N 2-(7-Bromo-9-butyl-9H-carbazol-2-yl)-9,9-diethyl-N 2,N 7,N 7-triphenyl-9H-fluorene-2,7-diamine

In the title mol­ecule, C51H46BrN3, the central fluorene residue is planar (r.m.s. deviation = 0.0203 Å), as is the carbazole system (r.m.s. deviation = 0.0154 Å), and these groups are almost orthogonal [dihedral angle = 79.72 (3)°]. The three-dimensional architecture is consolidated by C—H⋯π inter­actions. The butyl substituent is disordered with two sites resolved for the terminal propyl atoms; the major component had a site-occupancy factor of 0.686 (3)

N-(9,9-Dipropyl-9H-fluoren-2-yl)-7-(piperidin-1-yl)-2,1,3-benzothia­diazol-4-amine

In the title compound, C30H34N4S, each of the benzothia­diazole and fluorene fused ring systems is almost planar (r.m.s. deviations = 0.010 and 0.013 Å, respectively) and they are inclined to each other with a dihedral angle of 61.69 (3)°; the S atom is directed away from the rest of the mol­ecule. Each of the benzothiadiazole ring N atoms forms a significant intra­molecular contact, i.e. N—H⋯N or C—H⋯N. In the crystal, linear supra­molecular chains along the c axis are generated by C—H⋯N inter­actions involving the tertiary amine N atom

N,N-Dimethyl-4-[(E)-2-(3,6,7-tribromo-9-butyl-9H-carbazol-2-yl)ethen­yl]aniline

In the title mol­ecule, C26H25Br3N2, a dihedral angle of 6.15 (10)° is present between the carbazole and benzene ring systems with an E conformation about the C=C bond [1.335 (4) Å]. The butyl group is almost perpendicular to the carbazole plane [C—N—C—C torsion angle = −98.7 (3)°]. In the crystal, supra­molecular double chains along [-7,18,-16] are formed via C—H⋯Br and π–π inter­actions [centroid(carbazole five-membered ring)⋯centroid(carbazole six-membered ring) distance = 3.6333 (13) Å]

4,4′-Dibromo-2-nitro­biphen­yl

The title compound, C12H7Br2NO2, a biphenyl derivative, displays a twisted conformation with the two benzene rings making a dihedral angle of 55.34 (14)°. The dihedral angle between the nitro group and its parent benzene ring is 26.8 (2)°. The crystal structure is stabilized by inter­molecular C—H⋯Br and C—H⋯O inter­actions, which lead to the formation of chains propagating along the c-axis direction

2,3,6,7-Tetra­bromo-9-butyl-9H-carbazole

In he title compound, C16H13Br4N, the carbazole skeleton is nearly planar [maximum deviation = 0.026 (4) Å] and makes a dihedral angle of 73.8 (4)° with the butyl chain. The butyl chain adopts a trans conformation. In the crystal, mol­ecules are linked by π–π stacking inter­actions [centroid–centroid distance = 3.559 (2) Å]

Increased C-reactive protein is associated with the severity of thoracic radiotherapy-induced cardiomyopathy

Background: Irradiation of the heart during cancer radiotherapy is associated with a dose-dependent risk of heart failure. Animal studies have demonstrated that irradiation leads to an inflammatory response within the heart as well as a reduction in cardiac reserve. In the current study we aimed to evaluate whether inflammatory biomarkers correlated with changes in cardiac function and reserve after radiotherapy for breast or lung cancer. Methods and results: We studied 25 subjects with a history of breast or lung cancer without a prior diagnosis of cardiovascular disease or heart failure, 1.8 years [0.4–3.6] post-radiotherapy involving at least 5 Gray (Gy) to at least 10% of the heart. High-sensitivity C-reactive protein (CRP) was abnormal (≥2 mg/L) in 16 (64%) subjects. Cardiac function and reserve was measured with Doppler echocardiography before and after exercise and defined as left-ventricular ejection fraction (LVEF), early diastolic mitral annulus velocity (e’), and increase in LV outflow tract velocity time integral cardiac output (cardiac reserve) with exercise. Subjects with abnormal CRP had significantly lower LVEF (51 [44–59] % vs 61 [52–64] %, P = 0.039), lower e’ (7.4 [6.6–7.9] cm/sec vs 9.9 [8.3–12.0] cm/sec, P = 0.010), and smaller cardiac reserve (+ 1.5 [1.2–1.7] L/min vs + 1.9 [1.7–2.2] L/min, P = 0.024). Conclusion: Elevated systemic inflammation is associated with impaired left-ventricular systolic and diastolic function both at rest and during exercise in subjects who have received radiotherapy with significant incidental heart dose for the treatment of cancer

Naturally occurring genetic variants in the oxytocin receptor alter receptor signaling profiles

The hormone oxytocin is commonly administered during childbirth to initiate and strengthen uterine contractions and prevent postpartum hemorrhage. However, patients have wide variation in the oxytocin dose required for a clinical response. To begin to uncover the mechanisms underlying this variability, we screened the 11 most prevalent missense genetic variants in the oxytocin receptor

A cryptic pocket in Ebola VP35 allosterically controls RNA binding

Protein-protein and protein-nucleic acid interactions are often considered difficult drug targets because the surfaces involved lack obvious druggable pockets. Cryptic pockets could present opportunities for targeting these interactions, but identifying and exploiting these pockets remains challenging. Here, we apply a general pipeline for identifying cryptic pockets to the interferon inhibitory domain (IID) of Ebola virus viral protein 35 (VP35). VP35 plays multiple essential roles in Ebola\u27s replication cycle but lacks pockets that present obvious utility for drug design. Using adaptive sampling simulations and machine learning algorithms, we predict VP35 harbors a cryptic pocket that is allosterically coupled to a key dsRNA-binding interface. Thiol labeling experiments corroborate the predicted pocket and mutating the predicted allosteric network supports our model of allostery. Finally, covalent modifications that mimic drug binding allosterically disrupt dsRNA binding that is essential for immune evasion. Based on these results, we expect this pipeline will be applicable to other proteins