Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned ...by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with L-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of L- and D-amino acids by near-exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods.
The fundamental aim of this paper is to riddle out the joint space trajectory tracking problem for a fully actuated 9-Link bipedal robot while climbing the staircase using a faster and accurate fast ...terminal discrete-time sliding mode control. Second objective is to provide a more realistic and practical approach for contact modeling ensuring a much stable staircase walk. For contact modeling, we have proposed a novel fuzzy based impedance modulation approach considering a virtual spring-damper model with variable stiffness and damping coefficients. To obtain a discrete-time model, Euler’s method for discretization is considered after obtaining Lagrange’s dynamics. A higher control accuracy of order Δ
t
3
where Δ
t
is constant time step, can be achieved with fast terminal discrete-time sliding mode control in comparison to conventional discrete-time sliding mode control with controller accuracy of order Δ
t
2
. Brief comparison has been shown between conventional discrete-time controller and our proposed controller with same initial conditions and in same disturbance environment to corroborate robustness of the controllers. Delayed Estimation method is used to estimate the unknown disturbances. All simulations have been performed in MATLAB and Simulink to manifest the efficacy of our proposed approach.
Objectives
To describe, evaluate, and identify the characteristics, prognostic factors, and visual outcomes in patients with intraocular foreign body (IOFB) in a Latin American population.
Methods
A ...retrospective, observational case-series of patients with a diagnosis of IOFB. Variables analyzed included age, gender, initial and final best correct visual acuity (BCVA), ocular trauma score, intraocular pressure, mechanism of injury, material and number of IOFB, zone of injury, timing of primary repair and IOFB removal, complications, and follow up.
Results
Sixty-one patients with IOFB were identified of which 97% were male with a mean age of 37.9 years (SD 2.16). The most common IOFB location was intravitreal (43%). IOFBs were metallic in 78%, vegetal in 3%, and other materials in 11%. Primary repair and secondary IOFB removal were performed at a mean timepoint of 3 days and 5 days, respectively. Systemic and topical antibiotics were administered to all patients. The initial BCVA was 1.62 logMAR and the final was 0.6 logMAR, which was statistically significant (Pearson’s chi-squared test,
p
value 0.01). No cases of endophthalmitis were seen.
Conclusion
IOFB removal can be delayed when there are no signs of infection or evidence of retinal detachment, without an increased risk of endophthalmitis and a negative impact on visual outcomes. Use of topical and systemic antibiotics appear sufficient to prevent endophthalmitis in these cases.
To review systematically the diagnostic accuracy of various ocular signs for pediatric abusive head trauma (AHT).
Intraocular hemorrhages (IOH), perimacular retinal folds, traumatic retinoschisis and ...optic nerve sheath hemorrhages have been reported as cardinal signs of AHT. The evidence base supporting the accuracy of this interpretation, however, has not been systematically reviewed.
A systematic keyword search of MEDLINE, EMBASE, and Evidence-Based Medicine Reviews was conducted for original studies reporting ocular findings in AHT. Articles were graded using a checklist for systematic reviews of diagnostic accuracy.
The initial search yielded 971 articles, of which 55 relevant studies were graded, and 20 studies met inclusion criteria and were included in the review. The overall sensitivity of IOH for AHT was 75% and their specificity was 94%. Intraretinal hemorrhage at the posterior pole was the most common finding, although extensive, bilateral, and multilayered IOH were the most specific for AHT. Optic nerve sheath hemorrhages had a sensitivity and specificity for AHT of 72% and 71%, respectively. Traumatic retinoschisis and perimacular retinal folds were reported in 8% and 14% of AHT, respectively, but were not reported in other conditions.
Prospective, consecutive studies confirm that IOH in infants-particularly bilateral, extensive, and multilayered-are highly specific for AHT. Optic nerve sheath hemorrhages are significantly more common in AHT than in other conditions, in autopsy studies. Traumatic retinoschisis and perimacular folds are present in a minority of AHT, but rarely seen in other conditions.
Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single ...GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA-KOR-Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.
Through the one-bead two-compound (OB2C) ultra-high-throughput screening method, we discovered a new small-molecule compound LLS2 that can kill a variety of cancer cells. Pull-down assay and LC/MS-MS ...indicated that galectin-1 is the target protein of LLS2. Galectin-1 is known to be involved in the regulation of proliferation, apoptosis, cell cycle, and angiogenesis. Binding of LLS2 to galectin-1 decreased membrane-associated H-Ras and K-Ras and contributed to the suppression of pErk pathway. Importantly, combination of LLS2 with paclitaxel (a very important clinical chemotherapeutic agent) was found to exhibit synergistic activity against several human cancer cell lines (ovarian cancer, pancreatic cancer, and breast cancer cells)
Furthermore,
therapeutic study indicated that combination treatment with paclitaxel and LLS2 significantly inhibits the growth of ovarian cancer xenografts in athymic mice. Our results presented here indicate that the OB2C combinatorial technology is a highly efficient drug screening platform, and LLS2 discovered through this method can be further optimized for anticancer drug development.
.
The main goal of this narrative review was to examine the literature on the barriers that low-vision patients experience while utilizing low-vision care services (LVCS). Reviewing the difficulties or ...the barriers that an eye care professional (ECP) encounters when delivering the LVCS is also important. To review the studies about the people with visual impairment and the barriers they encounter in receiving the appropriate LVCS, and the articles discussing the barriers an ECP faces when providing LVCS, an electronic search was carried out using Google Scholar and PubMed. The inclusion criteria were all original articles published between 2012 and 2022 and the subjects who were visually impaired as per the criteria of the WHO and the studies that included the ECPs, to assess their perspectives regarding the LVCS being less approachable. A total of 12 studies met the inclusion criteria, and were reviewed further. Very few studies have been conducted in the last 10 years to investigate the challenges faced by the low-vision patients and the eye care practitioners. The most frequent barriers identified from the patients’ perspective were lack of knowledge, money, transportation, social acceptability and linkage with other health-related problems. Shortage of training, missed referrals, lack of LVCS and devices, and most importantly, lack of awareness were the barriers, according to the ECPs. The majority of the barriers were simple to overcome. So, if the medical community wants to, they can be easily removed. Therefore, the purpose of this review was to describe and highlight such barriers.
AbstractIntroduction and ObjectivesAKI is known to be associated with increased risk of mortality, however limited information is available on how AKI impacts healthcare costs and resource ...utilization in hospitalized patients with cirrhosis. Previous studies have had variable definitions of AKI, resulting in inconsistent reporting of the true impact of AKI in patients with cirrhosis. MethodsData from the Nationwide Inpatient Sample (NIS) which contains data from 44 states and 4378 hospitals, accounting for over 7 million discharges were analyzed. The inclusion data were all discharges in the 2012 NIS dataset with a discharge diagnosis of cirrhosis. ResultsA total of 32,605 patients were included in the analysis, incidence of AKI was 12.12% in patients with cirrhosis. Crude mortality was much higher for patients with cirrhosis and AKI (14.9% vs. 1.8%, OR 9.42, p< 0.001) than for patients without AKI. In addition, mean LOS was longer (8.5 vs. 4.3 days, p< 0.001) and median total hospital charges were higher for patients with AKI ($43,939 vs. $22,270, p< 0.001). In multivariate logistic regression, controlling for covariates and mortality risk score, sepsis, ascites and SBP were predictors of AKI. ConclusionsAKI is relatively common in hospitalized patients with cirrhosis. Presence of AKI results in significantly higher inpatient mortality as well as LOS and resource utilization. Median hospitalization cost was twice as high in AKI patients. Early identification of patients at high risk for AKI should be implemented to reduce mortality and contain costs. Prognosis could be enhanced by utilizing biomarkers which could rapidly detect AKI.
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