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PubMed2005

Maximal leg-strength training improves cycling economy in previously untrained men.

PURPOSE: This study examined cycling economy before and after 8 wk of maximal leg-strength training. METHODS: Seven previously untrained males (25 +/- 2 yr) performed leg-strength training 3 d.wk(-1) for 8 wk using four sets of five repetitions at 85% of one repetition maximum (1RM). Body mass, lean-leg muscle mass (LLM), percentage of body fat, and leg strength (1RM) were measured at 0, 4, and 8 wk of training. Cycling economy was calculated as the deltaVO2/deltaWR (change in the O2 cost of exercise divided by the change in the power between two different power outputs). RESULTS: There were significant increases in LLM and 1RM from 0 to 4 wk of training (LLM: 25.8 +/- 0.7 to 27.2 +/- 0.8 kg; 1RM: 138 +/- 9 to 215 +/- 9 kg). From 4 to 8 wk of training, 1RM continued to increase significantly (215 +/- 9 to 266 +/- 8 kg) with no further change observed in LLM. Peak power during incremental cycling increased significantly (305 +/- 14 to 315 +/- 16 W), whereas the power output achieved at the gas-exchange threshold (GET) remained unchanged. Peak O2 uptake and the O2 uptake achieved at the GET also remained unchanged following training. Cycling economy improved significantly when the power output was increased from below the GET to above the GET but not for power outputs below the GET. CONCLUSION: Maximal leg-strength training improves cycling economy in previously untrained subjects. Increases in leg strength during the final 4 wk of training with unchanged LLM suggest that neural adaptations were present.

Adaptation, Physiological↗
PubMed1978

Clinical evaluation of a sensory feedback device: the limb load monitor.

Based on records of 81 patients who used the LLM, and on questionnaire answers and comments from clinicians, the following can be concluded: 1. The LLM can be operated easily after a minimum of training. It does not break down with extended clinical use when handled properly. 2. The LLM manual provides sufficient information for proper operation and clinical use of the device. 3. The number of patients in a clinic who can benefit from LLM training can be predicted, if consideration is given to the type of facility and the size of the patient population and physical therapy staff. 4. The largest diagnostic group of patients who can benefit from LLM therapy are lower-limb amputees, followed by hemiplegic and orthopedic patients. 5. The general selection criteria outlined initially proved sufficient. A patient who is selected properly can be expected to respond to the feedback signal (i.e., make a weight-bearing adjustment) within the first or second session.

Adolescent↗
PubMed1992

Time course of lipid-laden pulmonary macrophages with acute and recurrent milk aspiration in rabbits.

High levels of lipid-laden macrophages (LLM) in bronchial washings have been associated with food aspiration. We studied the time course of appearance and clearance of LLM in rabbits undergoing either a single milk instillation, five weekly milk instillations or saline (control) instillations into the airways. Cells were obtained by bronchoalveolar lavage of intubated rabbits at uniform time intervals following the single or the last of five milk/saline instillations. LLM semi-quantitative indexes were derived using oil-red-O staining. Significantly elevated indexes were found in both milk groups 6 hr after milk instillation. In the single saline and milk instillation groups the indexes were not different beginning on the 4th day, and indexes from 8 of 9 rabbits had returned to baseline by the 6th day. However, indexes remained significantly elevated up to 17 days in the group receiving weekly milk instillations. Indexes from all rabbits in the repeat milk instillation group remained elevated for 12 days or longer. This group also developed increased numbers of binucleated macrophages. Quantitation of LLM in this model appears to be a sensitive indicator of recurrent lipid aspiration, these cells remaining in the airways for several days after the last aspiration event.

Animals↗
PubMed2025

Integrating expert knowledge into large language models improves performance for psychiatric reasoning and diagnosis.

BACKGROUND AND METHODS: The authors sought to evaluate the performance of common large language models (LLMs) in psychiatric diagnosis, and the impact of integrating expert-derived reasoning on their performance. Clinical case vignettes and associated diagnoses were retrieved from the DSM-5-TR Clinical Cases book. Diagnostic decision trees were retrieved from the DSM-5-TR Handbook of Differential Diagnosis and refined for LLM use. Three LLMs were prompted to provide diagnosis candidates for the vignettes either by directly prompting or using the decision trees. These candidates and diagnostic categories were compared against the correct diagnoses. The positive predictive value (PPV), sensitivity, and F1 statistic were used to measure performance. RESULTS: When directly prompted to predict diagnoses, the best LLM by F1 statistic (gpt-4o) had sensitivity of 76.7 % and PPV of 40.4 %. When making use of the refined decision trees, PPV was significantly increased (65.3 %) without a significant reduction in sensitivity (70.9 %). Across all experiments, the use of the decision trees statistically significantly increased the PPV, significantly increased the F1 statistic in 5/6 experiments, and significantly reduced sensitivity in 4/6 experiments. DISCUSSION: When used to predict psychiatric diagnoses from case vignettes, direct prompting of the LLMs yielded most true positive diagnoses but had significant overdiagnosis. Integrating expert-derived reasoning into the process using decision trees improved LLM performance (as measured by F1 statistic), primarily by suppressing overdiagnosis with a lower-magnitude negative impact on sensitivity. This suggests that the integration of clinical expert-derived reasoning could improve the performance of LLM-based tools in the behavioral health setting.

Humans↗
PubMed2026

An embedding-based framework enables statistical testing of gene-set function hypotheses inferred by large language models.

Emerging large language models (LLMs) can infer gene functions directly from gene lists, enabling hypothesis generation without predefined gene sets. However, these LLM-derived predictions are qualitative, and principled statistical validation is lacking. Here, we develop an embedding-based statistical framework that transforms gene and function descriptions into vector representations, enabling statistical testing of gene-gene and gene-function relationships and quantitative prioritization of de novo functional hypotheses inferred by LLMs. We benchmark seven state-of-the-art embedding models using curated and retrieval-augmented literature-derived gene descriptions across diverse biological contexts. OpenAI's text-embedding-3-large and Google's gemini-embedding-001 perform best, capturing gene-gene functional relationships in 88.7-92.5% of Gene Ontology biological processes and approximately 98.6% of canonical pathways. In gene-function association analyses, these models achieve high sensitivity (95.2-98.4%) and specificity (72.7-84.3%). Through contamination analysis and evaluation using experimentally informed protein assembly gene sets, our framework distinguishes biologically meaningful LLM-inferred hypotheses from noise, outperforming confidence-based inference and conventional enrichment analysis. We further develop the open-source R package DEGEmbedR and demonstrate its utility for interpreting a drug perturbation-derived differentially expressed gene (DEG) signature lacking significant conventional enrichment results. Together, these results establish LLM-derived embeddings as a quantitative foundation for functional genomics and the statistical validation of LLM-based gene function inference.

Large Language Models↗
PubMed2002

A new training device for rehabilitation of lateral mandibular movements: a pilot study.

Laterotrusive training is often used together with mouth-opening training in order to achieve adequate translation of the affected condyle in treatment of TMJ closed lock. This training is usually performed by voluntary laterotrusive movement (VLM) or by laterotrusive movement using only the fingers (FLM). However, satisfactory results are often not obtained by using these methods. To resolve this problem, we devised a new laterotrusive training device (LT device). In this paper, we describe the method of the training of laterotrusive movement using the LT device (LLM) and present a comparison of the results obtained by using LLM with those obtained by using VLM and FLM. The subjects were ten patients with TMJ closed lock. The following results were obtained: 1. the range of LLM was significantly larger than those of VLM and FLM; and 2. all of the patients reported that LLM could be performed more easily than VLM and FLM. In conclusion, the LT device is thought to be useful for laterotrusive training in TMJ closed lock.

Adult↗
PubMed2006

Design and NMR conformational study of a beta-sheet peptide based on Betanova and WW domains.

A good approach to test our current knowledge on formation of protein beta-sheets is de novo protein design. To obtain a three-stranded beta-sheet mini-protein, we have built a series of chimeric peptides by taking as a template a previously designed beta-sheet peptide, Betanova-LLM, and incorporating N- and/or C-terminal extensions taken from WW domains, the smallest natural beta-sheet domain that is stable in absence of disulfide bridges. Some Betanova-LLM strand residues were also substituted by those of a prototype WW domain. The designed peptides were cloned and expressed in Escherichia coli. The ability of the purified peptides to adopt beta-sheet structures was examined by circular dichroism (CD). Then, the peptide showing the highest beta-sheet population according to the CD spectra, named 3SBWW-2, was further investigated by 1H and 13C NMR. Based on NOE and chemical shift data, peptide 3SBWW-2 adopts a well defined three-stranded antiparallel beta-sheet structure with a disordered C-terminal tail. To discern between the contributions to beta-sheet stability of strand residues and the C-terminal extension, the structural behavior of a control peptide with the same strand residues as 3SBWW-2 but lacking the C-terminal extension, named Betanova-LYYL, was also investigated. beta-Sheet stability in these two peptides, in the parent Betanova-LLM and in WW-P, a prototype WW domain, decreased in the order WW-P > 3SBWW-2 > Betanova-LYYL > Betanova-LLM. Conclusions about the contributions to beta-sheet stability were drawn by comparing structural properties of these four peptides.

Amino Acid Sequence↗
PubMed2001

Proteasome inhibitors differentially affect heat shock protein response in cancer cells.

The heat shock proteins (HSPs) are molecular chaperones that are emerging as biochemical regulators of cell growth, apoptosis, protein homeostasis and intracellular targeting of peptides. The immunological function of the HSPs are imparted by tissue specific peptides associated with the HSPs and as such autologous cancer derived HSP-peptide complexes are unique therapeutic agents. Since a majority of the intracellular peptides are generated by the proteasome, we examined the consequence of abrogation of proteasome function by proteasome inhibitors (PIs) such as Lactacystin, MG-132 and LLM on the growth and induction profile of HSP70 and gp96 using hematopoietic, lymphoid, and epithelial derived cancer cell lines. The effect on growth was measured by the XTT assay and induction of the heat shock proteins by western blot analyses using HSP70 and gp96 specific antibodies. Of the PIs tested, cancer cells, were most sensitive to MG-132 and least sensitive to LLM. MG-132 also showed a 10-fold differential sensitivity between estrogen receptor positive, (ER+) MCF-7 cells and negative cells, (ER-) MDA-MB-231. Induction of heat shock proteins, gp96 and HSP70 was, however, noted in response to LLM. Since LLM exhibited minimal cytotoxic effect, metabolic stress that results in induction of HSPs may not be translated in cell growth inhibition and that there may exist a cell-type specific phenomenon in the HSP response to PI mediated metabolic stress.

Acetylcysteine↗
PubMed2001

Serial analysis of fat-containing macrophages in bronchoalveolar lavage fluid in a patient with fat embolism syndrome.

Recent studies suggest that an increase in fat-containing macrophages in bronchoalveolar lavage (BAL) fluid may be helpful in the diagnosis of fat embolism syndrome (FES). Nevertheless, none of these studies have explored the sequential findings of BAL fluid. We report the case of a 19-year-old man admitted to our intensive care unit because of dyspnea with radiographic evidence of bilateral alveolar infiltrate after traumatic fracture. Analysis of BAL fluid on the third hospital day revealed 8.3% fat-containing macrophages and a lipid-laden macrophages (LLM) index of 23. Pathologic examination of lung biopsy showed numerous fat globules within arterioles. For comparison, the BAL fluid from four other patients with acute respiratory distress syndrome (ARDS) but without FES was also analyzed. The underlying diseases leading to ARDS included Wegener's granulomatosis in one case, pneumonia in two cases, and alveolar proteinosis in one case. The percentages of fat-containing macrophages in these specimens were 1.3%, 52%, 2.3%, and 74%, respectively. The LLM indexes were 1, 133, 3, and 243, respectively. As the patient's condition improved, the percentage of fat-containing macrophages in the BAL fluid decreased to 4.7% on the eighth hospital day and the LLM index also decreased to 6. These findings suggest that the presence of fat-containing macrophages in BAL fluid is not specific for the diagnosis of FES, but serial changes in the percentage of these cells and the LLM index may be helpful in the follow-up of disease severity.

Adult↗
PubMed1991

Detection of differential sensitivity to 5-fluorouracil in Ehrlich ascites tumour cells by 19F NMR spectroscopy.

Quantitative analysis of extracts from two Ehrlich ascites tumour cell lines (Lettre cells) by 19F NMR in vitro demonstrated that one Lettre cell line (designated LLM) metabolized 30-50% less 5-fluorouracil to 5-fluoronucleotides when compared to the other cell line (designated LHM). HPLC analysis of these cellular extracts showed a significant decrease in the concentration of the cytotoxic nucleotide 5-fluorouridine triphosphate in LLM cells compared to LHM cells. No major differences could be observed in the 31P and 1H NMR spectra of the two cell lines. Growth inhibition studies in vitro demonstrated that LLM cells were less sensitive to 5-fluorouracil than LHM cells. These results are consistent with the hypothesis that 19F NMR visible levels of 5-fluoronucleotides can predict the cytotoxicity of the anti-cancer drug 5-fluorouracil.

Adenosine Diphosphate↗
PubMed1980

Local leukocyte mobilization in irradiated or cyclophosphamide-treated rats.

Sprague-Dawley rats made neutropenic by 60Co irradiation or cyclophosphamide treatment retained a limited capacity for mounting a local leukocyte mobilization (LLM) response. Rats irradiated with 700 rad 60Co lacked an LLM. Rats treated with 100 mg/kg cyclophosphamide showed no LLM following an initial low response when assayed originally.

Agranulocytosis↗
PubMed2006

Laryngeal leiomyosarcoma: a case report and review of the literature.

Laryngeal leiomyosarcoma (LLM) is a rare malignancy originating from the smooth muscles of blood vessels or from aberrant undifferentiated mesenchymal tissue. Histological diagnosis may be particularly difficult and correct diagnosis is based on immunohistochemical investigations and electron microscopy. A case report of a LLM in a 74-year-old man is presented. Direct laryngoscopy revealed a large glottic lesion causing airway compromise and an emergency tracheotomy was performed. Subsequent total laryngectomy confirmed the diagnosis of leiomyosarcoma. Lung metastases developed 8 months following treatment, despite the absence of local or regional recurrence, and the patient died 3 months later. A review of the English and French literature revealed 30 previous cases of LLM. Clinical presentation, histological diagnosis, and management of this rare malignancy are analyzed aiming to improve our knowledge regarding the best treatment modality.

Aged↗
PubMed2005

Trace metal partitioning in Thalassia testudinum and sediments in the Lower Laguna Madre, Texas.

Seagrass communities dominate the Laguna Madre, which accounts for 25% of the coastal region of Texas. Seagrasses are essential to the health of the Laguna Madre (LM) and have experienced an overall decline in coverage in the Lower Laguna Madre (LLM) since 1967. Little is known on the existing environmental status of the LLM. This study focuses on the trace metal chemistry of four micronutrient metals, Fe, Mn, Cu, and Zn, and two non-essential metals, Pb and As, in the globally important seagrass Thalassia testudinum. Seasonal trends show that concentrations of most essential trace metals increase in the tissue during the summer months. With the exception of (1) Cu in the vertical shoot and root, and (2) Mn in the roots, no significant positive correlation exists between the rhizosphere sediment and T. testudinum tissue. Iron indicates a negative correlation between the morphological units and the rhizosphere sediments. No other significant relationship was found between the sediments and the T. testudinum tissue. Mn was enriched up to 10-fold in the leaf tissue relative to the other morphological units and also enriched relative to the rhizosphere sediments. Both Cu and Mn appear to be enriched in leaf tissue compared to other morphological units and also enriched relative to the Cu and Mn in the rhizoshpere sediments. Sediments cores taken in barren areas were slightly elevated in Zn relative to the rhizosphere sediments, whereas no other metals showed statistical differences between barren sediment cores and rhizosphere sediments. However, no correlation was measured in T. testudinum tissue and Zn in rhizosphere sediments. Previous studies suggested that Fe/Mn ratios could indicate differences between seagrass environments. Our results indicate that there is an influence from the Rio Grande in the Fe/Mn signature in sediments, and that ratio is not reflected in the T. testudinum tissue. The results from this study show that the LLM contains trace metal concentrations less than or equal to values for uncontaminated locations worldwide. In addition, there appears to be a complex partitioning in the trace metals in the morphological units of T. testudinum tissue and that analysis only of the leaf may not be indicative of the trace metal levels in this important seagrass species.

Environmental Monitoring↗
PubMed2005

IL-8 and airway neutrophilia in children with gastroesophageal reflux and asthma-like symptoms.

Gastroesophageal reflux (GER) may induce respiratory symptoms (RS) through inhalation of acid gastric contents. To characterize the airway inflammation associated with this condition, 20 children [7.4 (0.9) yr old] with "difficult to treat" RS and a positive 24-h oesophageal pH monitoring (pHm) were studied and bronchoalveolar lavage (BAL) performed. The control group included 10 children [7.3 (1.3) yr], non-atopics, with a respiratory clinical history similar to the cases but no reflux, as demonstrated by a negative 24-h oesophageal pHm. On BAL samples, in addition to inflammatory indexes, the lipid-laden macrophage (LLM) index was determined as index of gastric content inhalation. As compared to controls, GER children had higher neutrophil proportion (P=0.002), higher LLM index (P=0.004) and higher concentrations of interleukin (IL)-8 (P=0.005), myeloperoxidase (MPO) (P=0.001) and elastase (P=0.045) in BAL fluid. In GER children, but not in controls, neutrophil proportion significantly correlated with LLM index (r=0.65, P=0.002), with IL-8 (r=0.62, P=0.003) and MPO levels (r=0.54, P=0.014) but not with elastase concentrations. These results suggest an active pathogenetic role of IL-8 in the recruitment and activation of neutrophils in the airways of children with GER, respiratory symptoms and BAL findings suggestive of gastric content aspiration.

Asthma↗
PubMed2025

Automating candidate gene prioritization with large language models: from naive scoring to literature-grounded validation.

MOTIVATION: Identifying promising therapeutic targets from thousands of genes in transcriptomic studies remains a major bottleneck in biomedical research. While large language models (LLMs) show potential for gene prioritization, they suffer from hallucination and lack systematic validation against expert knowledge. RESULTS: The framework identified 609 sepsis-relevant genes with >94% filtering efficiency, demonstrating strong enrichment for inflammatory pathways including TNF-α signaling, complement activation, and interferon responses. Literature validation yielded 30 ultra-high confidence therapeutic candidates, including both established sepsis genes (IL10, TREM1, S100A9, NLRP3) and novel targets warranting investigation. Benchmark validation against expert-curated databases achieved 71.2% recall, with systematic correlation between computational confidence and evidence quality. The final candidate set balanced discovery (11 novel genes) with validation (19 known genes), maintaining biological coherence throughout the filtering process. This framework demonstrates that rigorous methodology can transform unreliable LLM outputs into systematically validated biological insights. By combining computational efficiency with literature grounding, the approach provides a practical tool for prioritizing experimental validation efforts. The modular design enables adaptation to other diseases through knowledge base substitution, offering a systematic approach to literature-guided biomarker discovery. AVAILABILITY AND IMPLEMENTATION: We developed a two-stage computational framework that combines LLM-based screening with literature validation for systematic gene prioritization. Starting with 10 824 genes from the BloodGen3 repertoire, we applied multi-criteria evaluation for sepsis relevance, followed by retrieval-augmented generation using 6346 curated sepsis publications. A novel faithfulness evaluation system verified that LLM predictions aligned with retrieved literature evidence. Source code and implementation details are available at https://github.com/taushifkhan/llm-geneprioritization-framework, vector database at https://doi.org/10.5281/zenodo.15802241, and Interactive demonstration at https://llm-geneprioritization.streamlit.app/.

Humans↗
PubMed2025

Target and biomarker exploration portal for drug discovery.

MOTIVATION: The discovery of novel drug targets and precision biomarkers remains a major challenge in drug development, with traditional differential expression analysis often overlooking key regulatory proteins. Here, we present a novel, web-based bioinformatics tool, the Target and Biomarker Exploration Portal (TBEP), designed to accelerate the drug discovery process by integrating large-scale biomedical data with network analysis techniques. RESULTS: TBEP harnesses machine-learning approaches to mine and combine multimodal datasets, including human genetics, functional genomics, and protein-protein interaction networks, to decode causal disease mechanisms and uncover novel therapeutic targets and precision biomarkers for specific phenotypes. A unique feature of the tool is its ability to process large-scale data in real-time, facilitated by an efficient cloud-based architecture. Additionally, the tool incorporates an integrated large language model (LLM), which assists researchers in exploring and interpreting complex biological relationships within the generated networks and multi-omics data using natural language (English). By offering an intuitive, interactive interface, the LLM enhances the exploration of biological insights, making it easier for scientists to derive actionable conclusions. This powerful integration of network analysis, multi-omics data, and LLM provides a robust framework for accelerating the identification of novel drug targets. AVAILABILITY AND IMPLEMENTATION: The tool is publicly available at https://tbep.missouri.edu. The source code, documentation and installation instructions are available at GitHub repository: https://github.com/mizzoudbl/tbep.

Drug Discovery↗
PubMed2006

Immunohistochemical detection of myogenin and p21 in methylcholanthrene-induced mouse rhabdomyosarcomas.

3-Methylcholanthrene (MC)-induced 10 embryonal (ERSs) and 24 pleomorphic rhabdomyosarcomas (PRSs) of the dermis in mouse were examined immunohistochemically for myogenin, p21 and proliferating cell nuclear antigen (PCNA) nuclear reactivity and myosin reactivity. ERSs had higher expression of myogenin and p21 compared with that of myosin. PRSs were divided into two groups having high (moderate or marked reactivity; HLM) and low (mild reactivity; LLM) levels of myosin expression. Expression of p21 was higher in HLM-PRSs than in LLM-PRSs. Statistically significant association was observed between myosin and p21 expression in PRSs, but not between myosin and myogenin expression. Myogenin and p21 reactivity were observed in myoblast-like cells, but rarely in multinucleated cells. In ERSs, small undifferentiated myogenic precursor cells were also positive for p21. No difference of PCNA reactivity was observed between HLM-PRSs and LLM-PRSs, although its reactivity was higher in PRSs than in ERSs. The results suggest that myogenin is related to myoblast-like cell differentiation in PRSs and that p21 plays essential roles in myotube formation and myosin expression. In ERSs, p21 may be involved in inhibition of myogenic precursor cell proliferation and differentiation.

Animals↗
PubMedDate not supplied

Patterns and effectiveness of lipid-lowering therapies in a managed care environment.

OBJECTIVE: To investigate the effectiveness of statin therapy and to compare the effectiveness results of this study with the reported efficacy of the corresponding data from randomized clinical trials in a moderate-to-high risk coronary heart disease (CHD) managed care population. METHODS: Subjects, > or = 18 years old, with a new hyperlipidemia diagnosis or a new prescription claim for a lipid-lowering medication (LLM) between January 1, 1999 and March 31, 2001 were followed for 12 months. Subjects were classified into six medication categories of LLM use based partly on efficacy levels on package inserts. CHD risk factors were measured in the 24-month period prior, and subjects were required to have an established CHD or a CHD-related condition, or have two or more CHD risk factors. RESULTS: The study population consisted of 39,124 hyperlipidemic subjects with moderate-to-high CHD risk; 22,048 (56.4%) were untreated with LLMs. Absolute mean low-density lipoprotein cholesterol (LDL-C) reductions ranged from a 32 mg/dL decrease in the low-efficacy groups to a 57 mg/dL decrease in the high efficacy statin group; percent reductions ranged from a 19% reduction from baseline to a 32% reduction from baseline, respectively. Less than half of subjects (47%) reached LDL goals set forth by NCEP Adult Treatment Panel (ATP III) guidelines, however, the rate of reaching goal increased as statin efficacy increased. CONCLUSIONS: While a dose-response relationship was observed, the effectiveness of statin therapy was less than stated in package labeling and only 72% of the users of the highest efficacy statins reached their ATP III goal. LLM use was inconsistent with that recommended by the NCEP ATP III CHD risk assessment. Hyperlipidemia treatment in the managed care setting remains in need of improvement.

Adolescent↗