crystalline defects. It is found that vertical and smooth {110} sidewalls emerged on the SGOI fins after the hydrogen etching and that the SiGe wires consisted of a Si-rich core region and a surrounding Ge-rich layer formed by the Ge-condensation mechanism through the oxidation. Detailed strain analyses reveal that uniaxial and compressive strain accumulated in the Ge-rich layer via an elastic lattice deformation without generating dislocations.
MTHFR A1298C polymorphism: a predictor of reduced risk of preeclampsia in Punjab, Pakistan

ABSTRACT Objectives This study aimed to investigate the genetic association between MTHFR (A1298C) SNP and preeclampsia (PE) in Punjab, Pakistan. Methods A sample of 80 pregnant women (40 healthy pregnant women and 40 with PE) was pooled for genotyping MTHFR A1298C polymorphism by using the tetra-primer amplification refractory mutation system (ARMS) PCR. The Genotypic and allelic assessments were performed using various statistical techniques. Results The AC genotype and C allele of MTHFR A1298C were found to be associated with decreased risk of PE (odds ratio [OR]: 0.31, risk ratio [RR]: 0.58, p = 0.01), and (odds ratio [OR]: 0.49, risk ratio [RR]: 0.61, p = 0.04), respectively. Conclusion In conclusion, genetic polymorphism A1298C in MTHFR may pose a protective effect in the studied population.
FAM69C functions as a kinase for eIF2α and promotes stress granule assembly

Stress granules are dynamic cytoplasmic ribonucleoprotein granules that assemble in response to cellular stress. Aberrant formation of stress granules has been linked to neurodegenerative diseases. However, the molecular mechanisms underlying the initiation of stress granules remain elusive. Here we report that the brain‐enriched protein kinase FAM69C promotes stress granule assembly through phosphorylation of eukaryotic translation initiation factor 2 (eIF2α). FAM69C physically interacts with eIF2α and functions as a stress‐specific kinase for eIF2α, leading to stress‐induced protein translation arrest and stress granule assembly. Primary microglia derived from Fam69c knockout mice exhibit aberrant stress granule assembly in response to oxidative stress and ATP. Defective stress granule assembly in microglia correlates with the formation of ASC specks and NLRP3 inflammasome activation, whereas induction of stress granule precludes inflammasome formation. Consistently, increased NLRP3 levels, caspase‐1 cleavage and Il18 expression corroborate microglia‐associated neuroinflammation in aged Fam69c knockout mice. Our study demonstrates that FAM69C is critical for stress granule assembly and suggests its role in the regulation of microglia function.
Integrated analysis reveals important differences in the gut and oropharyngeal microbiota between children with mild and severe hand, foot, and mouth disease

ABSTRACT Little is known about alternation and difference in gut microbiota between patients with mild and severe hand, foot, and mouth disease (HFMD). We investigated the differences in gut and oropharynx microbiota between mild and severe HFMD in young children and changes in bacterial profiles as the disease progresses from acute to convalescent phase. Forty-two patients with confirmed HFMD were studied, among which 32 had severe HFMD and 10 had mild HFMD. First rectal swabs were collected from all patients at an average of 2 days (acute phase) after the onset of symptoms, and second rectal swabs were collected from 8 severe patients at day 9 (convalescent phase) after the onset. Oropharyngeal swabs were obtained from 10 patients in the acute phase and 6 in the convalescent phase. 16S rRNA sequencing was performed for all 70 samples. Compared with mild HFMD, severe HFMD exhibited significantly decreased diversity and richness of gut microbiota. Gut microbiota bacterial profiles observed in the acute and convalescent phases resembled each other but differed from those in mild cases. Additionally, 50% of patients with severe HFMD in the acute phase harboured a dominant pathobiontic bacterial genus. However, none of the patients with mild HFMD had such bacteria. Similar bacterial compositions in oropharynx microbiota were detected between mild and severe cases. Our findings indicate that severe HFMD exhibits significantly impaired diversity of gut microbiota and frequent gut and oropharyngeal inflammation-inducing bacteria. However, the results should be interpreted with caution as the number of subjects was limited.
A Phase II Trial of Guadecitabine plus Atezolizumab in Metastatic Urothelial Carcinoma Progressing after Initial Immune Checkpoint Inhibitor Therapy

Abstract Purpose: On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti–programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy. Patients and Methods: We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors. Results: Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8–11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients’ plasma was associated with short survival. Conclusions: No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.
Metric entropy and n-widths of function spaces on data defined manifolds and quasi-metric measure spaces

We first determine the asymptotics of the Kolmogorov metric entropy and n-widths of Sobolev spaces on some classes of data defined manifolds and quasi-metric measure spaces. Secondly, we develop constructive algorithms to represent those functions within a prescribed accuracy. The constructions can be based on either spectral information or scattered samples of the target function. Our algorithmic scheme is asymptotically optimal in the sense of n-widths and asymptotically optimal up to a logarithmic factor with respect to the metric entropy.
Derotational femoral osteotomy locations and their influence on joint reaction forces in dysplastic hips

Femoral version (FV) deformities are common in patients with developmental dysplasia of the hip (DDH) and may contribute to cartilage damage due to abnormal joint loading. Derotational femoral osteotomy (DFO) surgery corrects FV deformities. However there is little consensus about the femoral transection location for DFO, and its influence on joint loads is unknown. The purpose of this study was to compare the effects of two common DFO locations on muscle forces and hip joint reaction forces (JRFs) in patients with DDH. DFO was simulated in nine patients with DDH and abnormal FV using patient‐specific musculoskeletal models. Femoral transection for DFO was separately simulated proximal and distal to the lesser trochanter and FV values were corrected to an idealized 15°. JRFs during early and late stance of gait were compared between the two simulated transection locations. Most changes to JRFs were similar between proximal and distal DFO, however, statistically significant differences were found for the medial JRF component during late stance among patients with femoral anteversion (p = 0.01). Force changes from five hip muscles were significantly different between DFO locations, however, changes were minimal. Most changes after DFO in patients with femoral retroversion were opposite of those with femoral anteversion, with anteroposterior and superior JRFs increasing after retroversion correction. After DFO correction, superior and medial JRFs in DDH patients remained elevated compared to controls. Understanding the influence of DFO location on muscle‐generated hip forces can help surgeons justify decisions and potentially standardize surgical correction of FV deformities in patients with DDH.
Minced muscle autografting improves bone healing but not muscle function in a porcine composite injury model

Composite tissue injuries (CTIs) in extremities include segmental bone defects (SBDs) and volumetric muscle loss. The objective of this study was to determine if skeletal muscle autografting with minced muscle grafts (MMGs) could improve healing in an SBD and improve muscle function in a porcine CTI model that includes an SBD and adjacent volumetric muscle loss injury. Adult Yucatan Minipigs were stratified into three groups including specimens with an isolated SBD, an SBD with volumetric muscle loss (CTI), and an SBD with volumetric muscle loss treated with MMG (CTI + MMG). Bone healing was quantified with serial x‐rays and postmortem computed tomography scanning. Muscle function was quantified with a custom in vivo force transducer. Muscle tissue content was determined by biochemical analyses and histology. Anterior cortex‐modified Radiographic Union Score for Tibia fractures (mRUSTs) decreased from 2.7 to 1.9 (p = 0.003) in CTI versus SBD animals. MMG improved anterior mRUST scores to 2.5 in CTI + MMG specimens (p = 0.030 compared to CTI specimens) and overall mRUST scores increased from 9.4 in CTI specimens to 11.1 in CTI + MMG specimens (p = 0.049). Residual strength deficits at euthanasia were 42% in SBD (p < 0.001), 44% in CTI (p < 0.001), and 48% in CTI + MMG (p < 0.001) compared to preoperative values. There were no differences in strength deficits between the three groups. Biochemical and histologic analyses demonstrated scattered differences between the three groups compared to contralateral muscle. MMG improved bone healing. However, the primary cause of muscle dysfunction and biochemical changes was the presence of an SBD. Clinical significance: Early mitigation of SBDs may be necessary to prevent muscle damage and weakness in patients sustaining composite extremity trauma.
Torque‐teno virus for the prediction of graft rejection and infection disease after kidney transplantation: A systematic review and meta‐analysis

Torque teno virus (TTV) is a promising novel marker for quantifying the immune function in solid organ recipients, whose diagnostic accuracy of acute rejection (AR) and infection after kidney transplantation (KT) has not been evaluated. We performed a systematic review and meta‐analysis to evaluate the diagnostic accuracy of TTV for discriminating AR and infection after KT. Eleven studies were included in the meta‐analysis. Seven studies focused on the diagnostic accuracy of TTV for AR, and the pooled analysis indicated patients who developed AR had a significant lower TTV viral DNA load (log10 copies/mL, MD: −0.74, p < 0.01). The pooled sensitivity, specificity, and area under the receiver operating characteristics curve for TTV in AR differentiation were 0.61 (0.36−0.82), 0.81 (0.64−0.91), and 0.79 (0.75−0.82), respectively. The overall diagnostic odds ratio (DOR) was 6.74 (2.60−17.50), positive likelihood ratio (PLR) was 3.22 (1.75−5.95), and negative likelihood ratio (NLR) was 0.48 (0.27−0.84), respectively. Similarly, seven studies investigated the infection discrimination and found that patients who subsequently developed posttransplant infection had higher plasma TTV DNA loads (log10 copies/mL, MD: 0.65; p < 0.01) than those remaiing infection‐free. Pooled sensitivity, specificity, and area under the receiver operating characteristics curve for TTV in infection differentiation were 0.72 (0.39−0.91), 0.57 (0.30−0.80), and 0.68 (0.64−0.72), respectively. The overall DOR was 3.28 (95% confidence interval [CI]: 2.08−5.17), the pooled PLR and NLR were 1.65 (95% CI: 1.25−2.18) and 0.50 (95% CI: 0.29−0.86), respectively. TTV might be a modest indicator for risk stratification of AR after KT, but it is a poor to discriminate posttransplant infection.
Dissecting the neurocomputational bases of patch-switching

Abstract The survival and well-being of humans require solving the patch-switching problem: we must decide when to stop collecting rewards in a current patch and travel somewhere else where gains may be higher. Previous studies suggested that frontal regions are underpinned by several processes in the context of foraging decisions such as tracking task difficulty, and/or the value of exploring the environment. To dissociate between these processes, participants completed an fMRI patch-switching learning task inspired by behavioral ecology. By analyzing >11,000 trials collected across 21 participants, we found that the activation in the cingulate cortex was closely related to several patch-switching-related variables including the decision to leave the current patch, the encounter of a new patch, the harvest value, and the relative forage value. Learning-induced changes in the patch-switching threshold were tracked by activity within frontoparietal regions including the superior frontal gyrus and angular gyrus. Our findings suggest that frontoparietal regions shape patch-switching learning apart from encoding classical non-learning foraging processes. These findings provide a novel neurobiological understanding of how learning emerges neurocomputationally shaping patch-switching behavior with implications in real-life choices such as job selection and pave the way for future studies to probe the causal role of these neurobiological mechanisms.