Description of Discocotyle ciray n. sp. (Monogenea: Discocotylidae) from Parahucho perryi (Brevoort) from Hokkaido, Japan, with a redescription of D. sagittata (Leuckart, 1842).

Discocotyle sagittata (Leuckart, 1842) (Monogenea: Discocotylidae) is redescribed, based on specimens collected from the type host, Salmo trutta Linnaeus, from the type locality, Freiburg, Germany, supplemented with specimens from S. trutta and rainbow trout, Oncorhynchus mykiss (Walbaum) reared in an Austrian aquarium. The diagnosis of the genus Discocotyle Diesing, 1850 is emended. Discocotyle ciray n. sp. is described, based on immature, preadult and adult specimens from the salmonid, Parahucho perryi (Brevoort) at Eniwa, Hokkaido, Japan. Adult specimens of the new species were about twice as large as those of D. sagittata from S. trutta. When the type specimens of D. ciray n. sp. were examined together with museum specimens from P. perryi at Tsurui, Hokkaido, the body and clamp sizes were positively correlated to the host size. Their measurements from a smaller P. perryi at Tsurui overlapped with those of D. sagittata, showing that these size differences were not suitable differentiating keys. Discocotyle ciray n. sp. can be separated from D. sagittata by the morphologies of the female genital system (relatively anteriorly positioned ovary, short joint vaginal duct and much more strongly winding uterus). The genetic distances of COI mtDNA sequence between D. ciray n. sp. and D. sagittata were 18.0-18.6%. These remarkable genetic divergences also supported the distinct taxonomic status of D. ciray n. sp.

Amino- and Alkoxybenziodoxoles: Facile Preparation and Use as Arynophiles.

We report here on the facile synthesis of amino- and alkoxy-λ3-iodanes supported by a benziodoxole (BX) template and their use as arynophiles. The amino- and alkoxy-BX derivatives can be readily synthesized by reacting the respective amines or alcohols with chlorobenziodoxole in the presence of a suitable base. Unlike previously known nitrogen- and oxygen-bound iodane compounds, which have primarily been employed as electrophilic group transfer agents or oxidants, the present amino- and alkoxy-BX reagents manifest themselves as nucleophilic amino and alkoxy transfer agents toward arynes. This reactivity leads to the aryne insertion into the N-I(III) or O-I(III) bond to afford ortho-amino- and ortho-alkoxy-arylbenziodoxoles, iodane compounds nontrivial to procure by existing methods. The BX group in these insertion products exhibits excellent leaving group ability, enabling diverse downstream transformations.

Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

Carboiodanation of Arynes: Organoiodine(III) Compounds as Nucleophilic Organometalloids.

Organic iodine(III) compounds represent the most widely used hypervalent halogen compounds in organic synthesis, where they typically perform the role of an electrophile or oxidant to functionalize electron-rich or -nucleophilic organic compounds. In contrast to this convention, we discovered their unique reactivity as organometallic-like nucleophiles toward arynes. Equipped with diverse transferable ligands and supported by a tethered spectator ligand, the organoiodine(III) compounds undergo addition across the electrophilic C-C triple bond of arynes while retaining the trivalency of the iodine center. This carboiodanation reaction can forge a variety of aryl-alkynyl, aryl-alkenyl, and aryl-(hetero)aryl bonds along with the concurrent formation of an aryl-iodine(III) bond under mild conditions. The newly formed aryl-iodine(III) bond serves as a versatile linchpin for downstream transformations, particularly as an electrophilic reaction site. The amphoteric nature of the iodine(III) group as a metalloid and a leaving group in this sequence enables the flexible and expedient synthesis of extended π-conjugated molecules and privileged biarylphosphine ligands, where all of the iodine(III)-containing compounds can be handled as air- and thermally stable materials.

Free-energy landscapes of transmembrane homodimers by bias-exchange adaptively biased molecular dynamics.

Membrane proteins play essential roles in various biological functions within the cell. One of the most common functional regulations involves the dimerization of two single-pass transmembrane (TM) helices. Glycophorin A (GpA) and amyloid precursor protein (APP) form TM homodimers in the membrane, which have been investigated both experimentally and computationally. The homodimer structures are well characterized using only four collective variables (CVs) when each TM helix is stable. The CVs are the interhelical distance, the crossing angle, and the Crick angles for two TM helices. However, conformational sampling with multi-dimensional replica-exchange umbrella sampling (REUS) requires too many replicas to sample all the CVs for exploring the conformational landscapes. Here, we show that the bias-exchange adaptively biased molecular dynamics (BE-ABMD) with the four CVs effectively explores the free-energy landscapes of the TM helix dimers of GpA, wild-type APP and its mutants in the IMM1 implicit membrane. Compared to the original ABMD, the bias-exchange algorithm in BE-ABMD can provide a more rapidly converged conformational landscape. The BE-ABMD simulations could also reveal TM packing interfaces of the membrane proteins and the dependence of the free-energy landscapes on the membrane thickness. This approach is valuable for numerous other applications, including those involving explicit solvent and a lipid bilayer in all-atom force fields or Martini coarse-grained models, and enhances our understanding of protein-protein interactions in biological membranes.

[A Case of Resection of T2N0 Colon Cancer with Synchronous Solitary Lung Metastasis].

A 73-year-old man was referred to our hospital for anemia. He underwent a colonoscopy; a 15-mm Ip polyp and a 30- mm type 1 lesion were found in the sigmoid colon. Pathological examination results indicated a well-differentiated adenocarcinoma. Thoracic computed tomography(CT)revealed a mass lesion 12 mm in diameter in the left lung lobe. The patient underwent a laparoscopic sigmoidectomy and D3 lymph node dissection and was discharged in a good condition. He then underwent a diagnostic-therapeutic segmental pulmonary resection for the pulmonary mass. Postoperative pathological findings indicated pT1b(SM), ly0, v0 and pT2(MP), ly1, v1, pN0 for the 2 lesions of the colon. The pulmonary mass was diagnosed as a metastatic adenocarcinoma based on immunostaining examination(CK7: negative, CK20: positive, TTF-1: negative, and CDX-2: positive). The patient is currently under follow-up as an outpatient without recurrence.

Synthesis and Properties of Azahomocorannulenyl Cations and Radicals.

Cycloheptatrienyl (tropyl) molecules are representative non-alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium-catalyzed cyclization. X-ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character.

Stereoselective Approach to Multisubstituted Enolates from Unactivated Alkynes: Oxyalkylidenation of Alkynyl Ketone Enolates with Aldehydes.

The preparation of multisubstituted enolates with precise regio- and stereocontrol is a nontrivial task when conventional deprotonation methods are used on the corresponding carbonyl compounds. We describe herein an approach to preparing stereodefined enolates by leveraging the stereoselective oxyfunctionalization of unactivated alkynes, particularly in the context of the alkynylogous aldol reaction. trans-Iodo(III)acetoxylation of alkynes and subsequent Sonogashira coupling allow for the facile preparation of multisubstituted enynyl acetates, which can be deacetylated by MeLi into the corresponding enolates. The alkynyl enolates react with aldehydes to afford γ,δ-unsaturated ß-diketones through a cascade of alkynylogous aldol addition, intramolecular Michael addition, and ring opening of the oxetene intermediate.

Proteomic alterations in the brain and blood-brain barrier during brain Aß accumulation in an APP knock-in mouse model of Alzheimer's disease.

BACKGROUND: Blood-brain barrier (BBB) dysfunction is supposed to be an early event in the development of Alzheimer's disease (AD). This study aimed to investigate the relationship between BBB alterations and AD progression in terms of amyloid-ß peptide (Aß) accumulation in the brains of humanized amyloid precursor protein knock-in (APP-KI) mice. METHODS: Brain Aß accumulation was examined using immunohistochemical analysis. Alterations in differentially expressed proteins were determined using sequential window acquisition of all theoretical fragment ion mass spectroscopy (SWATH-MS)-based quantitative proteomics, and Metascape, STRING, Gene Ontology, and KEGG were used for network analyses of altered biological pathways and processes. Statistical significance was determined using the unpaired two-tailed Student's t-test and Welch's t-test for two groups and one-way analysis of variance followed by Tukey's test for more than two groups. Correlations between two groups were determined using Pearson's correlation analysis. RESULTS: Brain Aß accumulation in APP-KI mice was detectable at 2 months, increased significantly at 5 months, and remained elevated at 12 months of age. The levels of differentially expressed proteins in isolated brain capillaries were higher in younger mice, whereas those in the brain were higher in older mice. Network analyses indicated changes in basement membrane-associated and ribosomal proteins in the brain capillaries. There were no significant changes in key proteins involved in drug or Aß transport at the BBB. In contrast, solute carrier transporter levels in astrocytes, microglia, and neurons were altered in the brain of older mice. Moreover, the levels of the lipid transporters Apoe and Apoj were upregulated in both the brain and isolated brain capillaries after Aß accumulation. CONCLUSIONS: Our results suggest that changes in the brain occurred after advanced Aß accumulation, whereas initial Aß accumulation was sufficient to cause alterations in the BBB. These findings may help elucidate the role of BBB alterations in AD progression and predict the distribution of drugs across the BBB in the brain of patients with AD.

Development of a method for isolating brain capillaries from a single neonatal mouse brain and comparison of proteomic profiles between neonatal and adult brain capillaries.

BACKGROUND: The functions and protein expressions of the blood-brain barrier are changed throughout brain development following birth. This study aimed to develop a method to isolate brain capillaries from a single frozen neonatal mouse brain and elucidate the enrichment of brain capillaries by quantitative proteomic analysis. We further compared the expression profile of proteins between neonatal and adult brain capillary fractions. METHODS: The brain capillary fraction was prepared by the optimized method from a single frozen mouse neonatal brain on postnatal day 7. The brain capillary fractions and brain lysates were digested by trypsin and analyzed by liquid chromatography-mass spectrometry for quantitative proteomics. RESULTS: By optimizing the isolation method, we observed brain capillaries in the fraction prepared from a single neonatal mouse brain (nBC fraction). A protein amount of 31.5 µg, which is enough for proteomic analysis, was recovered from the nBC fraction. By proteomics analysis, the brain capillary selective proteins, including Abcb1a/Mdr1, Slc2a1/Glut1, Claudin-5, and Pecam-1, were found to be concentrated > 13.4-fold more in nBC fractions than in whole brain lysates. The marker proteins for neurons and astrocytes were not concentrated in nBC fractions, while those of pericytes and microglia were concentrated. Compared to adult mouse brain capillary fractions (aBC fractions), the expressions of Abcb1a/Mdr1a, Abcc4/Mrp4, and Slc2a1/Glut1 were significantly lower in nBC fractions than in aBC fractions, whereas those of Slc1a4/Asct1, Slc1a5/Asct2, Slc7a1/Cat1, and Slc16a1/Mct1 were significantly higher. Amino acid transporters, Slc38a5/Snat5, showed the greatest nBC-to-aBC ratio among transporters (9.83-fold). Network analysis of proteins expressed differentially between nBC and aBC fractions revealed that the proteins with terms related to the extracellular matrix were enriched. CONCLUSIONS: We succeeded in isolating brain capillaries from a single frozen brain of a neonatal mouse at postnatal day 7. Proteomic analysis revealed the differential expression in brain capillaries between neonatal and adult mice. Specifically, amino acid transporters, including Slc1a5/Asct2 and Slc38a5/Snat5, were found to be induced in neonatal brain capillaries. The present isolation method will promote the study of the function and expression of the neonatal blood-brain barrier.

Effect of antibiotic-administration period on hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries.

Antibiotic administration affects pharmacokinetics through changes in the intestinal microbiota, and bile acids are involved in this regulation. The purpose of the present study was to clarify the effect of different periods of antibiotic administration on the hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries. Vancomycin and polymyxin B were orally administered to mice for either 5- or 25-days. The hepatic bile acid profile of the 25-day treatment group was distinct. In the liver, the protein expression of cytochrome P450 (Cyp)3a11 showed the greatest reduction to 11.4% after the 5-day treatment and further reduced to 7.01% after the 25-day treatment. Similar reductions were observed for sulfotransferase 1d1, Cyp2b10, carboxylesterase 2e, UDP-glucuronosyltransferase (Ugt)1a5, and Ugt1a9. In the kidney and brain capillaries, no drug-metabolizing enzymes or drug transporters were changed with >1.5-fold or <0.66-fold statistical significance in either period. These results suggest that bile acids and metabolizing enzymes in the liver are affected in a period-dependent manner by antibiotic treatment, while the blood-brain barrier and kidneys are less affected. Drug-drug interactions of antibiotics via the intestinal microbiota should be considered by changing drug metabolism in the liver.

Allosteric regulation of ß-reaction stage I in tryptophan synthase upon the α-ligand binding.

Tryptophan synthase (TRPS) is a bifunctional enzyme consisting of α- and ß-subunits that catalyzes the last two steps of L-tryptophan (L-Trp) biosynthesis. The first stage of the reaction at the ß-subunit is called ß-reaction stage I, which converts the ß-ligand from an internal aldimine [E(Ain)] to an α-aminoacrylate [E(A-A)] intermediate. The activity is known to increase 3-10-fold upon the binding of 3-indole-D-glycerol-3'-phosphate (IGP) at the α-subunit. The effect of α-ligand binding on ß-reaction stage I at the distal ß-active site is not well understood despite the abundant structural information available for TRPS. Here, we investigate the ß-reaction stage I by carrying out minimum-energy pathway searches based on a hybrid quantum mechanics/molecular mechanics (QM/MM) model. The free-energy differences along the pathway are also examined using QM/MM umbrella sampling simulations with QM calculations at the B3LYP-D3/aug-cc-pVDZ level of theory. Our simulations suggest that the sidechain orientation of ßD305 near the ß-ligand likely plays an essential role in the allosteric regulation: a hydrogen bond is formed between ßD305 and the ß-ligand in the absence of the α-ligand, prohibiting a smooth rotation of the hydroxyl group in the quinonoid intermediate, whereas the dihedral angle rotates smoothly after the hydrogen bond is switched from ßD305-ß-ligand to ßD305-ßR141. This switch could occur upon the IGP-binding at the α-subunit, as evidenced by the existing TRPS crystal structures.

π-Extended Pyrrole-Fused Heteropine: Synthesis, Properties, and Application in Organic Field-Effect Transistors.

Sulfur-embedded polycyclic aromatic compounds have been used as building blocks for numerous organic semiconductors over the past few decades. While the success is based on thiophene-containing compounds, aromatic compounds that contain thiepine, a sulfur-containing seven-membered-ring arene, has been less well investigated. Here we report the synthesis and properties of π-extended pyrrole-fused heteropine compounds such as thiepine and oxepine. A π-extended pyrrole-fused thiepine exhibited a "pitched π-stacking" structure in the crystal, and exhibited a high charge carrier mobility of up to 1.0 cm2 V-1 s-1 in single-crystal field-effect transistors.

Oncologic outcomes after laparoscopic versus open multivisceral resection for local advanced colorectal cancer: A meta-analysis.

Laparoscopic (lap) colectomies for advanced colorectal cancer (CRC) often require resection of other organs. We systematically reviewed currently available literature on lap multi-visceral resection for CRC, with regard to short- and long-term oncological outcomes, and compared them with open procedures. We performed a systematic literature search in MEDLINE, EMBASE, Google Scholar and PubMed from inception to November 30, 2020. The aim of this study was to synthesize short-term and oncological outcomes associated with laparoscopic versus open surgery. Pooled proportions and risk ratios (RRs) were calculated using an inverse variance method. We included six observational cohort studies published between 2012 and 2020 (lap procedures: n = 262; open procedures: n = 273). Collectively, they indicated that postoperative complications were significantly more common after open surgeries than lap surgeries (RR: 0.53; 95% confidence interval [CI]: 0.39-0.72; P < 0.00001), but the two approaches did not significantly differ in positive resection margins (RR: 0.75; 95% CI: 0.38-1.50; P = 0.42), local recurrence (RR: 0.66; 95% CI: 0.28-1.62; P = 0.37), or (based on two evaluable studies) 5-year OS (RR: 0.70; 95% CI: 0.46-1.04; P = 0.08) or 5-year DFS (RR: 0.86; 95% CI: 0.67-1.11) for T4b disease. In conclusion, laparoscopic and open multi-visceral resections for advanced CRC have comparable oncologic outcomes. Although a randomized study would be ideal for further research, no such studies are currently available.

A case of sigmoid colon volvulus with transanal ileus tube placement and Sharon's operation performed safely.

Although endoscopic repair is often performed for sigmoid colon volvulus without intestinal necrosis, surgery is the common choice of treatment due to recurrence. With no established treatment, Hartmann's operation or sigmoid colon resection is often performed. We report a case of a 65-year-old man with transanal ileus tube placement before surgery for sigmoid colon volvulus to prevent recurrence and achieve intestinal decompression followed by Sharon's operation to achieve one-stage anastomosis. The patient showed good postoperative course, with no recurrence 3 months after surgery. This report discusses the usefulness of the transanal ileus tube and Sharon's operation for sigmoid colon volvulus without intestinal necrosis along with a review of the literature.

Human Hepatic Transporter Signature Peptides for Quantitative Targeted Absolute Proteomics: Selection, Digestion Efficiency, and Peptide Stability.

PURPOSE: Quantitative targeted absolute proteomics (QTAP) quantifies proteins by measuring the signature peptides produced from target proteins by trypsin digestion. The selection of signature peptides is critical for reliable peptide quantification. The purpose of this study was to comprehensively assess the digestion efficiency and stability of tryptic peptides and to identify optimal signature peptides for human hepatic transporters and membrane marker proteins. METHODS: The plasma membrane fraction of the human liver was digested at different time points and the peptides were comprehensively quantified using quantitative proteomics. Transporters and membrane markers were quantified using the signature peptides by QTAP. RESULTS: Tryptic peptides were classified into clusters with low digestion efficiency, low stability, and high digestion efficiency and stability. Using the cluster information, we found that a proline residue next to the digestion site or the peptide position in or close to the transmembrane domains lowers digestion efficiency. A peptide containing cysteine at the N-terminus or arginine-glycine lowers peptide stability. Based on this information and the time course of peptide quantification, optimal signature peptides were identified for human hepatic transporters and membrane markers. The quantification of transporters with multiple signature peptides yielded consistent absolute values with less than 30% of coefficient variants in human liver microsomes and homogenates. CONCLUSIONS: The signature peptides selected in the present study enabled the reliable quantification of human hepatic transporters. The QTAP protocol using these optimal signature peptides provides quantitative data on hepatic transporters usable for integrated pharmacokinetic studies.

Factors associated with EMS on-scene time and its regional difference in road traffic injuries: a population-based observational study.

BACKGROUND: The outcome of road traffic injury (RTI) is determined by duration of prehospital time, patient's demographics, and the type of injury and its mechanism. During the emergency medical service (EMS) prehospital time interval, on-scene time should be minimized for early treatment. This study aimed to examine the factors influencing on-scene EMS time among RTI patients. METHODS: We evaluated 19,141 cases of traffic trauma recorded between April 2014 and March 2020 in the EMS database of the Nara Wide Area Fire Department and the prehospital database of the emergency Medical Alliance for Total Coordination of Healthcare (e-MATCH). To examine the association of the number of EMS phone calls until hospital acceptance, age ≥65 years, high-risk injury, vital signs, holiday, and nighttime (0:00-8:00) with on-scene time, a generalized linear mixed model with random effects for four study regions was conducted. RESULTS: EMS phone calls were the biggest factor, accounting for 5.69 minutes per call, and high-risk injury accounted for an additional 2.78 minutes. Holiday, nighttime, and age ≥65 years were also associated with increased on-scene time, but there were no significant vital sign variables for on-scene time, except for the level of consciousness. Regional differences were also noted based on random effects, with a maximum difference of 2 minutes among regions. CONCLUSIONS: The number of EMS phone calls until hospital acceptance was the most significant influencing factor in reducing on-scene time, and high-risk injury accounted for up to an additional 2.78 minutes. Considering these factors, including regional differences, can help improve the regional EMS policies and outcomes of RTI patients.

Stereoselective Synthesis of ß-Alkoxy-ß-amido Vinylbenziodoxoles via Iodo(III)etherification of Ynamides.

A trans-iodo(III)etherification reaction of ynamides with benziodoxole triflate and alcohols is reported. Despite the sensitivity of ynamides and enamides toward Brønsted acid, the reaction could be successfully performed under carefully controlled conditions to afford ß-alkoxy-ß-amido vinylbenziodoxoles in moderate to good yields. The products could be subjected to a sequence of cross-coupling via C-I(III) bond cleavage and electrophilic halogenation of the resulting α-alkoxyenamides, allowing for the preparation of densely functionalized esters.