Persistent Reverse End Diastolic Flow in Fetal Middle Cerebral Artery: A Rare Finding with Poor Outcomes.

Doppler findings of persistent reverse end-diastolic flow (PREDF) in a fetal middle cerebral artery (MCA) are a very rare sonographic finding and are a marker of poor fetal condition. This finding often leads to intrauterine fetal death or early neonatal death. Reverse end-diastolic flow in the middle cerebral artery is an advanced hemodynamic event. Fetal cerebral circulation normally has a high impedance; in the event of fetal hypoxemia, impedance decreases, resulting in the central redistribution of blood flow to vital organs, which maintains the oxygen delivery to the brain. Reverse flow in the middle cerebral arteries describes the loss of this autoregulatory process. PREDF is a sequence that occurs due to increased extracranial or intracranial pressure. Previous case reports mentioned intracranial hemorrhage, fetal growth restriction, fetal anemia, and fetal hepatic abnormalities as problems leading to PREDF. This condition presumably arises due to cerebral edema associated with severe hypoxemia. We reported Doppler findings of PREDF MCA in a 33-year-old female patient at 30 weeks gestation who was referred to the hospital with severe preeclampsia accompanied by fetal growth restriction and oligohydramnios. A cesarean section was performed due to severe preeclampsia and a low bishop score. Hypotheses on various etiologies and their association with intrauterine/neonatal death as well as the best management still require further investigation.

Clinical and Management Dilemmas Concerning Early-Stage Cervical Cancer in Pregnancy - A Case Report.

Background: Cervical cancer in pregnancy is rare and its management remains a formidable challenge. Clinical upstaging is a serious concern. Presentation may mimic pregnancy-related conditions, thus delaying diagnosis and leading to an advanced stage at presentation. In addition, concerns regarding chemotherapy safety in pregnancy may hinder its administration. Definitive therapy may also be delayed due to pregnancy. Case Report: A 37-year-old G3P2A0 10-11 weeks pregnant woman was diagnosed with stage IB2 cervical cancer. We originally planned to perform neoadjuvant chemotherapy with paclitaxel 175mg/m2 and carboplatin 6 AUC every 21 days followed by caesarean section and radical hysterectomy. However, preoperatively, the tumor had grown further and progressed to stage IIB. Postpartum radiotherapy was thus indicated. Lower segmental caesarean section along with bilateral salpingectomy and ovarian transposition were performed. Radiotherapy was administered through external beam radiation therapy and brachytherapy. The patient delivered a small for gestational age male baby with no abnormalities. At 2-month follow-up, the infant appeared generally healthy. Conclusion: Cancer diagnosis during pregnancy adversely impacts women's physical and psychological states. Symptoms may mimic pregnancy-related conditions, thus delaying diagnosis. Its management involves a multidisciplinary team to protect both maternal and fetal health.

Analysis of Clinical Profiles and Echocardiographic Cardiac Outcomes in Peripartum Cardiomyopathy (PPCM) vs. PPCM with Co-Existing Hypertensive Pregnancy Disorder (HPD-PPCM) Patients: A Systematic Review and Meta-Analysis.

Peripartum cardiomyopathy (PPCM) is a form of new-onset heart failure that has a high rate of maternal morbidity and mortality. This was the first study to systematically investigate and compare clinical factors and echocardiographic findings between women with PPCM and co-incident hypertensive pregnancy disorders (HPD-PPCM) and PPCM-only women. We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) framework. We used four databases and a single search engine, namely PubMed/Medline, Scopus, Web of Science, and Cochrane. We used Cochrane Risk of Bias (RoB) 2.0 for quality assessment. Databases were searched for relevant articles published from 2013 to the end of April 2023. The meta-analysis used the DerSimonian-Laird random-effects model to analyze the pooled mean difference (MD) and its p-value. We included four studies with a total of 64,649 participants and found that systolic blood pressure was significantly more likely to be associated with the PPCM group than the HPD-PPCM group (SMD = -1.63) (95% CI; -4.92,0.28, p = 0.01), while the other clinical profiles were not significant. HPD-PPCM was less likely to be associated with LVEF reduction (SMD = -1.55, [CI: -2.89, -0.21], p = 0.02). HPD-PPCM was significantly associated with less LV dilation (SMD = 1.81; 95% (CI 0.07-3.01), p = 0.04). Moreover, HPD-PPCM was less likely to be associated with relative wall thickness reduction (SMD = 0.70; 95% CI (-1.08--0.33), p = 0.0003). In conclusion, PPCM and HPD-PPCM shared different clinical profiles and remodeling types, which may affect each disease's response to pharmacological treatment. Patients with HPD-PPCM exhibited less eccentric remodeling and seemed to have a higher chance of recovering their LV ejection fraction, which means they might not benefit as much from ACEi/ARB and beta-blockers. The findings of this study will guide the development of guidelines for women with PPCM and HPD-PPCM from early detection to further management.

Computational benchmarking of putative KIFC1 inhibitors.

The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo-bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell-targeting weapon. The kinesin-14 motor protein KIFC1 is a minus end-directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever-increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in-depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first-of-kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision-making in the selection and design of potent inhibitors.

Donor acceptor fluorophores: synthesis, optical properties, TD-DFT and cytotoxicity studies.

Donor-π-acceptor (D-π-A) fluorophores consisting of a donor unit, a π linker, and an acceptor moiety have attracted attention in the last decade. In this study, we report the synthesis, characterization, optical properties, TD-DFT, and cytotoxicity studies of 17 near infrared (NIR) D-π-A analogs which have not been reported so far to the best of our knowledge. These fluorophores have chloroacrylic acid as the acceptor unit and various donor units such as indole, benzothiazole, benzo[e]indole, and quinoline. The fluorophores showed strong absorption in the NIR (700-970 nm) region due to their enhanced intramolecular charge transfer (ICT) between chloroacrylic acid and the donor moieties connected with the Vilsmeier-Haack linker. The emission wavelength maxima of the fluorophores were in between 798 and 870 nm. Compound 20 with a 4-quinoline donor moiety showed an emission wavelength above 1000 nm in the NIR II window. The synthesized fluorophores were characterized by 1H NMR and 13C NMR, and their optical properties were studied. Time dependent density functional theory (TD-DFT) calculations showed that the charge transfer occurs from the donor groups (indole, benzothiazole, benzo[e]indole, and quinoline) to the acceptor chloroacrylic acid moiety. Fluorophores with [HOMO] to [LUMO+1] transitions were shown to possess a charge separation character. The cytotoxicity of selected fluorophores, 4, 7, 10 and 12 was investigated against breast cancer cell lines and they showed better activity than the anti-cancer agent docetaxel.

EvoDesign: Designing Protein-Protein Binding Interactions Using Evolutionary Interface Profiles in Conjunction with an Optimized Physical Energy Function.

EvoDesign (https://zhanglab.ccmb.med.umich.edu/EvoDesign) is an online server system for protein design. The method uses evolutionary profiles to guide the sequence search simulation and demonstrated significant advantages over physics-based approaches in terms of more accurately designing proteins that adopt desired target folds. Despite the success, the previous EvoDesign program focused only on monomer protein design, which limited its ability and usefulness in terms of designing functional proteins. In this work, we propose a new EvoDesign server, which extends the principles of evolution-based design to design protein-protein interactions. Starting from a two-chain complex structure, structurally similar interfaces are identified from known protein-protein interaction databases. An interface evolutionary profile is then constructed from a multiple sequence alignment of the interface analogies, which is combined with a newly developed, atomic-level physical energy function to guide the replica-exchange Monte Carlo simulation search. The purpose of the server is to redesign the specified complex chain to increase its stability and binding affinity for the other chain in the complex. With the improved scope and accuracy of the methodology, the new EvoDesign pipeline should become a useful online tool for functional protein design and drug discovery studies.

From strong to weak NF bonds: on the design of a new class of fluorinating agents.

A set of 50 molecules with NF bonds was investigated to determine the factors that influence the strength of a NF bond, with the aim of designing a new class of fluorinating agents. The intrinsic bond strength of the NF bonds was used as bond strength measure, derived from local stretching NF force constants obtained at the CCSD(T)/aug-cc-pVTZ and ωB97XD/aug-cc-pVTZ levels of theory. The investigation showed that the NF bond is a tunable covalent bond, with bond strength orders ranging from 2.5 (very strong) to 0.1 (very weak). NF bond strengthening is caused by a combination of different factors and can be achieved by e.g. ionization. Whereas, the NF bond weakening can be achieved by hypervalency on the N atom, using a N→Ch (Ch: O, S, Se) donor-acceptor type bond with different electron-withdrawing groups. These new insights into the nature of the NF bond were used to propose and design a new class of fluorinating agents. Hypervalent amine-chalcogenides turned out as most promising candidates for efficient electrophilic fluorinating agents.

Recent advances in automated protein design and its future challenges.

INTRODUCTION: Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered: The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics.

Quantitative Assessment of Aromaticity and Antiaromaticity Utilizing Vibrational Spectroscopy.

Vibrational frequencies can be measured and calculated with high precision. Therefore, they are excellent tools for analyzing the electronic structure of a molecule. In this connection, the properties of the local vibrational modes of a molecule are best suited. A new procedure is described, which utilizes local CC stretching force constants to derive an aromaticity index (AI) that quantitatively determines the degree of π-delocalization in a cyclic conjugated system. Using Kekulé benzene as a suitable reference, the AIs of 30 mono- and polycyclic conjugated hydrocarbons are calculated. The AI turns out to describe π-delocalization in a balanced way by correctly describing local aromatic units, peripheral, and all-bond delocalization. When comparing the AI with the harmonic oscillator model of AI, the latter is found to exaggerate the antiaromaticity of true and potential 4n π-systems or to wrongly describe local aromaticity. This is a result of a failure of the Badger relationship (the shorter bond is always the stronger bond), which is only a rule and therefore cannot be expected to lead to an accurate description of the bond strength via the bond length. The AI confirms Clar's rule of disjoint benzene units in many cases, but corrects it in those cases where peripheral π-delocalization leads to higher stability. [5]-, [6]-, [7]-Circulene and Kekulene are found to be aromatic systems with varying degree of delocalization. Properties of the local vibrational modes provide an accurate description of π-delocalization and an accurate AI.

Direct Measure of Metal-Ligand Bonding Replacing the Tolman Electronic Parameter.

The Tolman electronic parameter (TEP) derived from the A1-symmetrical CO stretching frequency of nickel-tricarbonyl complexes L-Ni(CO)3 with varying ligands L is misleading as (i) it is not based on a mode decoupled CO stretching frequency and (ii) a generally applicable and quantitatively correct or at least qualitatively reasonable relationship between the TEP and the metal-ligand bond strength does not exist. This is shown for a set of 181 nickel-tricarbonyl complexes using both experimental and calculated TEP values. Even the use of mode-mode decoupled CO stretching frequencies (L(ocal)TEPs) does not lead to a reliable description of the metal-ligand bond strength. This is obtained by introducing a new electronic parameter that is directly based on the metal-ligand local stretching force constant. For the test set of 181 nickel complexes, a direct metal-ligand electronic parameter (MLEP) in the form of a bond strength order is derived, which reveals that phosphines and related ligands (amines, arsines, stibines, bismuthines) are bonded to Ni both by σ-donation and π-back-donation. The strongest Ni-L bonds are identified for carbenes and cationic ligands. The new MLEP quantitatively assesses electronic and steric factors.

Re-evaluation of the bond length-bond strength rule: The stronger bond is not always the shorter bond.

A set of 42 molecules with N-F, O-F, N-Cl, P-F, and As-F bonds has been investigated in the search for potential bond anomalies, which lead to reverse bond length-bond strength (BLBS) relationships. The intrinsic strength of each bond investigated has been determined by the local stretching force constant obtained at the CCSD(T)/aug-cc-pVTZ level of theory. N-F or O-F bond anomalies were found for fluoro amine radicals, fluoro amines, and fluoro oxides, respectively. A rationale for the deviation from the normal Badger-type inverse BLBS relation is given and it is shown that electron withdrawal accompanied by strong orbital contraction and bond shortening is one of the prerequisites for a bond anomaly. In the case of short electron-rich bonds such as N-F or O-F, anomeric delocalization of lone pair electrons in connection with lone pair repulsion are decisive whether a bond anomaly can be observed. This is quantitatively assessed with the help of the CCSD(T) local stretching force constants, CCSD(T) charge distributions, and G4 bond dissociation energies. Bond anomalies are not found for fluoro phosphines and fluoro arsines because the bond weakening effects are no longer decisive.

Hidden Bond Anomalies: The Peculiar Case of the Fluorinated Amine Chalcogenides.

Bond anomalies have been investigated for a set of 53 molecules with either N-F, Ti-P, Cr-H, Pb-C, or Pb-F bonds for which reverse rather than inverse bond length-bond strength relationships have been previously claimed. The intrinsic strength of each bond investigated was determined utilizing the associated local stretching force constant obtained at the CCSD(T)/aug-cc-pVTZ level of theory. For the metal containing molecules, LC-ωPBE calculations with the aug-cc-pVTZ (Cr, Pb) and the 6-31++G(d,p) basis set (Ti) were carried out. For bonds containing a metal atom, any bond anomaly could not be confirmed. Previously reported results were due to ill-defined bond strength descriptors or lacking accuracy. In the case of the fluoro amines, methyl fluoro amines, and the fluoro amine oxides, direct or hidden bond anomalies were detected, which result from two or more opposing electronic effects: a dominant bond shortening effect due to electron withdrawal and a bond weakening due to lone pair repulsion or hybridization defects. Bond anomalies can be disguised by a complex interplay of electronic effects. These hidden bond anomalies could be identified in this work for the fluoro amine chalcogenides.

Strength of the pnicogen bond in complexes involving group Va elements N, P, and As.

A set of 36 pnicogen homo- and heterodimers, R3E···ER3 and R3E···E'R'3, involving differently substituted group Va elements E = N, P, and As has been investigated at the ωB97X-D/aug-cc-pVTZ level of theory to determine the strength of the pnicogen bond with the help of the local E···E' stretching force constants k(a). The latter are directly related to the amount of charge transferred from an E donor lone pair orbital to an E' acceptor σ* orbital, in the sense of a through-space anomeric effect. This leads to a buildup of electron density in the intermonomer region and a distinct pnicogen bond strength order quantitatively assessed via k(a). However, the complex binding energy ΔE depends only partly on the pnicogen bond strength as H,E-attractions, H-bonding, dipole-dipole, or multipole-multipole attractions also contribute to the stability of pnicogen bonded dimers. A variation from through-space anomeric to second order hyperonjugative, and skewed π,π interactions is observed. Charge transfer into a π* substituent orbital of the acceptor increases the absolute value of ΔE by electrostatic effects but has a smaller impact on the pnicogen bond strength. A set of 10 dimers obtains its stability from covalent pnicogen bonding whereas all other dimers are stabilized by electrostatic interactions. The latter are quantified by the magnitude of the local intermonomer bending force constants XE···E'. Analysis of the frontier orbitals of monomer and dimer in connection with the investigation of electron difference densities, and atomic charges lead to a simple rationalization of the various facets of pnicogen bonding. The temperature at which a given dimer is observable under experimental conditions is provided.

A first principles study of fluorescence quenching in rhodamine B dimers: how can quenching occur in dimeric species?

Rhodamine B (RhB) is widely used in chemistry and biology due to its high fluorescence quantum yield. In high concentrations, the quantum yield of fluorescence decreases considerably which is attributed to the formation of RhB dimers. In the present work, a possible mechanism of fluorescence quenching in RhB dimers is investigated with the use of time-dependent density functional theory (TD-DFT). The excited states of monomeric and dimeric RhB species have been studied both in the gas phase and in solution with the use of the TD-BLYP/6-311G* method. Results of the calculations suggest that quenching can occur via an internal conversion to the charge-transfer singlet excited states, which can be followed by an intersystem crossing with the charge-transfer triplet states. A possibility to reduce the loss of the fluorescence quantum yield is discussed.