OpenFold: retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization.

AlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (1) tackle new tasks, like protein-ligand complex structure prediction, (2) investigate the process by which the model learns and (3) assess the model's capacity to generalize to unseen regions of fold space. Here we report OpenFold, a fast, memory efficient and trainable implementation of AlphaFold2. We train OpenFold from scratch, matching the accuracy of AlphaFold2. Having established parity, we find that OpenFold is remarkably robust at generalizing even when the size and diversity of its training set is deliberately limited, including near-complete elisions of classes of secondary structure elements. By analyzing intermediate structures produced during training, we also gain insights into the hierarchical manner in which OpenFold learns to fold. In sum, our studies demonstrate the power and utility of OpenFold, which we believe will prove to be a crucial resource for the protein modeling community.

One-Pot Synthesis of Polycyclic 4,5-Dihydropyridazine-3(2H)-ones by Inverse Electron-Demand Diels-Alder (IEDDA) Reactions from Alkenes.

In the classical Inverse Electron-Demand Diels-Alder (IEDDA) reactions between alkenes and tetrazines, 4,5-dihydropyridazines are formed. 4,5-Dihydropyridazines are rapidly converted to the more energetically stable 1,4-dihydropyridazines by 1,3-prototropic isomerization. In this study, instead of 1,4-dihydropyridazines, 4,5-dihydropyridazine-3(2H)-ones were obtained as a result of IEDDA reactions between tetrazines with leaving groups at the 3,6-positions, and norbornene and barrelene-derived polycyclic alkenes in the presence of moisture in air or solvent. To show that this new method works not only on strained polycyclic alkenes but also on monocyclic and linear alkenes, the corresponding 4,5-dihydropyridazine-3(2H)-ones were obtained in high yields from the reactions performed with styrene and cyclopentene as well. The chemical structures of the polycyclic 4,5-dihydropyridazine-3(2H)-ones were determined by NMR and HRMS analyses. In addition, the exact structures of the polycyclic 4,5-dihydropyridazine-3(2H)-ones were also experimentally proven by converting them to pyridazine-3(2H)-ones known in the literature.

Transcatheter Aortic Valve Implantation in Bicuspid Aortic Valve Patients with Coagulation Factor 7 and 11 Deficiency and Atrial Fibrillation.

Although transcatheter aortic valve implantation (TAVI), which is a less invasive standard treatment for aortic stenosis than surgery, has been recommended even in low-risk patients, its effectiveness in bicuspid aortic valve is still unclear. Cardiac surgery has been proven to cause serious complications in hematological diseases with factor deficiency or bleeding diathesis. In this case, which is the first in the literature to our knowledge, we tried to present the successful TAVI procedure in a young patient with bicuspid aortic stenosis and factor 7, 11 deficiency complicated by atrial fibrillation.

Pistachio genomes provide insights into nut tree domestication and ZW sex chromosome evolution.

Pistachio is a nut crop domesticated in the Fertile Crescent and a dioecious species with ZW sex chromosomes. We sequenced the genomes of Pistacia vera cultivar (cv.) Siirt, the female parent, and P. vera cv. Bagyolu, the male parent. Two chromosome-level reference genomes of pistachio were generated, and Z and W chromosomes were assembled. The ZW chromosomes originated from an autosome following the first inversion, which occurred approximately 8.18 Mya. Three inversion events in the W chromosome led to the formation of a 12.7-Mb (22.8% of the W chromosome) non-recombining region. These W-specific sequences contain several genes of interest that may have played a pivotal role in sex determination and contributed to the initiation and evolution of a ZW sex chromosome system in pistachio. The W-specific genes, including defA, defA-like, DYT1, two PTEN1, and two tandem duplications of six VPS13A paralogs, are strong candidates for sex determination or differentiation. Demographic history analysis of resequenced genomes suggest that cultivated pistachio underwent severe domestication bottlenecks approximately 7640 years ago, dating the domestication event close to the archeological record of pistachio domestication in Iran. We identified 390, 211, and 290 potential selective sweeps in 3 cultivar subgroups that underlie agronomic traits such as nut development and quality, grafting success, flowering time shift, and drought tolerance. These findings have improved our understanding of the genomic basis of sex determination/differentiation and horticulturally important traits and will accelerate the improvement of pistachio cultivars and rootstocks.

Predictors and Prognostic Implications of Myocardial Injury After Transcatheter Aortic Valve Replacement.

Myocardial injury (MI) is not unusual after transcatheter aortic valve replacement (TAVR). To determine precipitating factors and prognostic outcomes of MI after TAVR, we retrospectively investigated relationships between MI after TAVR and aortic root dimensions, baseline patient characteristics, echocardiographic findings, and procedural features. Of 474 patients who underwent transfemoral TAVR for severe aortic stenosis in our tertiary center from June 2011 through June 2018, 188 (mean age, 77.7 ± 7.7 yr; 96 women [51%]) met the study inclusion criteria. Patients were divided into postprocedural MI (PMI) (n=74) and no-PMI (n=114) groups, in accordance with high-sensitivity troponin T levels. We found that MI risk was associated with older age (odds ratio [OR]=1.054; 95% CI, 1.013-1.098; P=0.01), transcatheter heart valve type (OR=10.207; 95% CI, 2.861-36.463; P=0.001), distances from the aortic annulus to the right coronary artery ostium (OR=0.853; 95% CI, 0.731-0.995; P=0.04) and the left main coronary artery ostium (OR=0.747; 95% CI, 0.616-0.906; P=0.003), and baseline glomerular filtration rate (OR=0.985; 95% CI, 0.970-1.000; P=0.04). Moreover, the PMI group had a longer time to hospital discharge (P=0.001) and a higher permanent pacemaker implantation rate (P=0.04) than did the no-PMI group. Our findings may enable better estimation of which patients are at higher risk of MI after TAVR and thus improve the planning and course of clinical care.

From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts.

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M-1, encompassing two conformers M-1(+) and M-1(-), trap CX4 (X=Cl, Br) to give CX4 ⊂M-1(+) and CX4 ⊂M-1(-), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M-1 via a M-1(+)→M-1(-)→CBr4 ⊂M-1(-) pathway corresponding to conformational selection. For M-1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line-shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.

Multivalent C-H⋠⋠⋠Cl/Br-C Interactions Directing the Resolution of Dynamic and Twisted Capsules.

In this work, we report a mechanism by which stereoisomeric and twisted capsules P/M-1 direct their dynamic chirality in the presence of haloalkane guests. The capsule comprises a static, but twisted, cage that is linked to a dynamic tris(2-pyridylmethyl)amine (TPA) lid at its top. From the results of experimental (NMR spectroscopy and X-ray crystallography) and computational (DFT) studies, the TPA lid was shown to assume clockwise (+) and counterclockwise (-) folds with diastereomeric (but racemic) capsules M-1(+) and M-1(-) interconverting at a rapid rate (ΔG≠ 189K =9.1 kcal mol-1 ). The relative stability of the capsules was found to be a function of guest(s) residing in their interior (243/262 Å3 ) with small CH2 Cl2 (61 Å3 ) yielding roughly equal population of diastereomeric inclusion complexes. Larger guests, such as CCl4 (89 Å3 ) and CBr4 (108 Å3 ), however, formed M-1(-)⊂CX4 at the expense of M-1(+)⊂CX4 in circa 3:1 ratio. To account for the observation, theory (DFT:M06-2X/6-31+G*) and experiments (1 H NMR spectroscopy) were used to deduce that CX4 guests become localized inside the twisted cage of the capsule by forming a C-X⋅⋅⋅π halogen bond [Nc =d/(rH +rX )=0.91-0.92] with the benzene "floor" while encountering electrostatic repulsions with closer naphthalimide boundaries. At last, the TPA lid used its central methylene hydrogens to establish, within the M-1(-)⊂CX4 , three stabilizing C-H⋅⋅⋅X-C interactions with the guest. The same C-H⋅⋅⋅X-C interactions, however, became weaker (or possibly vanished) after the conformational reorganization of the lid and the formation of less stable M-1(+)⊂CX4 complex. On individual basis, C-H⋅⋅⋅X-C intermolecular contacts are weak and hardly detectable in the solution phase. In the case of capsule P/M-1, however, these contacts were multivalent and altogether strong enough to direct the host's dynamic chirality.

Inhibition of acetylcholinesterase and butyrylcholinesterase with uracil derivatives: kinetic and computational studies.

Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) inhibitors are interesting compounds for different therapeutic applications, among which Alzheimer's disease. Here, we investigated the inhibition of these cholinesterases with uracil derivatives. The mechanism of inhibition of these enzymes was observed to be due to obstruction of the active site entrance by the inhibitors scaffold. Molecular docking and molecular dynamics (MD) simulations demonstrated the possible key interactions between the studied ligands and amino acid residues at different regions of the active sites of AChE and BuChE. Being diverse of the classical AChE and BuChE inhibitors, the investigated uracil derivatives may be used as lead molecules for designing new therapeutically effective enzyme inhibitors.

Surgical treatment of hydatid cyst infiltrating into myocardium and causing mitral valve regurgitation.

Hydatid cyst is a parasitic disease caused by Echinococcus granulosus. It is endemic in Asia, Africa, South America, and the Mediterranean region including Turkey. Cardiac involvement is rare. Surgery is the definitive treatment of cardiac hydatid cysts; however, to avoid recurrence after surgery, medical therapy should be also continued. Left ventricular free wall is the most common location, followed by the right ventricle and interventricular septum. Involvement of mitral valve is extremely rare. Herein, we present a case of hydatid cyst with myocardial involvement leading to severe mitral valve regurgitation which was successfully treated with surgery.

Characterization of hawthorn (Crataegus spp.) genotypes by SSR markers.

Hawthorn (Crataegus spp.) is an edible wild fruit that is used in traditional medicine, landscape studies, and food and beverage industries in many countries. It is an important wild plant species in Turkey and is numerous in the Yozgat Province. Genetic and breeding studies on hawthorn are very limited. Therefore, we aimed to characterize 91 hawthorn genotypes using simple sequence repeat (SSR) markers. The SSRs were developed from apple and pear and were screened in hawthorn for amplification and polymorphisms. A total of 265 alleles were detected from thirty-two SSR primer pairs, and those were used to identify genetic relationships. The number of alleles ranged from 2 to 21 alleles per locus with a mean value of 8.28. The Hi05b09 locus showed the highest allele number (Na = 21). The polymorphism information content (PIC) values ranged from 0.16 (CH03d10) to 0.89 (C6554) with a mean value of 0.60. An Unweighted Pair Group Method with Arithmetic Average method was used to cluster the genotypes, and four major clusters were obtained from the amplification of the SSRs. STRUCTURE software identified four populations (ΔK = 4) and eight sub-populations (ΔK = 8), and four major clusters similar results to UPGMA analysis. Our study showed that the SSR markers could be utilized as a reliable tool for the determination of genetic variations and relationships of hawthorn genotypes. A basic molecular analysis on the hawthorn genotypes identified in this study will promote the collection of germplasm collection and the selection of parents' in future cross-breeding studies.

Effects of aryl methanesulfonate derivatives on acetylcholinesterase and butyrylcholinesterase.

There is a dire need for new treatments for Alzheimer's disease (AD). Principal drugs have reached maturity, and the number of people affected by AD is growing at a rapid rate. After years of research and many clinical trials, only symptomatic treatments are available. An effective disease-modifying drug for AD needs to be discovered. The research presented in this paper aims to facilitate in the discovery of new potential targets that could help in the ongoing AD research. Aryl methanesulfonate derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. IC50 values between 0.660 and 3.397 µM against AChE and 0.885 and 2.596 µM against BuChE were obtained.

Coronary Artery Dominance May Predict Future Risk of Atrial Fibrillation.

BACKGROUND: Ischemia of the atria and conductive system of the heart results in greater atrial electrophysiological changes and propensity for atrial fibrillation. P wave duration and dispersion have been proposed to be useful for the prediction of paroxysmal atrial fibrillation (PAF). This study aimed to investigate the effect of coronary artery dominance on P wave duration and dispersion. METHODS: The study population included 194 patients with left dominant circulation (LDC) and 200 age- and gender-matched controls with right dominant circulation (RDC) and without coronary artery disease based on invasive coronary angiography findings. P wave dispersion (PWD) was defined as the difference between the maximum and minimum P wave duration. Arrhythmias were identified by 24-hour Holter electrocardiogram at 3 years of follow-up. RESULTS: PWD was significantly prolonged in the patients with LDC compared to the controls with RDC (p = 0.001). There were positive correlations between PWD and age (r: 0.502, p = 0.009), left ventricular mass (LVM) (r: 0.614, p = 0.001), LVM index (r: 0.727, p < 0.001) and left atrium (LA) diameter (r: 0.558, p = 0.003) in the LDC group. Multivariate logistic regression analysis showed that age, LVM index, LA diameter and LDC were independent predictors of prolonged PWD. At 3 years of follow-up, 7 (3.9%) patients with LDC and 1 (0.5%) patient with RDC had PAF in Holter electrocardiogram (p < 0.001). CONCLUSIONS: LDC could lead to an increased risk of atrial fibrillation through prolonged PWD. We recommend following up these patients to assess the development of atrial fibrillation.

Coexistence of Gitelman Syndrome and Hypertrophic Cardiomyopathy in a Pregnant Woman.

Gitelman syndrome (GS) is transmitted as an autosomal recessive trait and characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The symptoms and severity of the disease can vary greatly from one person to another and can range from mild to severe. Sudden cardiac arrest has been reported occasionally as well. Here, for the first time, we reported a 34-year-old pregnant GS woman who was diagnosed to have hypertrophic obstructive cardiomyopathy during her cardiac examination for the complaints of palpitation and presyncope.

Evaluation of QT dispersion and T-peak to T-end interval in patients with early-stage sarcoidosis.

INTRODUCTION AND AIM: Sarcoidosis increases inhomogeneity in ventricular repolarization due to the presence of sarcoid granuloma, which significantly correlates with ventricular fibrillation. Various studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (T-peak to T-end [Tpe] interval) may correspond to the transmural dispersion of repolarization and that increased Tpe interval and Tpe/QT ratio are associated with malignant ventricular arrhythmias. The present study hypothesized that QT and Tpe intervals are significantly prolonged in sarcoidosis patients without apparent cardiac involvement. METHODS: The study population consisted of 54 patients (37 female; mean age 43.4±10.6 years) under follow-up for sarcoidosis and 56 healthy subjects (37 female; mean age 42.4±8.6 years). RESULTS: There was no statistically significant difference between the groups in maximum QT interval, QT dispersion or corrected QT (QTc) interval, but QTc dispersion and Tpe interval were significantly prolonged in the sarcoidosis group compared to the control group (QTc dispersion 59.9±22.5 and 44.4±23.8, respectively, p=0.001; Tpe interval 79.4±9.3 and 70.7±7.03, respectively, p<0.001). We also found that the Tpe/QT ratio was significantly higher in sarcoidosis patients compared to the control group (0.21±0.02 and 0.18±0.23, respectively, p<0.001). CONCLUSION: Our study revealed that QTc dispersion, Tpe and Tpe/QT ratio were greater in sarcoidosis patients compared to the control group. To our knowledge, the present study is the first to use Tpe interval analysis in patients without cardiac involvement in sarcoidosis. Tpe interval and Tpe/QT ratio may be promising markers for cardiovascular morbidity and mortality due to ventricular arrhythmias in patients with and without cardiac involvement in sarcoidosis.

Quadricuspid Aortic Valve Associated with Aortic Regurgitation, Mitral Regurgitation, and Aortic Dilatation.

The quadricuspid aortic valve (QAV) is a very uncommon congenital malformation with an estimated incidence of 0.003% to 0.043% of all congenital heart diseases. Combinations of QAV with several different congenital malformations have been described. The case is reported of a type A QAV associated with moderate aortic regurgitation, mild mitral regurgitation, and ascending aorta dilatation. This interesting case was referred for close follow up.

Lichenoid type cutaneous hyperpigmentation induced by nebivolol.

Cutaneous hyperpigmentation is a common and well-defined side effect of many drugs, such as non-steroidal anti-inflammatory drugs, beta-blockers, and tetracyclines, but to the best of our knowledge there is no case of skin discoloration related to nebivolol in the literature. Presently described is lichenoid type cutaneous hyperpigmentation in a 46-year-old female patient. Hyperpigmentation emerged 3 months after initiating use of nebivolol and resolved after cessation of drug use. It was concluded that effect emerged as result of therapeutic doses of nebivolol.

An unusual presentation of papillary fibroelastoma originating from right ventricular outflow tract.

Papillary fibroelastomas (PFEs) are primary cardiac tumors with a benign and avascular nature. Majority of the PFEs are originated from the valvular endocardium, while the most common site is aortic valve. In this case, we present a patient with multiple PFEs originating from the right ventricular outflow tract who was admitted to our clinic with exertional dyspnea. As far as we know, this is the first case of this unusual presentation of multiple PFEs and also had a history of breast cancer and permanent pacemaker reported in the literature.

Comparison between fractional flow reserve and visual assessment for moderate coronary artery stenosis.

BACKGROUND: Fractional flow reserve (FFR) is an interventional diagnostic method, based on intracoronary pressure measurement, used for the assessment of the severity of coronary artery stenoses. AIM: Our study aimed to compare visual measurements made by multiple observers with FFR measurement in the assessment of angiographically moderate coronary artery stenosis. METHODS: The angiographic images of moderate coronary artery lesions of 359 patients enrolled in the study were interpreted independently by three interventional cardiologists assigned as observers (O1, O2, O3). RESULTS: In FFR, 37.9% were haemodynamically significant, while 62.1% were insignificant. 40.3% of the lesions were considered severe by O1, 39.9% by O2, and 44.4% by O3. When we compare the FFR results to the observers' decisions about lesion severity, the serious lesion percentages of all three observers were different both from each other and from the FFR result, at a statistically significant level (respectively, p < 0.001, p < 0.001). The kappa analysis performed to check the agreement between the observers' decisions and FFR revealed significant difference between FFR results and the decisions made by all observers (p < 0.001). The kappa agreement analysis performed by matching observers' decisions in pairs revealed a good agreement between O1 and O2 and a moderate agreement between O2 and O3 as well as O1 and O3, although there was still a significant disagreement between all pairs of observers (p < 0.001). CONCLUSIONS: Visual assessment, even when performed by experienced interventional cardiologists, does not yield similar results with FFR procedure in the process of determination of the functional importance of moderately severe coronary artery stenoses.

Successful simultaneous ipsilateral stenting of common iliac artery stenosis and transfemoral aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) was designed to treat elderly patients with severe aortic stenosis at high risk for surgery, and is most commonly performed with retrograde approach through femoral arteries. However, in up to 30% of cases, it is either not possible to use this access route or it is considered to have high risk of vascular injury. Alternative approaches have been described for patients with no suitable femoral access: trans-subclavian, transaortic, or direct aortic access; however, since the introduction of new valves deployed with low-profile delivery systems, another alternative transcatheter approach has been discovered. Presently described is experience in 2 cases in which patients were treated with transfemoral TAVR using Edwards SAPIEN 3 transcatheter heart valves immediately following ipsilateral common iliac artery stenting.

Novel eugenol derivatives: Potent acetylcholinesterase and carbonic anhydrase inhibitors.

Eugenol was used as starting material to obtain some phenolic compounds. The synthesis of these phenolic compounds was performed in a two-step procedure. The structures of the formed products (novel eugenol derivatives 1-6) have been determined on the basis of NMR spectroscopy and other spectroscopic methods. The compounds were tested in terms of carbonic anhydrase (CA) inhibition potency. Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes, which catalyse the reaction between carbon dioxide (CO2) and water (H2O), to generate bicarbonate (HCO3-) and protons (H+). CO2, HCO3- and H+ are essential molecules and ions for many important physiologic processes occurring in all living organisms. Acetylcholinesterase (AChE, E.C.3.1.1.7) is found in high concentrations in the red blood cells and brain. Novel eugenol derivatives (1-6) were tested for the inhibition of two cytosolic CA isoforms I, and II (hCA I, and II) and AChE. These compounds demonstrated effective inhibitory profiles with Ki values in ranging of 113.48-738.69nM against hCA I, 92.35-530.81nM against hCA II, and 90.10-379.57nM against AChE, respectively. On the other hand, acetazolamide clinically used as CA inhibitor, shoed Ki value of 594.11nM against hCA I, and 120.68nM against hCA II, respectively. Also, AChE was inhibited by tacrine as an AChE inhibitor at the 71.18nM level.