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Results for “Latent diffusion”

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At least 19 recordsLinked to original sources

PubMed2026

CRISPGen: A deep generative framework for multi-objective CRISPR/Cas9 guide RNA design via Conditional Latent Diffusion and Dual-Critic Reinforcement Learning.

MOTIVATION: The CRISPR-Cas9 system offers transformative potential for precision genome editing, yet its clinical translation remains constrained by the risk of unintended off-target double-strand breaks. While current discriminative models excel at evaluating pre-specified candidate guides, resolving the fundamental antagonism between on-target cleavage efficiency and off-target specificity within a fixed sequence search space remains a major challenge. RESULTS: We present CRISPGen, a unified deep generative framework that reframes sgRNA design as a multi-objective constrained sequence synthesis problem. It integrates (i) DNABERT-2 genomic-language embeddings, (ii) a conditional latent diffusion generator conditioned on a user-specified on-target efficiency target, and (iii) a dual-critic reinforcement-learning (RL) stage that couples a frozen on-target efficiency critic with a cross-attention off-target discriminator (validation Pearson R=0.8157) trained on a unified corpus of experimental off-target events from six detection platforms. Across 1000 generated sgRNAs, CRISPGen reduces the mean off-target discriminator score by 99.7% relative to the pre-RL baseline and, under an exhaustive whole-genome screen of all 302,631,056 NGG PAM sites in GRCh38, yields zero perfect-match and only 55 one-mismatch genomic hits. We further show, transparently, that the internal on-target critic saturates under RL optimization - an instance of Goodhart's Law - and therefore assess on-target viability using an independent external CRISPRon screen (mean 47.10/100). Repeating the RL fine-tuning stage under three random seeds (with the diffusion generator, DNABERT-2 embeddings, and off-target discriminator held fixed) yields a stable operating point across seeds. Full diversity, per-mismatch, and reproducibility statistics are reported in the Results. AVAILABILITY: Source code is available at https://github.com/malekpouri/CRISPGen; the pre-trained checkpoints and the 3,000,000-sequence library are hosted on Hugging Face (https://huggingface.co/malekpouri/CRISPGen-Checkpoints) and archived on Zenodo under DOI 10.5281/zenodo.21428641.

CRISPR-Cas9↗

PubMed2026

Enhancing pan-cancer spatial transcriptomics at single-cell resolution with stPainter.

Subcellular spatial transcriptomics can resolve tissue architecture at cellular scale, but sparse gene panels and limited detection sensitivity constrain downstream analysis. Existing enhancement methods often require tissue-matched single-cell RNA sequencing (scRNA-seq) references and dataset-specific retraining. Here we show that stPainter, a conditional generative model pretrained on a pan-cancer scRNA-seq atlas, can enhance spatial transcriptomics data without matched references or retraining. Using a latent diffusion architecture guided by Stochastic Differential Equations (SDE), stPainter reconstructs expanded expression profiles from sparse measurements and produces latent representations for clustering and cell-state analysis. When we apply stPainter upon 6 spatial transcriptomics datasets of different cancer types, we demonstrate that our model empowers downstream biological analyses, including fine-grained subpopulation clustering and pathway enrichment. Comparison with spatially resolved proteomics (CODEX) provided independent support for regional agreement between imputed cellular compositions and protein-level tissue organization. These results establish stPainter as a scalable approach for analyzing tumor microenvironments without auxiliary sequencing data.

Spatial Transcriptomics↗

PubMed1978

Production and life-span of platelets and of fibrinogen in acute leukaemia. 75Se-selenomethionine- and 51Cr (Na-chromate)-studies.

The life-span of platelets and of fibrinogen was studied by the use of 75Se-selenomethionine and 51Cr in 28 cases of acute leukaemia (AL), and in 2 cases of chronic myelocytic leukaemia with blast-cell transformation. The patients were grouped on the basis of clinical remission or activity. In all groups, whether examined by means of 75Se or 51Cr, a reduction of variable degree was found in platelet life-span, and platelet turnover was reduced in the majority of the cases. The sequestration data were atypical. Simultaneous 75Se studies for platelet and fibrinogen life-span revealed a latent diffuse intravascular coagulation (DIC) in three cases, the process being still in progress in one case and in remission in two cases at the time of observation. Fibrinogen life-span was reduced in some of the cases. Thrombocytopenia in AL is attributed to a complex origin in which infiltration of the bone marrow, the destructive effect of antimetabolic therapy, abnormally increased consumption of storage of the functionally impaired platelets, possibly latent DIC or episodic excessive sequestration may be equally involved. Remission may be accompanied by normalization of both thrombopoiesis and platelet kinetics.

Adolescent↗

PubMed1976

[Diffuse bronchial calcinosis revealing latent primary hyperparathyroidism].

The authors report an unusual case of diffuse bronchial calcinosis of established histology, found during a routine bronchoscopy in a pulmonary tuberculous patient aged 46. The lesions consisted in several small pale bulgings on the wall of the main bronchi on both sides. This finding led to the diagnosis of rough primary hyperparathyroidism.

Alkaline Phosphatase↗

PubMed1976

[Results of comprehensive respiratory function tests in CNSLD (author's transl)].

34 persons with CNSLD, but fit for work, were examined with the aim to record the degree of disturbance of pulmonary function and the underlying pathophysiological mechanism. The results were compared with 30 healthy subjects. The following function tests were carried out under resting conditions and bicycle ergometer exercises: Analysis of ventilation (FVC% pred., FEV1% FVC, RV% pred., RV% TLC), analysis of lung mechanic (Raw, CL) measurement of diffusion (DL, DM, Vc, DL% pred.) and analysis of lung inhomogeneity (RE/REO, V2/V1, CL6/CL100, deltaFN2/deltaV500, deltaFCO2/deltaV500,IHB). The results were analyzed and evaluated by using the digital computer C 8205. Persons suffering from CNSLD were showing among typical clinical symptoms the following disturbances of lung function: The obstructive ventilation disturbance stands in the foreground in connection with signs of inhomogeneity of lung mechanics and ventilation. While the resistance already shows the airway obstruction objectively under resting conditions, the decreased compliance is measurable at first under exercise. The disturbance of diffusion, which is pointed out, is mainly a latent decreased diffusing capacity of alveolo-capillary membrane. These disturbance of diffusion gets more importance because the inhomogeneity of lung hides the real disturbance of diffusion. The pathophysiological consequence of disturbed partial functions of respiration is the latent hypoxaemia without hypercapnia, therefore the signs of respiratory partial insufficiency.

Adult↗

PubMedDate not supplied

Serological and chemical studies of latent allotypes in the rabbit.

Genetic data has shown that antigenic variants or allotypes of variable and constant regions of the heavy and light chains of immunoglobulins represent products of allelic structural genes. New findings in several animal systems have demonstrated the non-allelic behavior of immunoglobulin allotypes. In the present study we report the results of our efforts to confirm the presence of latent allotypes in rabbit sera. Varying amounts of latent allotypes for groups a and b markers were detected in 95% of all normal and immune sera tested. Several rabbits expressed high levels of latent a and b allotypes (in excess of 200 micrograms/ml of serum). By gel diffusion and radioimmune inhibition analysis, the latent b4 marker from one b6b6 rabbit, B240, was identical to the nominal b4 allotype. Also, the L chains bearing the latent b4 marker were isolated from B240 IgG and analyzed chemically by taking advantage of an acid-labile aspartic acid-proline bond at positions 109 and 110, which is unique for b4 and b9 kappa L chains.

Alleles↗

PubMed1979

A latent adenosine triphosphatase form of dynein 1 from sea urchin sperm flagella.

Treatment of demembranated sea urchin sperm axonemes with an extraction solution containing 0.6 M NaCl, pH 7.0 for 10 min at 4 degrees C yields a solution of dynein 1 having a low, latent specific ATPase activity of about 0.25 mumol of Pi mg(-1) min(-1). Exposure of this dynein solution to 0.1% Triton-X-100 for 10 min at 25 degrees C causes an increase in its ATPase activity to about 3 mumol of Pi mg(-1) min(-1). A similar activation can be obtained by treating at 42 degrees C or by reacting with 60 mol of p-chloromercuribenzene sulfonate/10(6) g of protein. The effects of these activating procedures are not additive, suggesting that they lead to a common activated state. Purification of the latent activity dynein 1 by sucrose density gradient centrifugation yields a monodisperse preparation sedimenting at 21 S, and having a molecular weight of 1,250,000 as determined by sedimentation diffusion and sedimentation equilibrium. Activation of the latent dynein 1 with Triton X-100 converts it to a form sedimenting at 10 to 14 S. The 21 S dynein is also converted to a 10 S form by dialysis against 5 mM imidazole/NaOH buffer, 0.1 mM EDTA, 5 mM 2-mercaptoethanol, pH 7, although in this case, the ATPase activity is increased only about 3-fold, with another 3-fold activation being obtainable upon subsequent treatment with Triton X-100. The 21 S latent form of dynein 1 may represent the intact dynein arms that form moving cross-bridges and generate active sliding between adjacent doublet tubules of the flagellar axoneme. Electrophoretic analysis on polyacrylamide gels in the presence of sodium dodecyl sulfate suggests a model in which the 21 S dynein 1 particle is composed of three subunits of about 330,000 daltons and one of each of three medium weight subunits of 126,000, 95,000, and 77,000 daltons. When latent dynein 1 is added back to NaCl-extracted axonemes in the presence of 0.15 M NaCl, it recombines stoichiometrically and restores the arms on the doublet tubules with a 6-fold activation of its ATPase activity measured in the absence of KCl.

4-Chloromercuribenzenesulfonate↗

PubMed1975

Uptake of local anaesthetics: movement of ethanol into frog sciatic nerve.

The changes of nerve action potential with time of the excised bullfrog sciaticperoneal nerve were measured at 24 degrees C with the nerve immersed in oxygenated mineral oil containing various concentrations of ethanol. One series of measurements was made with intact nerve and a range of about 20 to 110 millimolar ethanol. Another series was made with nerves in which the epineural sheath was cut open longitudinally and using a range of about 15 to 51 millimolar ethanol. The results were analysed by means of simple diffusion theory, and below applied ethanol concentrations of about 70 millimolar the latent periods and times to total block fitted the theoretical pattern well. Disagreements between theory and measurement of previous workers is explainable by their neglecting to recognize that nerve bundles do not extend to the nerve periphery. It was found that the minimum oil concentration of ethanol capable of producing total block is 15 millimolar. Above 70 millimolar, behaviour was observed consistent with nerve damage. It was found possible, by measuring the ratio latent period: time to total block, to separate the relative contribution of the epineural sheath and epineurium as a diffusion barrier to ethanol from that of the perineurium and perilemma.

Action Potentials↗

PubMed1979

[Clinical morphology of early breast cancer].

True early forms of mammary cancer include tumours undetectable in routine clinical examinations and histologically presenting intraductal and lobular cancer (cancer in situ and with beginning invasion) in the absence of metastases. Parallel histological and cytological examinations and cytospectrophotometric determination of the DNA content increase the validity of the differential diagnosis between benign displasias and carcinoma in situ. Stages of composite clinico-roentgenilogical and morphological diagnosis of early mammary cancer have been developed. Two mammographic signs: accumulations of finest calcinates and filamentous tumour node less than 10 mm in diameter, permit to diagnose clinically latent cancer which has two forms of growth, diffuse and nodular. The diffuse form in some cases presents a stage preceeding the nodular form.

Breast Neoplasms↗

PubMed1977

[Excretion of alanine aminopeptidase in the urine after administration of lysosomotrophic substances in patients with latent or florid pyelonephritis].

It is described a test for the presence of diffuse nephropathies which is based on the fact that after application 20 ml of the renal diatrizoate X-ray contrast medium Visotrast or of 500 ml of a 10% mannitol solution in patients with preexisting renal diseases appear reversible, diagnostically relevant increases of the alanine aminopeptidase excretion with the urine. In persons with healthy kidneys the excretion of enzymes changes insignificantly. The increased excretion of alanine aminopeptidase is also observed in patients with latent pyelonephritis and is traced back to the increased formation of an osmotic nephropathy in patients with preexisting nephropathies.

Alanine↗

PubMed2026

Conditional Diffusion Model-Based Method for Annotation of Antibiotic Resistance Gene Properties.

The crisis of bacterial antibiotic resistance, which has led to a decline in the effectiveness of antibiotics originally used to combat bacterial infections, has emerged as an urgent challenge for public health. Antibiotic resistance genes (ARGs) are one of the key reasons for bacteria to develop resistance to antibiotics. Therefore, accurately identifying and annotating the critical properties of ARGs is of great importance for addressing the antibiotic resistance emergency. Although existing deep learning models demonstrate remarkable effectiveness in extracting local features from sequence data, they still face limitations in the capacity to further gain the enriched latent representations within the data. To address the critical challenge of extracting higher-quality representations from ARGs sequence data, we propose a novel ARGs properties annotation method based on the conditional diffusion model which is used to learn latent representations through domain-specific knowledge injection. Specifically, during the conditional information integration phase, we systematically incorporate ARGs' domain knowledge to guide the diffusion process in generating high-quality latent representations. To overcome information redundancy caused by direct concatenation of conditional information and intermediate features, we design a cross-attention mechanism that enables feature fusion between heterogeneous information sources, thereby enhancing further the quality of obtained representations. Experimental results on widely used data sets demonstrate the framework's effectiveness in achieving superior prediction performance compared to existing methods.

Anti-Bacterial Agents↗

PubMed2026

Deep generative models in biological sequence and structure analysis and design.

Deep generative models have transformed biological sequence modeling from predictive analysis toward increasingly controllable design. Early biological applications of Variational Autoencoders (VAEs) and Generative Adversarial Networks (GANs) established latent representation learning and sequence synthesis, while recent advances in transformer-based language models, discrete diffusion, flow-matching, and multimodal generative frameworks have substantially expanded the scope of biological design. This review examines generative models for DNA, RNA, and protein sequence design, emphasizing how different model classes represent biological constraints, operate over discrete and continuous spaces, and integrate sequence, structure, and function. We compare VAEs, GANs, autoregressive and masked language models, diffusion models, and flow-based approaches across genomics, transcriptomics, and proteomics, with particular attention to controllability, long-range dependency modeling, structural grounding, generalization, and experimental utility. We further examine evaluation strategies, out-of-distribution generalization, and closed-loop design-build-test-learn workflows that connect in silico generation with empirical validation. We distinguish fundamental modality-dependent constraints including sequence discreteness, context length, structural coupling, and physical or thermodynamic requirements from architecture-dependent advantages that reflect the current state of the field. Current studies suggest that long-context models are particularly useful for genome-scale representation and sequence modeling, whereas structure-aware diffusion, flow-based, and inverse-folding approaches provide better frameworks for geometry-constrained RNA and protein design. This perspective provides a critical framework for understanding the present capabilities, limitations, and convergence of generative approaches toward reliable and experimentally grounded biological design.

Biological sequence analysis↗

PubMed2025

Brain Health Loss Mediates the Effect of Infarct Volume on Functional Outcome in Ischemic Stroke.

IMPORTANCE: Brain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. OBJECTIVE: To determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. DESIGN: Observational multicenter cohort study. SETTING: We analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. PARTICIPANTS: Adult patients consecutively diagnosed with AIS, with available admission MRI. EXPOSURE: At admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. ΔeR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if ΔeR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). MAIN OUTCOME MEASURE: Proportion of mediating effect. RESULTS: We included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, ΔeR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect (ß=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through ΔeR: ß=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not ≤67y. CONCLUSIONS AND RELEVANCE: Stroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS.

acute ischemic stroke↗

PubMed1978

[Serological diagnosis of bovine leukosis using the agar gel diffusion test].

Experiments were carried out to use the agar gel diffusion test (AGDT) in the study of bovine leukosis. An antigen was obtained from FLK-24 cells with a latent leukosis virus infection, which proved specific and suitable for AGDT. A total of 134 serum samples were examined applyig AGDT, for the presence of specific antibodies, originating from cattle of herds in which leukosis had been hematologically demonstrated. Investigated were also 56 sera of animals presenting an unknown clinical picture. Positive reaction was established in 70 per cent of the sera taken from herds with hematologically demonstrated leukosis. The specificity of AGDT was confirmed through establishing specific antibodies also in sera of lambs experimentally infected with a virus from a FBL-J 5 cell line with a latent infection. It is admitted that AGDT is a specific, sensitive, and readily applicable method, which can successfully be used in the diagnostics of leukosis in this country.

Agar↗

PubMed1975

[Pulmonary edemas due to acute heroin poisoning].

Their frequency is estimated with difficulty, although on autopsy pulmonary edema is found almost routinely. It is a major complication of overdoses (48 p. 100 of severe intoxications). Their formation can be suspected, when after the first phase of respiratory depressions, with coma, myosis, and a variable latent period, a second attack of respiratory insufficiency occurs with tachypnea, and cyanosis. The chest X-ray shows diffuse alveolar infiltration, sparing the apices. The heart being generally of normal size. Rapid disappearance of this infiltrate (24 to 48 hours) enables the elimination of two diagnoses: pneumonia due to inhalation of gastric fluid, an infectious pneumonia. Their pathogenesis remains very debatable: - in the majority of cases abrupt L.V.F. can be eliminated: -on the other hand it could be an allergic accident of the anaphylactic type, or local liberation of histamine, or a local toxic action on the pulmonary capillaries; - hypoxia, secondary to respiratory depression, could lead to pulmonary edema, by the same mechanism as at altitude; - finally, owing to the central neurological disorders a neurogenic theory can be put forward. Their treatment is essentially a combination of Nalorphine with oxygen therapy (by mask, or if necessary by assisted, controlled ventilation) with prevention of inhalation of gastric fluid (gastric emptying) or curative treatment of possible aspiration by antibiotics, and cortico-steroids. Diuretics can be useful, as well as cardiotonics.

Acute Disease↗

PubMed1977

Morphogenesis of early 1, 2-dimethylhydrazine-induced lesions and latent period reduction of colon carcinogenesis in mice by a variant of Citrobacter freundii.

The morphogenesis of 1, 2-dimethylhydrazine (DMH)-induced lesions in the colon of outbred NIH Swiss mice was determined for up to 5 months of treatment. The effect of hyperplasia on DMH carcinogenesis was also evaluated by introducing a transient hyperplastic stimulus to the colon during the chronic weekly treatment regimen of DMH. The hyperplastic stimulus was a naturally occurring disease of mice, transmissible murine colonic hyperplasia, which is caused by a variant of Citrobacter freundii. In control mice, those not receiving the bacterium, weekly injections of the carcinogen induced neoplastic changes first detectable at two months of treatment in all segments of the colon and in both sexes. The changes increased in frequency and severity with time. Diffuse mucosal hyperpladia and chronic inflammatory and degenerative changes were also associated with DMH after prolonged treatment. The hyperplastic stimulus of C. freundii reduced the latent period for appearance of early DMH tumors, but it had no influence on already established DMH tumors.

Animals↗

PubMed2026

Phenotyping strategies for chronic overlapping pain conditions and internalizing disorders in Veterans: Prevalence, comorbidity, and latent structure as evidence for construct validity.

Chronic overlapping pain conditions (COPCs), internalizing (INT) disorders, and opioid use disorder (OUD) are common, comorbid, and difficult to phenotype at scale. Electronic health record (EHR) studies commonly define cases using Any Code (AC; ≥1 ICD-9/10 code) and Multiple Code (MC; ≥1 inpatient or ≥2 outpatient codes) phenotyping strategies, but it is unclear whether these thresholds change only case numbers or also the clinical relationships among conditions. This cross-sectional study included approximately 950,000 Million Veteran Program participants with ≥2 visits. AC and MC phenotypes for 17 conditions spanning COPCs, INT, and OUD were compared in prevalence, case characteristics, comorbidity, and latent structure. Random-thinning analysis compared AC-MC differences to case reduction alone. Construct validity was evaluated through correspondence with expected patterns of association and latent organization. Back pain (AC=58.1%; MC=48.1%), major depressive disorder (41.5%; 36.2%), and post-traumatic stress disorder (32.6%; 29.1%) were most prevalent. MC excluded 33.5% of AC cases on average, and MC cases had greater healthcare utilization, diagnostic burden, opioid exposure, and psychiatric medication use than AC-only cases. The observed mean absolute correlation change (mean |Δr|=0.014) was smaller than in all 1000 random-thinning replicates. Both strategies supported a correlated, four-factor model consistent with "Anxious Misery," "Fear," "Diffuse Pain," and "Head Pain" (AC: CFI=0.987, RMSEA=0.015; MC: CFI=0.987, RMSEA=0.014). The MC strategy reduced prevalence and altered case composition but maintained the expected comorbidity and latent organization patterns among conditions. Findings provide evidence of phenotype construct validity and inform selection of EHR phenotyping strategies for epidemiological and genomic research. PERSPECTIVE: Commonly used EHR phenotyping strategies tested in nearly one million Veterans produce broadly similar latent organization across comorbid and prevalent chronic overlapping pain conditions, internalizing disorders, and opioid use disorder. Findings support construct validity and clarify trade-offs involving case inclusion, recorded burden, and healthcare observation in large-scale research.

Chronic overlapping pain conditions↗

PubMed1979

[Role of changes in the hemodynamics of the pulmonary circulation in pulmonary gas exchange].

High pressure in the lung artery was maintained with the aid of i. v. serotonin administration (0.5 mg/ml) in dogs during 10 min. The simultaneous increase of the intravascular pressure in minor circulation and of the lung volume circulation was followed by an increasing blood volume in lungs, diffusion capacity of lungs, oxygen tension in the arterial blood, and satiation of the latter with oxygen. The combined action of the above two hemodynamic factors aids to opening of latent vascular areas, to a more regular distribution of perfusion over the lung areas according to the ventilation level. This mechanism seems to be one of the first compensatory responses to disturbances in the lung gas exchange.

Animals↗