Size-consistency and orbital-invariance issues revealed by VQE-UCCSD calculations with the FMO scheme.

The fragment molecular orbital (FMO) scheme is one of the popular fragmentation-based methods and has the potential advantage of making the circuit shallow for quantum chemical calculations on quantum computers. In this study, we used a GPU-accelerated quantum simulator (cuQuantum) to perform the electron correlation part of the FMO calculation as unitary coupled-cluster singles and doubles (UCCSD) with the variational quantum eigensolver (VQE) for hydrogen-bonded (FH) 3 and (FH) 2 -H 2 O systems with the STO-3G basis set. VQE-UCCSD calculations were performed using both canonical and localized MO sets, and the results were examined from the point of view of size-consistency and orbital-invariance affected by the Trotter error. It was found that the use of localized MO leads to better results, especially for (FH) 2 -H 2 O. The GPU acceleration was substantial for the simulations with larger numbers of qubits, and was about a factor of 6.7-7.7 for 18 qubit systems.

Supplementation with autologous adipose stem cell-derived mitochondria can be a safe and promising strategy for improving oocyte quality.

PURPOSE: In our previous study, we confirmed that the supplementation of vitrified-warmed murine oocytes with autologous adipose stem cell (ASC)-derived mitochondria during intracytoplasmic sperm injection enhances post-fertilization developmental competence in mice. To ensure the safety of this technology, we conducted a thorough study in mice to investigate the potential presence of specific malformations in offspring developed from this approach. METHODS: A transgenerational comparative analysis was conducted on founder mice from embryos that developed after mitochondrial supplementation, and two subsequent generations. Reproductive performance, body growth rate, histopathological parameters, hematological parameters, daily activity patterns, and daily body temperature changes in male and female mice across these three generations were assessed in comparison to wild-type mice of the same age. RESULTS: Both male and female animals in all three generations showed comparable reproductive performance to the control group. Additionally, body growth rate by the age of 8 weeks were found to be comparable to controls across all three generations. Notably, no significant histopathological abnormalities were detected in vital organs, including the brain, heart, liver, kidneys, lungs, ovaries, and testes, in any individuals from the studied cohorts. The blood parameters were consistent with the control data. The continuous monitoring of activity and body temperature changes (both day and night) over a 1-week period revealed a pattern closely resembling that observed in the control animals. CONCLUSION: Injection of ASC-mitochondria into oocytes may be a promising technique to support developmental potential without causing adverse epigenetic events in the offspring in mice. However, before considering clinical application, additional safety screening using larger animals or non-human primates is essential.

Analysis of clinical outcomes and meiotic segregation modes following preimplantation genetic testing for structural rearrangements using aCGH/NGS in couples with balanced chromosome rearrangement.

Purpose: To retrospectively evaluate the effectiveness of PGT-SR by array comparative genomic hybridization (aCGH) or next-generation sequencing (NGS) in preventing recurrent miscarriages. Methods: Thirty one couples with balanced translocation who underwent 68 PGT-SR cycles between 2012 and 2020 were evaluated. A total of 242 blastocysts were biopsied for aCGH or NGS. The genetically transferable blastocysts were transferred in the subsequent frozen-thawed single embryo transfer cycle. Results: The genetically transferable blastocyst rate was 21.2% (51/241). Thirty five genetically transferable blastocysts were transferred into the uterine cavity. The clinical pregnancy rate was 57.1% (20/35), and the ongoing pregnancy rate was 100.0% (20/20). The incidence of interchromosomal effect (ICE) was influenced by ovarian stimulation protocol, female age, and carrier's gender, but dependent on the types of balanced translocation carriers. Furthermore, there was no significant difference in meiotic segregation modes in ovarian stimulation protocols and carrier's gender. Interestingly, the incidence of adjacent-1 segregation in ≧40 years group increased significantly compared with <35 years group. Conclusions: For the first time in Japan, we show the effectiveness of PGT-SR using aCGH or NGS, which enables comprehensive analysis of chromosomes, in the prevention of recurrent miscarriages. Furthermore, our results may support better genetic counseling of balanced translocation carriers for PGT-SR cycles.

Usefulness of combined NGS and QF-PCR analysis for product of conception karyotyping.

Purpose: Since chromosomal abnormalities can be detected in more than half of miscarriages, cytogenetic testing of the product of conception (POC) can provide important information when preparing for a subsequent pregnancy. Conventional karyotyping is the common diagnostic method for a POC but can be problematic due to the need for cell culture. Methods: We here conducted shallow whole-genome sequencing (sWGS) using next-generation sequencing (NGS) for alternative POC cytogenomic analysis. Since female euploidy samples can include 69,XXX triploidy, additional QF-PCR was performed in these cases. Results: We here analyzed POC samples from miscarriages in 300 assisted reproductive technology (ART) pregnancies and detected chromosomal abnormalities in 201 instances (67.0%). Autosomal aneuploidy (151 cases, 50.3%) was the most frequent abnormality, consistent with prior conventional karyotyping data. Mosaic aneuploidy was detected in seven cases (2.0%). Notably, the frequency of triploidy was 2.3%, 10-fold lower than the reported frequency in non-ART pregnancies. Structural rearrangements were identified in nine samples (3%), but there was no case of segmental mosaicism. Conclusions: These data suggest that NGS-based sWGS, with the aid of QF-PCR, is a viable alternative karyotyping procedure that does not require cell culture. This method could also assist with genetic counseling for couples who undergoes embryo selection based on PGT-A data.

Effects of exposure to methylglyoxal on sperm motility and embryonic development after fertilization in mice.

Methylglyoxal (MG) is a precursor for the generation of endogenous advanced glycation end-products involved in various diseases, including infertility. The present study evaluated the motility and developmental competence after in vitro fertilization of mouse sperm which were exposed to MG in the capacitation medium for 1.5 h. Sperm motility was analyzed using an SQA-V automated sperm quality analyzer. Intracellular reactive oxygen species (ROS), membrane integrity, mitochondrial membrane potential, and DNA damage were assessed using flow cytometry. The matured oocytes were inseminated with MG-exposed sperm, and subsequently, the fertilization and embryonic development in vitro were evaluated in vitro. The exposure of sperm to MG did not considerably affect the swim-up of sperm but resulted in a deteriorated sperm motility in a concentration-dependent manner, which was associated with a decreased mitochondrial activity. However, these effects was not accompanied by obvious ROS accumulation or DNA damage. Furthermore, MG diminished the fertilization rate and developmental competence, even after normal fertilization. Collectively, a short-term exposure to MG during sperm capacitation had a critical impact on sperm motility and subsequent embryonic development after fertilization. Considering that sperm would remain in vivo for up to 3 days until fertilization, our findings suggest that sperm can be affected by MG in the female reproductive organs, which may be associated with infertility.

Fragmentation at sp2 carbon atoms in fragment molecular orbital method.

In the fragment molecular orbital (FMO) method, a given molecular system is usually fragmented at sp3 carbon atoms. However, fragmentation at different sites sometimes becomes necessary. Hence, we propose fragmentation at sp2 carbon atoms in the FMO method. Projection operators are constructed using sp2 local orbitals. To maintain practical accuracy, it is essential to consider the three-body effect. In order to suppress the corresponding increase of computational cost, we propose approximate models considering local trimers. Numerical verification shows that the present models are as accurate as or better than the standard FMO2 method in total energy with fragmentation at sp3 carbon atoms.

Mitochondrial oxygen consumption rate of human embryos declines with maternal age.

PURPOSE: The fertility of women decreases with age because of factors such as an increased incidence of aneuploidies and-possibly-decreased mitochondrial activity in oocytes. However, the relationship between maternal aging and mitochondrial function of their embryos remains unknown. Here, we assessed the relationship between maternal age and mitochondrial functions in their oocytes and embryos METHODS: The relationships between maternal age and oxygen consumption rates (OCRs), mitochondrial DNA (mtDNA) copy numbers, or blastocyst development was investigated using 81 embryos donated from 63 infertility couples. The developmental rates from morulae to blastocysts were retrospectively analyzed using data of 105 patients. RESULTS: The OCRs of morulae decreased with maternal age (r2 = 0.48, P < 0.05) although there were no relationships between maternal age and mtDNA copy number in any stages. The more oxygen consumed at the morula stage, the shorter time was required for embryo development to the mid-stage blastocyst (r2 = 0.236, P < 0.05). According to the clinical data analysis, the developmental rate from morulae to blastocysts decreased with maternal age (P < 0.05, < 37 years, 81.1%, vs. ≥ 37 years, 64.1%). CONCLUSIONS: The data of the present study revealed that mitochondrial function at the morula stage of human embryos decreased with their maternal age and a decrease of mitochondrial function led to slow-paced development and impaired developmental rate from morulae to blastocysts.

Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

Effect of Preoperative Oral Antibiotics and Mechanical Bowel Preparations on the Intestinal Flora of Patients Undergoing Laparoscopic Colorectal Cancer Surgery: A Single-Center Prospective Pilot Study.

INTRODUCTION:  In the last few decades, considerable progress has been made in controlling surgical site infections (SSIs) using a combination of mechanical and oral antibiotic bowel preparation. However, the number of bacteria present after bowel preparation has not been clarified. In this study, we investigated the bacterial cultures of intestinal fluid samples from patients undergoing laparoscopic surgery for colorectal cancer after preoperative bowel preparation. METHODS: This prospective observational study was designed as a pilot study at a single center. We enrolled 25 consecutive patients who underwent laparoscopic surgery for colorectal cancer between March 2021 and February 2022 at our institution. RESULTS: The rate of bacterial culture positivity was 56.0%. The most abundant bacterium was Escherichia coli (44.0%). The positivity rates for E. coli on the right and left sides were 54.5% and 35.7%, respectively (P = 0.60). Moreover, there was a significant relationship between a low American Society of Anesthesiologists Physical Status score and E. coli positivity on the right side (P = 0.031). In the left-sided group, female sex and large tumor size were significantly associated with E. coli positivity (P = 0.036 and 0.049, respectively). Superficial SSI occurred in the patient in the left-sided group, but E. coli was negative. CONCLUSION: This study emphasizes the importance of understanding intestinal fluid contamination and its relationship to infection risk. Future prospective multicenter studies should be conducted to determine the association between intestinal bacteria and different types of preoperative preparation.

[Renewal of NIHS computer network system].

Updated version of National Institute of Health Sciences Computer Network System (NIHS-NET) is described. In order to reduce its electric power consumption, the main server system was newly built using the virtual machine technology. The service that each machine provided in the previous network system should be maintained as much as possible. Thus, the individual server was constructed for each service, because a virtual server often show decrement in its performance as compared with a physical server. As a result, though the number of virtual servers was increased and the network communication became complicated among the servers, the conventional service was able to be maintained, and security level was able to be rather improved, along with saving electrical powers. The updated NIHS-NET bears multiple security countermeasures. To maximal use of these measures, awareness for the network security by all users is expected.

Mitochondria Transfer from Adipose Stem Cells Improves the Developmental Potential of Cryopreserved Oocytes.

Although it is not a well-established technology, oocyte cryopreservation is becoming prevalent in assisted reproductive technologies in response to the growing demands of patients' sociological and pathological conditions. Oocyte cryopreservation can adversely affect the developmental potential of oocytes by causing an increase in intracellular oxidative stresses and damage to the mitochondrial structure. In this study, we studied whether autologous adipose stem cell (ASC) mitochondria supplementation with vitrified and warmed oocytes could restore post-fertilization development that decreased due to mitochondrial damage following cryopreservation. ASC mitochondria showed similar morphology to oocytes' mitochondria and had a higher ATP production capacity. The vitrified-warmed oocytes from juvenile mice were supplemented with ASC mitochondria at the same time as intracellular sperm injection (ICSI), after which we compared their developmental capacity and the mitochondria quality of 2-cell embryos. We found that, compared to their counterpart, mitochondria supplementation significantly improved development from 2-cell embryos to blastocysts (56.8% vs. 38.2%) and ATP production in 2-cell embryos (905.6 & 561.1 pmol), while reactive oxygen species levels were comparable. With these results, we propose that ASC mitochondria supplementation could restore the quality of cryopreserved oocytes and enhance the embryo developmental capacity, signifying another possible approach for mitochondrial transplantation therapy.

Light-driven oxidation of CH4 to C1 chemicals catalysed by an organometallic Ru complex with O2.

CH4 conversion is one of the most challenging chemical reactions due to its inertness in terms of physical and chemical properties. We have achieved photo-induced C-H bond breaking of CH4 and successive C-O bond formation to form CH3OH concomitant with HCHO by an organometallic Ru complex with O2.

Small Bowel Obstruction Caused by Small Intestinal Metastasis Secondary to Esophageal Carcinoma.

Despite the frequent rapid spread of esophageal cancers to other organs, metastases to the small intestine are uncommon. As such, this paper describes a case of a 60-year-old male who developed a small intestinal obstruction due to metastasis from esophageal carcinoma. This patient had received radical esophagectomy for esophageal carcinoma 14 months prior to the diagnosis. Furthermore, the important role of computed tomography scans played in composing the differential diagnosis will be explored. In order to relieve the obstruction, resection of the small intestine was performed, and the patient survived six months postoperatively.

Flexible ligand recognition of peroxisome proliferator-activated receptor-gamma (PPARgamma).

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a direct pharmacological target for drugs that enhance insulin sensitivity and are used clinically for the treatment of type II diabetes. Because the specificity of ligand recognition is lower for PPARgamma than for other nuclear receptors, PPARgamma can bind a larger variety of ligand types. In order to elucidate why the ligand recognition of PPARgamma is so flexible, we performed correlated fragment molecular orbital calculations for complexes of PPARgamma and each of two distinctive ligands, rosiglitazone and farglitazar. We found quite different patterns of ligand binding for these two ligands. The ligand-binding system of rosiglitazone, a drug in common clinical use, is based mainly on local electrostatic interactions around the thiazolidine ring, whereas both electrostatic interactions and van der Waals dispersion interactions with hydrophobic residues are required for the binding of farglitazar to PPARgamma. We suggest that the development of novel ligands will require adequately hydrophobic pharmacophores.

[Application of fragment molecular orbital (FMO) method to biomacromolecules].

Kitaura et al. (Chem. Phys. Lett. 312, 319-324 (1999)) have proposed an ab initio fragment molecular orbital (FMO) method by which large molecules such as proteins can be easily treated with chemical accuracy. In the ab initio FMO method, a molecule or a molecular cluster is divided into fragments, and the MO calculations on the fragments (monomers) and the fragment pairs (dimers) are performed to obtain the total energy that is expressed as a summation of the fragment energies and inter-fragment interaction energies (IFIEs). In this paper, we provide a brief description of the ab initio FMO method and demonstrate recent applications to the biomacromolecules.

Fragment Molecular Orbital method-based Molecular Dynamics (FMO-MD) as a simulator for chemical reactions in explicit solvation.

Fragment Molecular Orbital based-Molecular Dynamics (FMO-MD, Komeiji et al., Chem Phys Lett 2003, 372, 342) is an ab initio MD method suitable for large molecular systems. Here, FMO-MD was implemented to conduct full quantum simulations of chemical reactions in explicit solvation. Several FMO-MD simulations were performed for a sphere of water to find a suitable simulation protocol. It was found that annealing of the initial configuration by a classical MD brought the subsequent FMO-MD trajectory to faster stabilization, and also that use of bond constraint in the FMO-MD heating stage effectively reduced the computation time. Then, the blue moon ensemble method (Sprik and Ciccotti, J Chem Phys 1998, 109, 7737) was implemented and was tested by calculating free energy profiles of the Menschutkin reaction (H3N + CH3Cl --> +H3NCH3 + Cl-) in the presence and absence of the solvent water via FMO-MD. The obtained free energy profiles were consistent with the Hammond postulate in that stabilization of the product by the solvent, namely hydration of Cl-, shifted the transition state to the reactant-side. Based on these FMO-MD results, plans for further improvement of the method are discussed.

Fragment molecular orbital calculations on red fluorescent proteins (DsRed and mFruits).

We have performed a series of fragment molecular orbital (FMO) calculations for a family of red fluorescent proteins, DsRed and mFruits. The electronic transition energies were evaluated by the method of configuration interaction singles with perturbative doubles [CIS(D)] including higher-order corrections. The calculated values were in good agreement with the corresponding experimental peak values of spectra. Additionally, the chromophore environment was systematically analyzed in terms of the interaction energies between the pigment moiety and neighboring residues. It was theoretically revealed that the electrostatic interactions play a dominant role in the DsRed chromophore, whereas the color tunings in mFruits are controlled in a more delicate fashion.

Possibility of mutation prediction of influenza hemagglutinin by combination of hemadsorption experiment and quantum chemical calculation for antibody binding.

We have performed a quantum-chemical MP2/6-31G* calculation for the hemagglutinin (HA) antigen-antibody system of the H3N2 influenza virus with the fragment molecular orbital method, which provides one of the world's largest ab initio electron-correlated calculations for biomolecular systems. On the basis of the calculated interfragment interaction energies (IFIEs) representing the molecular interactions between the amino acid residues in the antigen-antibody complex, we have identified those residues in the antigenic region E of HA protein that are significantly recognized by the Fab fragment of antibody with strongly attractive interactions. Combining these IFIE results with those of hemadsorption experiments by which the mutation-prohibited sites are specified has enabled us to explain most of the historical mutation data (five of six residues), which would thus provide a promising method for predicting the HA residues that have a high probability of forthcoming mutation.

Fragment Molecular Orbital Calculations with Implicit Solvent Based on the Poisson-Boltzmann Equation: II. Protein and Its Ligand-Binding System Studies.

In this study, the electronic properties of bioactive proteins were analyzed using an ab initio fragment molecular orbital (FMO) methodology in solution: coupling with an implicit solvent model based on the Poisson-Boltzmann surface area called as FMO-PBSA. We investigated the solvent effects on practical and heterogeneous targets with uneven exposure to solvents unlike deoxyribonucleic acid analyzed in our recent study. Interfragment interaction energy (IFIE) and its decomposition analyses by FMO-PBSA revealed solvent-screening mechanisms that affect local stability inside ubiquitin protein: the screening suppresses excessiveness in bare charge-charge interactions and enables an intuitive IFIE analysis. The electrostatic character and associated solvation free energy also give consistent results as a whole to previous studies on the explicit solvent model. Moreover, by using the estrogen receptor alpha (ERα) protein bound to ligands, we elucidated the importance of specific interactions that depend on the electric charge and activatability as agonism/antagonism of the ligand while estimating the influences of the implicit solvent on the ligand and helix-12 bindings. The predicted ligand-binding affinities of bioactive compounds to ERα also show a good correlation with their in vitro activities. The FMO-PBSA approach would thus be a promising tool both for biological and pharmaceutical research targeting proteins.

Destabilization of DNA through interstrand crosslinking by UO22.

UO22+ was shown to form an interstrand crosslink between two different strands of a single DNA molecule. This crosslink hardly affected the hydrogen bonds between nucleobase pairs but destabilized the π-π stacking between the two nucleobases in the vicinity of UO22+-bound phosphate. Thereby, the fragility of the DNA backbone increased upon UO22+ binding.