From explainable to interpretable deep learning for natural language processing in healthcare: How far from reality?

Deep learning (DL) has substantially enhanced natural language processing (NLP) in healthcare research. However, the increasing complexity of DL-based NLP necessitates transparent model interpretability, or at least explainability, for reliable decision-making. This work presents a thorough scoping review of explainable and interpretable DL in healthcare NLP. The term "eXplainable and Interpretable Artificial Intelligence" (XIAI) is introduced to distinguish XAI from IAI. Different models are further categorized based on their functionality (model-, input-, output-based) and scope (local, global). Our analysis shows that attention mechanisms are the most prevalent emerging IAI technique. The use of IAI is growing, distinguishing it from XAI. The major challenges identified are that most XIAI does not explore "global" modelling processes, the lack of best practices, and the lack of systematic evaluation and benchmarks. One important opportunity is to use attention mechanisms to enhance multi-modal XIAI for personalized medicine. Additionally, combining DL with causal logic holds promise. Our discussion encourages the integration of XIAI in Large Language Models (LLMs) and domain-specific smaller models. In conclusion, XIAI adoption in healthcare requires dedicated in-house expertise. Collaboration with domain experts, end-users, and policymakers can lead to ready-to-use XIAI methods across NLP and medical tasks. While challenges exist, XIAI techniques offer a valuable foundation for interpretable NLP algorithms in healthcare.

Effect of different surgical options on the long-term survival of stage I gallbladder cancer: a retrospective study based on SEER database and Chinese Multi-institutional Registry.

BACKGROUND: Gallbladder cancer (GC) is a uncommon and highly malignant tumor. This study compared the effects of simple cholecystectomy (SC) and extended cholecystectomy (EC) on the long-term survival of stage I GC. METHODS: Patients with stage I GC between 2004 and 2015 in the SEER database were selected. Meanwhile, this study collected the clinical information of patients with stage I GC admitted to five medical centers in China between 2012 and 2022. Using clinical data from patients in the SEER database as a training set to construct a nomogram, which was validated in Chinese multicenter patients. Long-term survival between SC and EC were distinguished using propensity score matching (PSM). RESULTS: A total of 956 patients from the SEER database and 82 patients from five Chinese hospitals were included in this study. The independent prognostic factors were age, sex, histology, tumor size, T stage, grade, chemotherapy and surgical approach by multivariate Cox regression analysis. We developed a nomogram based on these variables. The nomogram has been proved to have good accuracy and discrimination in internal and external validation. The cancer-specific survival (CSS) and overall survival of patients receiving EC were better than those of SC before and after the propensity score match. The interaction test showed that EC was associated with better survival in patients aged ≥ 67 years (P = 0.015) and in patients with T1b and T1NOS (P < 0.001). CONCLUSION: A novel nomogram to predict CSS in patients with stage I GC after SC or EC. Compared with SC, EC for stage I GC had higher OS and CSS, especially in specific subgroups (T1b, T1NOS, and age ≥ 67 years).

Inter-Domain Repulsion of Dumbbell-Shaped Calmodulin during Electrospray Ionization Revealed by Molecular Dynamics Simulations.

The mechanisms whereby protein ions are released from nanodroplets at the liquid-gas interface have continued to be controversial since electrospray ionization (ESI) mass spectrometry was widely applied in biomolecular structure analysis in solution. Several viable pathways have been proposed and verified for single-domain proteins. However, the ESI mechanism of multi-domain proteins with more complicated and flexible structures remains unclear. Herein, dumbbell-shaped calmodulin was chosen as a multi-domain protein model to perform molecular dynamics simulations to investigate the structural evolution during the ESI process. For [Ca4CAM], the protein followed the classical charge residue model. As the inter-domain electrostatic repulsion increased, the droplet was found to split into two sub-droplets, while stronger-repulsive apo-calmodulin unfolded during the early evaporation stage. We designated this novel ESI mechanism as the domain repulsion model, which provides new mechanistic insights into further exploration of proteins containing more domains. Our results suggest that greater attention should be paid to the effect of domain-domain interactions on structure retention during liquid-gas interface transfer when mass spectrometry is used as the developing technique in gas phase structural biology.

Two different strategies of Diversispora spurca-inoculated walnut seedlings to improve leaf P acquisition at low and moderate P levels.

Walnut (Juglans regia) is an important nut tree species in the world, whereas walnut trees often face inadequate phosphorus (P) levels of soil, negatively limiting its growth and yield. Arbuscular mycorrhizal fungi (AMF) can colonize walnut roots, but whether and how AMF promotes walnut growth, physiological activities, and P acquisition is unclear. The present study aimed to evaluate the effects of Diversispora spurca on plant growth, chlorophyll component concentrations, leaf gas exchange, sugar and P concentrations, and expression of purple acid phosphatase (PAP) and phosphate transporter (PT) genes in leaves of J. regia var. Liaohe 1 seedling under moderate (100 µmol/L P) and low P (1 µmol/L P) levels conditions. Three months after inoculation, the root mycorrhizal colonization rate and soil hyphal length were 45.6-53.2% and 18.7-39.9 cm/g soil, respectively, and low P treatment significantly increased both root mycorrhizal colonization rate and soil hyphal length. Low P levels inhibited plant growth (height, stem diameter, and total biomass) and leaf gas exchange (photosynthetic rate, transpiration rate and stomatal conductance), while AMF colonization significantly increased these variables at moderate and low P levels. Low P treatment limited the level of chlorophyll a, but AMF colonization did not significantly affect the level of chlorophyll components, independent on soil P levels. AMF colonization also increased leaf glucose at appropriate P levels and leaf fructose at low P levels than non-AMF treatment. AMF colonization significantly increased leaf P concentration by 21.0-26.2% than non-AMF colonization at low and moderate P levels. Low P treatment reduced the expression of leaf JrPAP10, JrPAP12, and JrPT3;2 in the inoculated plants, whereas AMF colonization up-regulated the expression of leaf JrPAP10, JrPAP12, and JrPT3;2 at moderate P levels, although AMF did not significantly alter the expression of JrPAPs and JrPTs at low P levels. It is concluded that AMF improved plant growth, leaf gas exchange, and P acquisition of walnut seedlings at different P levels, where mycorrhizal promotion of P acquisition was dominated by direct mycorrhizal involvement in P uptake at low P levels, while up-regulation of host PAPs and PTs expressions at moderate P levels.

Tumors evade immune cytotoxicity by altering the surface topology of NK cells.

The highly variable response rates to immunotherapies underscore our limited knowledge about how tumors can manipulate immune cells. Here the membrane topology of natural killer (NK) cells from patients with liver cancer showed that intratumoral NK cells have fewer membrane protrusions compared with liver NK cells outside tumors and with peripheral NK cells. Dysregulation of these protrusions prevented intratumoral NK cells from recognizing tumor cells, from forming lytic immunological synapses and from killing tumor cells. The membranes of intratumoral NK cells have altered sphingomyelin (SM) content and dysregulated serine metabolism in tumors contributed to the decrease in SM levels of intratumoral NK cells. Inhibition of SM biosynthesis in peripheral NK cells phenocopied the disrupted membrane topology and cytotoxicity of the intratumoral NK cells. Targeting sphingomyelinase confers powerful antitumor efficacy, both as a monotherapy and as a combination therapy with checkpoint blockade.

Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling.

Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau. Methods: We analyzed genes differentially expressed in induced pluripotent stem cell-derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.

Metabolite profiling and identification in living cells by coupling stable isotope tracing and induced electrospray mass spectrometry.

Direct observation of metabolites in living cells by mass spectrometry offers a bright future for biological studies but also suffers a severe challenge to untargeted peak assignment to tentative metabolite candidates. In this study, we developed a method combining stable isotope tracing and induced electrospray mass spectrometry for living-cells metabolite measurement and identification. By using 13C6-glucose and ammonium chloride-15N as the sole carbon and nitrogen sources for cell culture, Escherichia coli synthesized metabolites with 15N and 13C elements. Tracing the number of carbon and nitrogen atoms could offer a complementary dimension for candidate peak searching. As a result, the identification confidence of metabolites achieved a universal improvement based on carbon/nitrogen labelling and filtration.

α-Synuclein as a Target for Metallo-Anti-Neurodegenerative Agents.

The unique thermodynamic and kinetic coordination chemistry of ruthenium allows it to modulate key adverse aggregation and membrane interactions of α-synuclein (α-syn) associated with Parkinson's disease. We show that the low-toxic RuIII complex trans-[ImH][RuCl4 (Me2 SO)(Im)] (NAMI-A) has dual inhibitory effects on both aggregation and membrane interactions of α-syn with submicromolar affinity, and disassembles pre-formed fibrils. NAMI-A abolishes the cytotoxicity of α-syn towards neuronal cells and mitigates neurodegeneration and motor impairments in a rat model of Parkinson's. Multinuclear NMR and MS analyses show that NAMI-A binds to residues involved in protein aggregation and membrane binding. NMR studies reveal the key steps in pro-drug activation and the effect of activated NAMI-A species on protein folding. Our findings provide a new basis for designing ruthenium complexes which could mitigate α-syn-induced Parkinson's pathology differently from organic agents.

NADPH oxidase 2 limits amplification of IL-1ß-G-CSF axis and an immature neutrophil subset in murine lung inflammation.

The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its antimicrobial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 (LTB4) production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the model fungal particle zymosan. We now identify interleukin-1ß (IL-1ß) and downstream granulocyte colony-stimulating factor (G-CSF) as critical amplifying signals that augment and sustain neutrophil accrual in CGD mice. Neutrophils, delivered into the lung via LTB4, were the primary source of IL-1ß within the airways, and their increased numbers in CGD lungs led to significantly elevated local and plasma G-CSF. Elevated G-CSF simultaneously promoted increased granulopoiesis and mobilized the release of higher numbers of an immature CD101- neutrophil subset from the marrow, which trafficked to the lung and acquired a significantly more proinflammatory transcriptome in CGD mice compared with wild-type mice. Thus, neutrophil-produced IL-1ß and downstream G-CSF act sequentially but nonredundantly with LTB4 to deploy neutrophils and amplify inflammation in CGD mice after inhalation of zymosan. NOX2 plays a critical role in dampening multiple components of a feed-forward pipeline for neutrophil recruitment, and these findings highlight NOX2 as a key regulator of neutrophil number, subsets, and function at inflamed sites.

Neutrophil and Macrophage NADPH Oxidase 2 Differentially Control Responses to Inflammation and to Aspergillus fumigatus in Mice.

Aspergillus fumigatus is an important opportunistic fungal pathogen and causes invasive pulmonary aspergillosis in conditions with compromised innate antifungal immunity, including chronic granulomatous disease, which results from inherited deficiency of the superoxide-generating leukocyte NADPH oxidase 2 (NOX2). Derivative oxidants have both antimicrobial and immunoregulatory activity and, in the context of A. fumigatus, contribute to both fungal killing and dampening inflammation induced by fungal cell walls. As the relative roles of macrophage versus neutrophil NOX2 in the host response to A. fumigatus are incompletely understood, we studied mice with conditional deletion of NOX2. When NOX2 was absent in alveolar macrophages as a result of LysM-Cre-mediated deletion, germination of inhaled A. fumigatus conidia was increased. Reducing NOX2 activity specifically in neutrophils via S100a8 (MRP8)-Cre also increased fungal burden, which was inversely proportional to the level of neutrophil NOX2 activity. Moreover, diminished NOX2 in neutrophils synergized with corticosteroid immunosuppression to impair lung clearance of A. fumigatus. Neutrophil-specific reduction in NOX2 activity also enhanced acute inflammation induced by inhaled sterile fungal cell walls. These results advance understanding into cell-specific roles of NOX2 in the host response to A. fumigatus. We show that alveolar macrophage NOX2 is a nonredundant effector that limits germination of inhaled A. fumigatus conidia. In contrast, reducing NOX2 activity only in neutrophils is sufficient to enhance inflammation to fungal cell walls as well as to promote invasive A. fumigatus. This may be relevant in clinical settings with acquired defects in NOX2 activity due to underlying conditions, which overlap risk factors for invasive aspergillosis.

Native Mass Spectrometry for Peptide-Metal Interaction in Picoliter Cell Lysate.

Native mass spectrometry, which takes a high concentration of ammonium acetate (NH4OAc) for ionization, coupled with tedious and solvent-consuming purification, which separates proteins from complicated environments, has shown great potential for proteins and their complexes. A high level of nonvolatile salts in the endogenous intracellular environment results in serious ion suppression and has been one of the bottlenecks for native mass spectrometry, especially for protein complexes. Herein, an integrated protocol utilizing the inner surface of a micropipette for rapid purification, desorption, and ionization of peptide-metal interaction at subfemtomole level in cell lysate was demonstrated for native mass spectrometry. The methods showed robust and reproducibility in protein measurement within 1 min from various buffers. The E. coli cells expressing with various proteins were lysed and used to test our method. The specific interaction between the peptide-metal complex in cell lysates could be reserved and distinguished by mass spectrometry.

Rapid Profiling of Metabolic Perturbations to Antibiotics in Living Bacteria by Induced Electrospray Ionization Mass Spectrometry.

Rapid monitoring of real bacterial metabolic perturbations to antibiotics may be helpful to better understand the mechanisms of action and more targeted treatment. In this study, the real metabolic responses to antibiotic treatment in living bacteria were profiled rapidly by induced electrospray ionization mass spectrometry. Significant metabolic perturbations were profiled after antibiotic treatment compared with untreated bacteria. Similar and unique metabolic responses were observed with different antibiotic treatments. Further multivariable analysis was performed to determine significant metabolites as potential biomarkers. Moreover, different metabolic disturbances were detected for serial dilutions of antibiotic treatments. Overall, combined with induced electrospray ionization mass spectrometry, the rapid and real bacterial metabolic status caused by antibiotics was monitored, suggesting the potential application of our method in mechanism exploration and clinical diagnosis.

Macrophage NOX2 NADPH oxidase maintains alveolar homeostasis in mice.

The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AMs) are the predominant immune cell in the airways at steady state, and limiting their activation is important, given the constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well understood. In this study, we showed a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, in CGD mice or mice with selective loss of NOX2 preferentially in macrophages. AMs lacking NOX2 had increased cytokine responses to Toll-like receptor-2 (TLR2) and TLR4 stimulation ex vivo. Moreover, between 4 and 12 week of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AMs with epigenetic and transcriptional profiles reflecting immune activation compared with WT AMs. The presence of CD11bhigh AMs in CGD mice correlated with an increased number of alveolar neutrophils and proinflammatory cytokines at steady state and increased lung inflammation after insults. Moreover, deletion of NOX2 preferentially in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying proinflammatory sequelae. In addition, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue specific, as those changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that the absence of NOX2 in alveolar macrophages leads to their proinflammatory remodeling and dysregulates alveolar homeostasis.

Comparison of Vancomycin Clearance Between Augmented Renal Clearance and Normal Renal Function in Critically Ill Infants: A Population Pharmacokinetics Study.

Augmented renal clearance presents as super-renal function with enhanced renal perfusion and glomerular hyperfiltration in many critically ill infants. This study was to compare vancomycin clearance (CL) between critically ill infants with augmented renal clearance and with normal renal function and to optimize the vancomycin dosage. Data were retrospectively obtained from infants treated in intensive care units. Population pharmacokinetics analysis was conducted using nonlinear mixed-effects model software. A total of 66 critically ill infants were included: 47 infants with augmented renal clearance and 19 infants with normal renal function. The median doses of vancomycin for infants with augmented renal clearance and with normal renal function were 48 and 47 mg/kg/day (P > .05), respectively. The median CL in infants with augmented renal clearance was increased 1.96-fold compared with infants who had normal renal function (0.98 versus 0.5 L/h, P < .001). Simulations indicated that the recommended dosage of 60, 70, 80, 90, and 100 mg/kg/day would be appropriate in critically ill infants with an estimated glomerular filtration rate (eGFR) of 130-149, 150-169, 170-189, 190-209, and >210 mL/min/1.73 m2 , respectively. Doses of 70 and 75 mg/kg/day were recommended for infants with augmented renal clearance and gestational ages of 27-32.9 and 33-39 weeks, respectively. Doses of 70, 75, 80, and 90 mg/kg/day were recommended for infants with augmented renal clearance and weights of 2.0-2.9, 3.0-3.9, 4.0-4.9, and 5.0-6.0 kg, respectively. In conclusion, the typical vancomycin dosage is insufficient for critically ill infants with augmented renal clearance. Premature infants and infants of low weight with augmented renal clearance need individualized dosing regimens to obtain an adequate area under the serum concentration time curve over 24 h/minimum inhibitory concentration ratio.

Suppression of Protein Structural Perturbations in Native Electrospray Ionization during the Final Evaporation Stages Revealed by Molecular Dynamics Simulations.

Native electrospray ionization was known to preserve the protein structure in solution, which overcame the uncontrollable acidification of droplets during transfer from solution into the gas phase in conventional electrospray ionization. However, detailed experimental studies on when and how could native electrospray ionization minimize structural perturbations remain quite unclear. Herein, we conducted molecular dynamics simulations to investigate the protein structure evolution during electrospray ionization. At a neutral droplet pH, the protein structure in solution could be retained after evaporation, which was in accordance with previous reports. As the droplet pH deviated from neutral, we have found that the compact protein structure would not unfold until the last 10 ns prior to the final desolvation, which demonstrated that the role of native electrospray ionization in preserving the protein structure was mainly reflected on the final evaporation stages. The present study might provide new insights into studying the microscopic biomolecular events occurring during the liquid-gas interface transition and their influence on solution-structure retention.

Hydroxysafflor yellow A mitigates myocardial fibrosis induced by isoproterenol and angiotensin II.

AIMS: To investigate the potential inhibitory effect of Hydroxysafflor yellow A (HSYA) on myocardial fibrosis induced by isoproterenol (ISO) and angiotensin II (Ang II) and the possible underlying mechanism. METHODS: Mice were injected subcutaneously with ISO and given HSYA by gavage in vivo. Masson's trichrome staining, immunohistochemical staining and immunofluorescence assays were conducted to evaluate the expression and localization of collagen and inflammatory cytokines, respectively. In vitro, cardiac fibroblasts (CFs) were treated with various doses of HSYA and induced with Ang II. Cell proliferation and migration were assessed using wound healing assay. Cell counting kit-8 was used to measure the cell viability. Collagen I, collagen III, phosphorylation of Smad2/3, Smad2/3, TGFß1, interleukin (IL)-1ß, IL-18, NLRP3 inflammasome-associated proteins were detected by Western blotting. Levels of reactive oxygen species (ROS) were evaluated using 2',7'-dichlorofluorescein diacetate assay. RESULTS: HSYA significantly inhibited ISO-induced myocardial fibrosis, NLRP3 inflammasome activation as well as IL-18 and IL-1ß expressions in mice. HSYA significantly reduced the proliferation and migration of CFs, and suppressed the accumulation of collagen I and collagen III. TGFß1 and P-Smad2/3 induced by Ang II was repressed by HSYA. HSYA downregulated IL-1ß and IL-18, blocked NLRP3 activation, and reduced ROS in CFs. CONCLUSION: HSYA may inhibit myocardial fibrosis by blocking NLRP3 pathway in CFs.

Laser-detected magnetic resonance spectra dressed by a radio-frequency field.

We theoretically and experimentally investigate the laser-detected magnetic resonance spectra dressed by a radio-frequency magnetic field in Fg = 4 of D1 line of cesium atoms. The analytical expression of the transmission spectrum for magnetic resonance dressed by a radio-frequency magnetic field is derived and has substantial agreement with the transmission spectra observed in the experiment. The theoretical prediction of the ratio of the amplitudes of the two sidebands with the detuning is basically consistent with the experimental data, which confirms the validity of the analytical expression. The separation between the two sidebands under resonance shows a highly linear proportion to the amplitude of the dressing field, which may provide a useful scheme for the measurement of radio-frequency magnetic field and magnetic imaging.

Ultranarrow spectral line of the radiation in double qubit-cavity ultrastrong coupling system.

The ultrastrongly coupling (USC) system has very important research significance in quantum simulation and quantum computing. In this paper, the ultranarrow spectrum of a circuit QED system with two qubits ultrastrongly coupled to a single-mode cavity is studied. In the regime of USC, the JC model breaks down and the counter-rotating terms in the quantum Rabi Hamiltonian leads to the level anti-crossing in the energy spectrum. Choosing a single-photon driving field at the point of avoided-level crossing, we can get an equivalent four-level dressed state model, in which the dissipation of the two intermediate states is only related to the qubits decay. Due to the electron shelving of these two metastable states, a narrow peak appears in the cavity emission spectrum. Furthermore, we find that the physical origin for the spectral narrowing is the vacuum-induced quantum interference between two transition pathways. And this interference effect couples the slowly decaying incoherent components of the density matrix into the equations of the sidebands. This result provides a possibility for the study of quantum interference effect in the USC system.

Metabolomic profiling of single enlarged lysosomes.

Lysosomes are critical for cellular metabolism and are heterogeneously involved in various cellular processes. The ability to measure lysosomal metabolic heterogeneity is essential for understanding their physiological roles. We therefore built a single-lysosome mass spectrometry (SLMS) platform integrating lysosomal patch-clamp recording and induced nano-electrospray ionization (nanoESI)/mass spectrometry (MS) that enables concurrent metabolic and electrophysiological profiling of individual enlarged lysosomes. The accuracy and reliability of this technique were validated by supporting previous findings, such as the transportability of lysosomal cationic amino acids transporters such as PQLC2 and the lysosomal trapping of lysosomotropic, hydrophobic weak base drugs such as lidocaine. We derived metabolites from single lysosomes in various cell types and classified lysosomes into five major subpopulations based on their chemical and biological divergence. Senescence and carcinoma altered metabolic profiles of lysosomes in a type-specific manner. Thus, SLMS can open more avenues for investigating heterogeneous lysosomal metabolic changes during physiological and pathological processes.