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PubMed2026

Comprehensive identification of carboxylic acids by using bromine isotope-based chemical isotope labelling and structure-guided molecular network.

Carboxylic acids (CAs) are important contributors to the flavor quality of sauce-flavor Chinese Baijiu, yet their comprehensive analysis remains challenging due to poor ionization efficiency, weak chromatographic retention, and limited annotation capability. Herein, we developed a workflow for the high-coverage discovery and annotation of CAs in Baijiu by coupling chemical isotope labeling-liquid chromatography-mass spectrometry with a structure-guided molecular network strategy (SGMNS). A bromine-containing derivatization reagent, 1-(3-aminopropyl)-3-bromoquinolin-1-ium bromide (APBQ), was designed and synthesized to exploit the natural isotope distribution of bromine and characteristic MS/MS fragmentation behavior. Following APBQ derivatization, the target CAs showed superior chromatographic retention and favorable analytical performance. Based on isotopic peak pairing in MS1 and diagnostic fragment validation in MS2, 372 potential CA derivatives were discovered from pooled Baijiu samples and 355 of them were validated by diagnostic fragments in MS2 spectra. To address the scarcity of derivatized spectral libraries, SGMNS was employed for annotation using a background network constructed from APBQ-labeled candidates derived from the Expanded Chinese Baijiu Compound Database. The developed method was further applied to profile Baijiu samples, revealing pronounced differences in CA composition across the seven fermentation rounds. Notably, rounds 3 to 5 exhibited the largest numbers of differential CAs. This study provided an effective analytical strategy for large-scale CA profiling, offering new insight into the chemical basis of flavor formation during multi-round fermentation of sauce-flavor Baijiu.

Isotope Labeling↗
PubMed2026

Clinical and endocrine correlates of genetic etiologies in severe hypospadias: Study from 34 patients.

OBJECTIVE: Hypospadias is a prevalent congenital anomaly (0.3%-1.0%); however, severe hypospadias (defined as proximal cases with the meatus at the penoscrotal junction, scrotum, or perineum) is a rare and clinically challenging entity with a multifactorial etiology. This study aimed to characterize the interrelationships among the clinical, endocrine, and genetic profiles in children with severe hypospadias. MATERIALS AND METHODS: We conducted a comprehensive analysis of 34 male patients with severe hypospadias. Preoperative hormone levels were measured using two methods: chemiluminescent immunoassay for luteinizing hormone and follicle-stimulating hormone, and liquid chromatography-tandem mass spectrometry for testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17α-hydroxyprogesterone (17α-OHP), and other steroids. Genetic analysis was conducted via whole exome sequencing. RESULTS: The diagnostic yield of clinically relevant genetic variants (including pathogenic and likely pathogenic, and variants of uncertain significance) in our cohort was 41.2% (14/34) of patients. Patients carrying these variants exhibited a more complex phenotypic profile compared to non-carriers, including a significantly higher rate of patients with ≥3 associated malformations and a greater prevalence of cryptorchidism. Furthermore, the group with clinically relevant variants showed selective elevations in adrenal-derived precursors, specifically 17α-OHP and DHEA. Correlation analysis revealed significant positive associations of both 17α-OHP levels and the T/DHT ratio with the number of associated malformations. CONCLUSION: This study reveals significant genetic heterogeneity in patients with severe hypospadias. Those carrying genetic variants was associated with more severe clinical phenotypes, while certain endocrine variations, including the elevation of adrenal-derived hormones, were also observed in this cohort.

Humans↗
PubMed2024

Identification of a Proteomic Signature for Predicting Immunotherapy Response in Patients With Metastatic Non-Small Cell Lung Cancer.

Immunotherapy has improved survival rates in patients with cancer, but identifying those who will respond to treatment remains a challenge. Advances in proteomic technologies have enabled the identification and quantification of nearly all expressed proteins in a single experiment. Integrating mass spectrometry with high-throughput technologies has facilitated comprehensive analysis of the plasma proteome in cancer, facilitating early diagnosis and personalized treatment. In this context, our study aimed to investigate the predictive and prognostic value of plasma proteome analysis using the SWATH-MS (Sequential Window Acquisition of All Theoretical Mass Spectra) strategy in newly diagnosed patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab therapy. We enrolled 64 newly diagnosed patients with advanced NSCLC treated with pembrolizumab. Blood samples were collected from all patients before and during therapy. A total of 171 blood samples were analyzed using the SWATH-MS strategy. Plasma protein expression in metastatic NSCLC patients prior to receiving pembrolizumab was analyzed. A first cohort (discovery cohort) was employed to identify a proteomic signature predicting immunotherapy response. Thus, 324 differentially expressed proteins between responder and non-responder patients were identified. In addition, we developed a predictive model and found a combination of seven proteins, including ATG9A, DCDC2, HPS5, FIL1L, LZTL1, PGTA, and SPTN2, with stronger predictive value than PD-L1 expression alone. Additionally, survival analyses showed an association between the levels of ATG9A, DCDC2, SPTN2 and HPS5 with progression-free survival (PFS) and/or overall survival (OS). Our findings highlight the potential of proteomic technologies to detect predictive biomarkers in blood samples from NSCLC patients, emphasizing the correlation between immunotherapy response and the idenfied protein set.

Humans↗
PubMed2025

Structural diversity and evolutionary constraints of oxidative phosphorylation.

The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.

Oxidative Phosphorylation↗
PubMed1994

Vagaries of the lavage white blood cell count in evaluating abdominal stab wounds.

BACKGROUND: The clinical value of an elevated white blood cell (WBC) count on a diagnostic peritoneal lavage (DPL) performed in an asymptomatic patient with a penetrating abdominal stab wound is controversial. METHODS: We performed a comprehensive analysis of asymptomatic patients (no signs of peritonitis) with stab wounds who underwent an exploratory laparotomy based solely on a WBC count > 500/mm3 in the effluent of an open DPL. RESULTS: Twenty-eight patients, 25 with injury to the gastrointestinal (GI) tract and 3 with injury to the liver, obtained true-positive results from DPL. Their mean WBC count in lavage effluent obtained at a mean of 7.6 hours after the stab wound was 3,380/mm3 and their mean serum WBC count, obtained at the same time, was 12,324/mm3. Fifteen patients had false-positive results from DPL. They were lavaged at a mean of 7.2 hours after the stab wound, and had a mean lavage WBC count of 1,228/mm3 and a mean serum WBC count of 9,084/mm3. CONCLUSIONS: Patients lavaged at a mean 6 to 7 hours after an abdominal stab wound will have a significant incidence of false-positive studies based on an elevated WBC count alone. Lavage WBC counts > 3,000/mm3, particularly when associated with a serum WBC count > 11,000, are likely to be true positives and to indicate injury to the GI tract.

Abdominal Injuries↗
PubMed1990

Using FACS vs. communication scores to measure spontaneous facial expression of emotion in brain-damaged patients: a reply to Mammucari et al. (1988).

Buck and Duffy (1980) and Borod et al. (1985) found evidence of deficits in spontaneous expressiveness in right brain-damaged (RBD) patients relative to LBD patients and controls. Using FACS, Mammucari et al. (1988) failed to replicate this result and questioned our methods and findings. This paper replies (a) that Mammucari et al. (1988)'s review of our work is selective and misleading; (b) that there are aspects of their study that can account for their null results, including the insufficient sensitivity of FACS for the measurement of spontaneous expressiveness; and (c) that the results of Mammucari et al. (1988) regarding "aversive eye movements" to a negative film in LBD and control, but not RBD, patients are in fact compatible with our findings. This paper also suggests a general strategy for the objective and comprehensive analysis of spontaneous emotional expressiveness.

Brain Damage, Chronic↗
PubMed1989

Interplay of hydrophobic and electrostatic interactions in biopolymer chromatography. Effect of salts on the retention of proteins.

The effect of salt on the retention behavior of proteins in electrostatic and hydrophobic interaction chromatography is described by a three-parameter equation, log k' = A - B log ms + Cms, where k' is the retention factor and ms is the molality of the salt in the eluent. Parameter B, termed the electrostatic interaction parameter, depends on the characteristic charge of the protein and the salt counterion and governs the change of retention with the salt concentration in ion-exchange chromatography. According to the model the magnitude of the hydrophobic interaction parameter C is determined by the hydrophobic contact area upon protein binding at the stationary phase surface and the properties of the salt as measured by its molal surface tension increment. Retention data measured at different salt concentrations in the eluent on a variety of ion exchangers can be fitted to the above equation which yields U-shaped plots of log k' against log ms. The limiting slopes of the appropriate plots at sufficiently low and high salt concentrations can be used to evaluate the electrostatic and hydrophobic interaction parameters, respectively. The approach, which is based on a combination of established treatments of electrostatic and hydrophobic interactions offers a convenient framework for analyzing retention data in biopolymer high-performance liquid chromatography and for the characterization of stationary phases. Furthermore, it may facilitate some characterization of protein molecules on the basis of their retention behavior as a function of the concentration and nature of the salt in the eluent. In the treatment of electrostatic interactions use is made of the counterion condensation theory that is believed to make possible a more comprehensive analysis than the traditional stoichiometric ion-exchange model which assumes binding of the proteins by coulombic interactions at discrete sites. The treatment of hydrophobic interactions is based on an adaptation of the solvophobic theory which predicts that the hydrophobic portion of the free energy of binding is proportional to the hydrophobic contact area and the microthermodynamic surface tension of the aqueous salt solution. Despite its simplicity the theory was successful in explaining the observed effect of the nature and concentration of salt in the eluent, the pH and the effect of the density of fixed charges at the surface of the stationary phase in the absence of specific salt effects.

Biopolymers↗
PubMed1996

Dental education and practice in the 21st century: opportunities for excellence.

This study describes the environment that can be expected for dental education and dental practice as the 21st century approaches. The study uses data from many sources, including the recent report from the Institute of Medicine, which provides a comprehensive analysis of the variables that will affect dental education and practice in the next decade. Dental education and practice will be able to thrive if the new forces are carefully examined and the challenges are met promptly.

Dental Clinics↗
PubMed1995

Curative treatment for pancreatic neoplasms. Radical resection.

The available data suggest that lymph node involvement is an important prognostic factor in patients with carcinoma of the head of the pancreas. Lymph node metastases occur in as many as 50% of the cases of even the smallest pancreatic cancers now being diagnosed and resected (i.e., those < 2 cm in diameter). There is some evidence, especially from clinical experience in Japan, that wider lymphatic dissections (i.e., wider than those commonly done with the standard Whipple resection) may prolong survival. Unfortunately, many of the available data around the world are retrospective and are not randomized between the standard and the radical operation. Moreover, the pathologic material has not been staged uniformly according to accepted criteria. Thus the various series are not comparable. Comparisons between series require standardization with respect to stage of disease, pathologic classification, and treatment protocols. Before any modification of the standard pancreaticoduodenectomy is adopted, an appropriately designed study should be performed to test its efficacy. This study would also require a more comprehensive analysis of the pathologic material than is commonly performed today in the United States and Europe.

Humans↗
PubMed1989

Patellofemoral instability in total knee arthroplasty.

Patellofemoral instability following total knee arthroplasty remains one of the major complications requiring operative intervention. In spite of recent advances in technique and instrumentation, the rate of this complication remains disturbingly high. A comprehensive analysis of cause reveals malalignment of any of the components to be potentially responsible, particularly valgus or internal rotation malalignment of either femoral or tibial component, as well as lateral displacement of the patellar component. Underresection of the patella or oversizing the femoral component may also contribute to excessive lateral retinacular tightness. When confronted with patellofemoral instability, the surgeon must first look for and correct the cause. Component malalignment requires component revision. Extensor mechanism imbalance requires either proximal or distal realignment. Lateral release alone invites recurrence of the problem.

Arthroplasty↗
PubMed1995

Prediction of thoracic and lumbar vertebral body compressive strength: correlations with bone mineral density and vertebral region.

The bone density of thoracolumbar vertebral columns (T1 to L5) from 18 individuals was measured using quantitative computed tomography and dual energy x-ray absorptiometry. Three hundred six isolated vertebral bodies were tested in a materials test device to determine their compressive strength. Between T1 and L5 the mean segmental increase in bone mineral content was 0.3 g, while the corresponding mean decrease in trabecular density was 4.7 HU. Midvertebral body cross-sectional area increased by an average of 46 mm2 per segment and the mean segmental increase in compressive strength was 0.17 kN. Compressive strength was significantly correlated with bone mineral density measured with dual energy x-ray absorptiometry (r = 0.86). Vertebral trabecular density samples measured with quantitative computed tomography were poorly correlated with compressive strength (r = 0.28); however, this was improved when the trabecular density was multiplied by the midvertebral body cross-sectional area (r = 0.83). This study provides information concerning the relationships between density and mechanical properties of all thoracic and lumbar vertebral bodies across a wide age range. While the load-bearing capacity of the vertebral bodies is largely dependent on their geometry and bone density, this relationship has been only extensively tested for the lumbar spine. This study extends these observations over the lumbar and thoracic regions to provide a comprehensive analysis of the strength characteristics of each vertebral body. This is particularly important given the paucity of data on the thoracic spine where age-related vertebral fractures predominate. These data provide a basis for the development of models to predict the potential for thoracolumbar fractures in the elderly vertebral column.

Absorptiometry, Photon↗
PubMed1989

How does gender influence age at first hospitalization for schizophrenia? A transnational case register study.

Numerous studies have reported a lower mean age at first hospitalization for schizophrenia in males than in females. For this finding not only a gender difference in age at first onset of schizophrenia, but also other factors can be responsible. With the aim of providing a comprehensive analysis of gender differences in onset, symptomatology and course of schizophrenia, we started by testing the hypothesis postulating a gender difference in mean age at first hospitalization. By using the Danish and the Mannheim psychiatric case registers we analysed all hospital admissions for schizophrenia and related diagnoses and all previous admissions for other diagnoses of the Danish population in 1976 and those of the inhabitants of the German city of Mannheim in the period of 1978-80. Artefacts were controlled for systematically. The impact of intervening variables such as selection factors as well as the influence of gender on the ascription of a diagnosis of schizophrenia for the first time were assessed. We found a mean difference of 5 to 6 years in age at first hospitalization between males and females in both countries when a broad definition of the diagnosis was used and of 4 to 5 years when a restrictive definition was applied. The higher mean age at first hospitalization among females is not attributable to artefacts, diagnostic procedures or to any essential extent to gender differences in help-seeking behaviour or occupational status. When a distinction was made between 'single' and 'married', the significant difference in age at first hospitalization between the sexes disappeared in singles. With case register data and without knowing the chronological order of marriage and onset of the disease, it remains an open question whether this finding can be explained by purely correlative associations between sex, marital status and age of onset or by causal effects.

Adolescent↗
PubMed1994

Changing epidemiology of human salmonellosis in Hong Kong, 1982-93.

A comprehensive analysis of the epidemiology of salmonellosis in a major hospital in Hong Kong from 1982-93 is reported. The trend of salmonella isolations over the past 12 years and changes in the occurrence of individual serotypes are delineated. A total of 5328 isolates were analyzed. Groups B (Salmonella typhimurium and S. derby) and E (S. anatum) were the commonest serogroups isolated from the intestinal tract in all age groups. A significant increase in the isolation of group D salmonellae has been observed since 1989. This is accounted for by a substantial rise in S. enteritidis isolation as seen in Western countries, despite a concomitant decrease of S. typhi. The extraintestinal isolation index (EII) is proposed as an index of the virulence potential of individual serotypes and serogroups. Group D salmonella was found to be the most invasive serogroup. While group D was the predominant serogroup isolated from extraintestinal sites in patients older than 1 year, group B serotypes (especially S. typhimurium) were more frequently seen in infants younger than 12 months.

Adolescent↗
PubMed1994

Hydrostatic pressure reverses osmotic pressure effects on the specificity of EcoRI-DNA interactions.

To characterize the role of water in protein-DNA interactions, we have studied the specificity of the EcoRI restriction endonuclease as a function of osmotic and hydrostatic pressure. The extent of cleavage by the enzyme at noncanonical ("star") sites is shown to depend uniquely upon the osmotic pressure in the reaction as controlled by the addition of a wide variety of neutral solutes. Alteration of cleavage specificity ("EcoRI* activity") is not uniformly correlated with any other colligative solvent property such as dielectric constant, viscosity, or water concentration. The application of hydrostatic pressure reverses the effects of osmotic pressure, restoring the natural selectivity of the enzyme for its canonical site GAATTC. This combination of observations provides compelling evidence that the site-specific recognition of canonical site DNA by EcoRI is mediated by discretely bound water molecules and that the release of these waters induces a fundamental change in the specificity of the interaction, leading to cleavage at alternative sites. This comprehensive analysis of solvent effects facilitates the unambiguous identification of structurally and functionally specific waters involved in macromolecular recognition events.

DNA↗
PubMed1994

Two-dimensional NMR characterization of the deoxymyoglobin heme pocket.

Traditionally, assigning the heme protein resonances has relied heavily on the comparison of spectra arising from protein reconstituted with specifically deuterated hemes and the native form. Such an approach can identify tentatively the broad, overlapping signals in the Fe(II) high-spin heme protein spectra. Although 2D NMR studies have reported alternative approaches to detect and assign paramagnetic signals, their effectiveness is limited primarily to Fe(III) low-spin systems and still depends upon isotopic labeling results to be definitive. For deoxymyoglobin, the reported 2D techniques have not produced any spin correlation maps. Nevertheless, our study demonstrates that the deoxymyoglobin spin correlations are indeed detectable and that a complete heme assignment, except for the meso protons, is achievable with only 2D NMR and saturation-transfer techniques. The 2D maps improve the spectral resolution dramatically and permit a comprehensive analysis of the deoxymyoglobin signals' temperature dependence, which supports the hypothesis that the electronic orbital ground state has contributions from both 5E and 5B2. The results also indicate a structural perturbation in the vicinity of the 2 vinyl group as the protein undergoes the transition from oxy- to deoxymyoglobin state and a significant contribution from zero field splitting. Moreover, saturation-transfer experiments show that NMR can observe directly oxygen binding kinetics.

Animals↗
PubMed1980

Conservation and rearrangement of mitochondrial structural gene sequences.

Mitochondria contain the simplest DNA molecules that are present in eukaryotes. Mitochondrial DNA (mtDNA) is easily purified, and is an important model system for studying eukaryote gene structure and basic molecular processes. The protein sequences of mitochondrial gene products have been shown to be conserved from yeast to man, and there are definite similarities at the DNA sequence level. In contrast, the overall organization of the mitochondrial genome is drastically different in these organisms. To understand this, we need to extend work on mtDNA to a wider range of species. We have chosen to study the mtDNA of Aspergillus nidulans because a particularly comprehensive analysis of this system can be achieved using genetics as well as biochemistry, and like most eukaryotes it is an obligate aerobe, whereas Saccharomyces cerevisiae is not. We have investigated whether defined pieces of particular yeast mitochondrial genes show enough homology to Aspergillus mtDNA fragments to enable the corresponding Aspergillus genes to be located on the physical map. The results reported here show that this is the case for all five genes tested, and present the first data on the physical organization of the structural genes in the mitochondrial genome of A. nidulans.

Adenosine Triphosphatases↗
PubMed1996

Transmission dynamics and epidemiology of BSE in British cattle.

A comprehensive analysis of the bovine spongiform encephalopathy (BSE) epidemic in cattle in Great Britain assesses past, present and future patterns in the incidence of infection and disease, and allows a critical appraisal of different culling policies for eradication of the disease.

Age Factors↗
PubMed1990

C-erbB2 mRNA expression in human breast tumours: comparison with c-erbB2 DNA amplification and correlation with prognosis.

In this study, we have investigated the expression of the proto-oncogene c-erbB2 in a total of 70 human primary breast tumours. In agreement with other workers, we observed c-erbB2 gene amplification in 17.5% of the tumours studied. In addition, we carried out a comprehensive analysis of c-erbB2 mRNA expression in the tumours using RNase mapping and in situ hybridisation techniques. Our results indicated a more frequent (30%) overexpression of c-erbB2 mRNA, which was associated only with breast carcinomas of a ductal origin. Furthermore, analysis of the c-erbB2 mRNA gene locus in the same tumours demonstrated that enhanced c-erbB2 expression could occur in the presence or absence of gene amplification, suggesting that additional molecular mechanisms may result in overexpression of c-erbB2 mRNA in human mammary tumours. In situ hybridisation showed that elevated levels of c-erbB2 mRNA were specific to malignant cells within the breast tumour. Analysis of the association between c-erbB2 mRNA overexpression and clinicopathological factors revealed a significant correlation with poor tumour grade, but not with steroid receptor status or patient menopausal status. No significant correlation was observed between overexpression of c-erbB2 mRNA and early disease recurrence in our group of patients, although there was a definite trend towards poorer prognosis.

Adult↗