Miracle-dz/UniFAR-FTUs huggingface dataset:
225Ac-H4py4pa for Targeted-Alpha-Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (, t1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10-6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest non-radioactive metal of the lanthanide series was adopted as a surrogate for 225Ac to enable a series of non-radioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La(py4pa)]- anion possessed a high degree of symmetry and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La(py4pa)]- complex also demonstrated a superb thermodynamic stability (log K[La(py4pa)]-~ 20.33, pLa = 21.0) compared to those of DOTA (log K[La(DOTA)]-~ 24.25, pLa = 19.2) or H2macropa (log K[La(macropa)]- = 14.99, pLa ~ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.
Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors

ABSTRACT Ebola virus (EBOV) can cause severe hemorrhagic fever in humans, and no approved treatment is currently available. Although several antibodies have achieved good protection in animal models, the potential emerging isolates of ebolavirus and the unknown effects of experimental antibodies in humans underscore the need to develop additional antibodies to address the threat of Ebola. Here, we isolated a series of memory B cell-derived monoclonal antibodies from healthy Chinese adults vaccinated with Ad5-EBOV. These antibodies were encoded by diverse germline genes and had high levels of somatic hypermutation. Most antibodies were cross-reactive and could bind at least two ebolavirus glycoproteins (GPs). Seven neutralizing antibodies were identified using HIV-EBOV GP-Luc pseudovirus, and they effectively neutralized authentic EBOV. In particular, monoclonal antibody 2G1 exhibited potent cross-neutralization against HIV-EBOV/SUDV/BDBV GP-Luc bearing different ebolavirus GPs. We used truncated GPs, competition assays, and software prediction to analyze seven neutralizing antibodies, which bound four different epitopes on GP. Importantly, three of these antibodies provided complete protection in mice when administered one day post-infection. Our study expands the list of candidate antibodies and the options for successfully treating ebolavirus infection.
Role of adiponectin in diabetes myocardial ischemia-reperfusion injury and ischemic postconditioning 1

Abstract Purpose Patients with diabetes are vulnerable to myocardial I/R (ischaemia/reperfusion) injury, but are not responsive to IPO (ischaemic post-conditioning). We hypothesized that decreased cardiac Adiponectin (APN) is responsible for the loss of diabetic heart sensitivity to IPO cardioprotecton. Methods Diabetic rats were subjected to I/R injury (30 min of LAD occlusion followed by 120 min of reperfusion). Myocardial infarct area was determined by TTC staining. Cardiac function was monitored by a microcatheter. ANP, 15-F2t-isoprostane, nitrotyrosine and MDA were measured by assay kits. Levels of p-Akt, total-Akt and GAPDH were determined by Western Blot. Results Diabetic rats subjected to myocardial IR exhibited severe myocardial infarction and oxidative stress injury, lower APN in the plasma and cardiac p-Akt expression ( P <0.05). IPO significantly attenuated myocardial injury and up-regulated plasma APN content and cardiac p-Akt expression in non-diabetic rats but not in diabetic rats. Linear correlation analysis showed that the expression of adiponectin was positively correlated with p-Akt and negatively correlated with myocardial infarction area ( P <0.01). Conclusion Protective effect of IPO was tightly correlated with the expression of adiponectin, exacerbation of I/R injury and ineffectiveness of IPO was partially due to the decline of adiponectin and inactivation of Akt in diabetes mellitus.
Recent Advance in Source, Property, Differentiation, and Applications of Infrapatellar Fat Pad Adipose-Derived Stem Cells

Infrapatellar fat pad (IPFP) can be easily obtained during knee surgery, which avoids the damage to patients for obtaining IPFP. Infrapatellar fat pad adipose-derived stem cells (IPFP-ASCs) are also called infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs) because the morphology of IPFP-ASCs is similar to that of bone marrow mesenchymal stem cells (BM-MSCs). IPFP-ASCs are attracting more and more attention due to their characteristics suitable to regenerative medicine such as strong proliferation and differentiation, anti-inflammation, antiaging, secreting cytokines, multipotential capacity, and 3D culture. IPFP-ASCs can repair articular cartilage and relieve the pain caused by osteoarthritis, so most of IPFP-related review articles focus on osteoarthritis. This article reviews the anatomy and function of IPFP, as well as the discovery, amplification, multipotential capacity, and application of IPFP-ASCs in order to explain why IPFP-ASC is a superior stem cell source in regenerative medicine.
The potential deployment of a pan-tuberculosis drug regimen in India: A modelling analysis

There is increasing interest in future, highly-potent ‘pan-TB’ regimens against tuberculosis (TB), that may be equally effective in both drug-susceptible and rifampicin-resistant (RR) forms of TB. Taking the example of India, the country with the world’s largest burden of TB, we show that adoption of these regimens could be: (i) epidemiologically impactful, and (ii) cost-saving to the national TB programme, even if the regimen itself is more costly than current TB treatment. Mathematical modelling suggests that deployment of a pan-TB regimen in 2022 would reduce the annual incidence of TB in 2030 by 23.9% [95% Bayesian credible intervals [CrI] 17.6–30.8%] if used to treat all TB cases, and by 2.30% [95% CrI 1.57–3.48%] if used to treat only RR-TB. Notably, with a regimen costing less than USD 359 (95% CrI 287–441), treating all diagnosed TB cases with the pan-TB regimen yielded greater cost-savings than treating just those diagnosed with RR-TB. One limitation of our approach is that it does not capture the risk of resistance to the new regimen. We discuss ways in which this risk could be mitigated using modern adherence support mechanisms, as well as drug sensitivity testing at the point of TB diagnosis, to prevent new resistant forms from becoming established. A combination of such approaches would be important for maximising the useful lifetime of any future regimen.
Stochastic simulation and statistical inference platform for visualization and estimation of transcriptional kinetics

Recent advances in single-molecule fluorescent imaging have enabled quantitative measurements of transcription at a single gene copy, yet an accurate understanding of transcriptional kinetics is still lacking due to the difficulty of solving detailed biophysical models. Here we introduce a stochastic simulation and statistical inference platform for modeling detailed transcriptional kinetics in prokaryotic systems, which has not been solved analytically. The model includes stochastic two-state gene activation, mRNA synthesis initiation and stepwise elongation, release to the cytoplasm, and stepwise co-transcriptional degradation. Using the Gillespie algorithm, the platform simulates nascent and mature mRNA kinetics of a single gene copy and predicts fluorescent signals measurable by time-lapse single-cell mRNA imaging, for different experimental conditions. To approach the inverse problem of estimating the kinetic parameters of the model from experimental data, we develop a heuristic optimization method based on the genetic algorithm and the empirical distribution of mRNA generated by simulation. As a demonstration, we show that the optimization algorithm can successfully recover the transcriptional kinetics of simulated and experimental gene expression data. The platform is available as a MATLAB software package at https://data.caltech. edu/records/1287.
Liver Transplantation for Colorectal and Neuroendocrine Liver Metastases and Hepatoblastoma. Working Group Report from the ILTS Transplant Oncology Consensus Conference.

Liver transplantation (LT) for unresectable colorectal liver metastases has long been abandoned because of dismal prognoses. After the dark ages, advances in chemotherapy and diagnostic imaging have enabled strict patient selection, and the pioneering study from the Oslo group has contributed to the substantial progress in this field. For unresectable neuroendocrine liver metastases, LT for patients who met the Milan criteria was able to achieve excellent long-term outcomes. The guidelines further adopted in the U.S. and Europe were based on these criteria. For hepatoblastoma, patients with unresectable and borderline-resectable disease are considered good candidates for LT; however, the indications are yet to be defined. In the budding era of transplant oncology, it is critically important to recognize the current status and unsolved questions for each disease entity. These guidelines were developed to serve as a beacon of light for optimal patient selection for LT and to set the stage for future basic and clinical studies.
Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016

Problem/Condition Autism spectrum disorder (ASD). Period Covered 2016. Description of System The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance program that provides estimates of the prevalence of ASD among children aged 8 years whose parents or guardians live in 11 ADDM Network sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). Surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by medical and educational service providers in the community. In the second phase, experienced clinicians who systematically review all abstracted information determine ASD case status. The case definition is based on ASD criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Results For 2016, across all 11 sites, ASD prevalence was 18.5 per 1,000 (one in 54) children aged 8 years, and ASD was 4.3 times as prevalent among boys as among girls. ASD prevalence varied by site, ranging from 13.1 (Colorado) to 31.4 (New Jersey). Prevalence estimates were approximately identical for non-Hispanic white (white), non-Hispanic black (black), and Asian/Pacific Islander children (18.5, 18.3, and 17.9, respectively) but lower for Hispanic children (15.4). Among children with ASD for whom data on intellectual or cognitive functioning were available, 33% were classified as having intellectual disability (intelligence quotient [IQ] ≤70); this percentage was higher among girls than boys (40% versus 32%) and among black and Hispanic than white children (47%, 36%, and 27%, respectively). Black children with ASD were less likely to have a first evaluation by age 36 months than were white children with ASD (40% versus 45%). The overall median age at earliest known ASD diagnosis (51 months) was similar by sex and racial and ethnic groups; however, black children with IQ ≤70 had a later median age at ASD diagnosis than white children with IQ ≤70 (48 months versus 42 months). Interpretation The prevalence of ASD varied considerably across sites and was higher than previous estimates since 2014. Although no overall difference in ASD prevalence between black and white children aged 8 years was observed, the disparities for black children persisted in early evaluation and diagnosis of ASD. Hispanic children also continue to be identified as having ASD less frequently than white or black children. Public Health Action These findings highlight the variability in the evaluation and detection of ASD across communities and between sociodemographic groups. Continued efforts are needed for early and equitable identification of ASD and timely enrollment in services.
Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging

Nitric oxide (NO) and S-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled receptor (GPCR) kinase 2 (GRK2) activity via S-nitrosylation of GRK2 at cysteine 340 (C340). This maintains GPCR homeostasis, including β-adrenergic receptors, through curbing receptor GRK2-mediated desensitization. Previously, we have developed a knockin mouse (GRK2-C340S) where endogenous GRK2 is resistant to dynamic S-nitrosylation, which led to increased GRK2 desensitizing activity. This unchecked regulation of cardiac GRK2 activity resulted in significantly more myocardial damage after ischemic injury that was resistant to NO-mediated cardioprotection. Although young adult GRK2-C340S mice show no overt phenotype, we now report that as these mice age, they develop significant cardiovascular dysfunction due to the loss of SNO-mediated GRK2 regulation. This pathological phenotype is apparent as early as 12 mo of age and includes reduced cardiac function, increased cardiac perivascular fibrosis, and maladaptive cardiac hypertrophy, which are common maladies found in patients with cardiovascular disease (CVD). There are also vascular reactivity and aortic abnormalities present in these mice. Therefore, our data demonstrate that a chronic and global increase in GRK2 activity is sufficient to cause cardiovascular remodeling and dysfunction, likely due to GRK2’s desensitizing effects in several tissues. Because GRK2 levels have been reported to be elevated in elderly CVD patients, GRK2-C340 mice can give insight into the aged-molecular landscape leading to CVD. NEW & NOTEWORTHY Research on G protein-coupled receptor kinase 2 (GRK2) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic GRK2 overactivity to further investigate the consequences of long-term GRK2 on cardiac function and structure. We report for the first time that chronic GRK2 overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.
Spatial complexity facilitates ordinal mapping with a novel symbol set

The representation of number symbols is assumed to be unique, and not shared with other ordinal sequences. However, little research has examined if this is the case, or whether properties of symbols (such as spatial complexity) affect ordinal learning. Two studies were conducted to investigate if the property of spatial complexity affects learning ordinal sequences. In Study 1, 46 adults made a series of judgements about two novel symbol sets (Gibson and Sunúz). The goal was to find a novel symbol set that could be ordered by spatial complexity. In Study 2, 84 adults learned to order nine novel symbols (Sunúz) with a paired comparison task, judging which symbol was ‘larger’ (whereby the larger symbol became physically larger as feedback), and were then asked to rank the symbols. Participants were assigned to either a condition where there was a relationship between spatial complexity and symbol order, or a condition where there was a random relationship. Of interest was whether learning an ordered list of symbols would be facilitated by the spatial complexity of the novel symbols. Findings suggest spatial complexity affected learning ability, and that pairing spatial complexity with relational information can facilitate learning ordinal sequences. This suggests that the implicit cognitive representation of number may be a more general feature of ordinal lists, and not exclusive to number per se.
Update on urine as a biomarker in cancer: a necessary review of an old story

ABSTRACT Introduction: Cancer causes thousands of deaths worldwide each year. Therefore, monitoring of health status and the early diagnosis of cancer using noninvasive assays, such as the analysis of molecular biomarkers in urine, is essential. However, effective biomarkers for early diagnosis of cancer have not been established in many types of cancer. Areas covered: In this review, we discuss recent findings with regard to the use of urine composition as a biomarker in eleven types of cancer. We also highlight the use of urine biomarkers for improving early diagnosis. Expert opinion: Urinary biomarkers have been applied for clinical application of early diagnosis. The main limitation is a lack of integrated approaches for identification of new biomarkers in most cancer. The utilization of urinary biomarker detection will be promoted by improved detection methods and new data from different types of cancers. With the development of precision medicine, urinary biomarkers will play an increasingly important clinical role. Future early diagnosis would benefit from changes in the utilization of urinary biomarkers.
Effectiveness of Nutrition Interventions in Vending Machines to Encourage the Purchase and Consumption of Healthier Food and Drinks in the University Setting: A Systematic Review

University food environments typically offer an abundance of unhealthy foods, including through vending machines. This review evaluated the effectiveness of nutrition interventions in vending machines in the university setting. Ten databases were searched for experimental studies published up to July 2019, evaluating nutrition interventions that aimed to encourage the purchase or consumption of healthier foods and drinks in vending machines in the university setting. In total, 401 articles were identified, and 13 studies were included. Studies were pre-post test (n = 7, 54%), randomized controlled trials (RCTs) (n = 5, 38%), and non-randomized controlled trial (n = 1, 8%). Most studies were from the USA (n = 10, 77%) and were published between 2014 and 2018 (n = 9, 69%). Eight interventions (62%) reported positive change in outcomes, including increased number/proportion of sales or revenue from healthier items (n = 6), improved adherence to guidelines for the ratio of healthy/unhealthy products available (n = 1), and improved consumer perception of items available (n = 1). Effective interventions involved the promotion, reduced pricing, increased availability, and/or optimized product placement of healthier items within vending machines. Strategies to improve the nutritional quality of food and drinks in vending machines are warranted. This may be achieved by making healthier options more available and promoting them; however, more robust intervention studies are needed to determine effectiveness.
Effectiveness of Ginger on Pain and Function in Knee Osteoarthritis: A PRISMA Systematic Review and Meta-Analysis.

BACKGROUND Ginger has been proposed as a complementary treatment for musculoskeletal pain. However, efficacy, type, and safety remains unclear. OBJECTIVES To determine the effectiveness of consumption or topical application of ginger for pain relief and knee function improvement in patients with knee osteoarthritis. STUDY DESIGN Systematic review with meta-analysis of randomized clinical trials. METHODS An electronic search was performed on Medline, Central, CINAHL, PEDro, SPORTDiscus, and LILACS databases. The eligibility criteria for selecting studies included clinical trials that compared consumption and/or topical ginger with placebo or other interventions for the pain relief and knee function in patients with medical diagnosis of knee osteoarthritis. RESULTS Seven clinical trials met the eligibility criteria, and for the quantitative synthesis, 4 studies were included. For the comparison capsules versus placebo, mean difference for pain was -7.88 mm; 95% confidence interval (CI), 11.92 to 3.85 (P = 0.00), and standard mean difference for knee function was -1.61 points; 95% CI, -4.30 to -1.09 (P = 0.24). For the comparison of topical ginger versus standard treatment, standard mean difference for pain was 0.79 mm; 95% CI, -1.97 to 0.39 (P = 0.19), and standard mean difference for knee function was -0.51 points; 95% CI, -1.15 to 0.13 (P = 0.12). LIMITATIONS The current evidence is heterogeneous and has a poor methodologic quality. CONCLUSIONS There is insufficient evidence to support the use of oral ginger compared with placebo in the pain relief and function improvement in patients with knee osteoarthritis. For other comparisons, no statistically significant differences were found. KEY WORDS Osteoarthritis, knee osteoarthritis, ginger, pain, randomized clinical trial, systematic review.
The effectiveness of spinal manipulation versus spinal manipulation in conjunction with core stabilisation exercises in the treatment of mechanical low back pain

Low back pain is estimated to effect 60-90% of the world's population sometime during their lives while 20-30% of people suffer from low back pain at any given time (Cassidy and Burton, 1992:3). Locally, epidemiological studies into low back pain have revealed incidence rates of 57.6% amongst black South Africans (Van der Meulen, 1997) and between 70 and 80% amongst Indians and Coloureds (Docrat, 1999). The use of spinal manipulation with the emphasis on restoring joint mobility, has been proven to be one of the most effective and cost effective approaches in the management low back pain of a mechanical origin (Di Fabio, 1992). McMorland (2000), showed in a study of 199 patients, that spinal manipulation resulted in an average of 52.5% and 52.9% reduction in low back pain and disability respectively. Panjabi (1992:1) has postulated a theory of a 'neutral zone' around which the passive lumbar spine operates. He describes the neutral zone as a region of intervertebral motion around the neutral posture where little resistance is offered by the passive spinal column. It is, according to Panjabi (1992:1), possible for this neutral zone to increase with injury to the spinal column or with weakness of stabilising muscles, which could result in low back pain. The trunk muscles therefore have to be able to co-contract isometrically to control the neutral zone and protect the spinal tissue from excessive motion (Richardson et aI.1990). The transversus abdominis muscle and multifidus muscle have been identified as playing an important role in the complex synergistic interaction of the trunk (Norris, 1995). The above concept involving muscles attempting to maintain a neutral zone is commonly referred to as 'core stabilisation' (Norris, 1995).