Search Results (141)

Background/Objectives: This study evaluated neoadjuvant disitamab vedotin plus programmed cell death protein 1 (PD-1) blockade and associations of post-treatment neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with response and progression-free survival (PFS) in muscle-invasive bladder cancer. Methods: This single-center retrospective cohort included 71 patients with cT2–T3N0M0, human epidermal growth factor receptor 2 (HER2)-expressing disease treated between September 2021 and October 2025. Logistic regression and receiver operating characteristic analyses evaluated response endpoints; Kaplan–Meier and Cox methods evaluated PFS. Benjamini–Hochberg correction was applied separately to response analyses. Results: Complete response (CR), objective response, and disease control rates were 66.2%, 84.5%, and 88.7%. Of 47 CRs, 5 were cystectomy-confirmed pathological CR (pCR) and 42 were clinical CR (cCR). Response associations did not remain significant after correction (minimum q = 0.082). AUCs were 0.659–0.708. In a two-variable Cox model based on 14 PFS events, treatment cycles (HR 0.615, 95% CI 0.419–0.903; p = 0.013) and SII per 100 units (HR 1.205, 95% CI 1.073–1.355; p = 0.002) were associated with PFS, but these estimates require cautious interpretation. Two deaths occurred. Conclusions: Neoadjuvant disitamab vedotin plus PD-1 blockade showed promising antitumor activity. The pooled CR endpoint may overestimate pathological response and is not directly comparable with cystectomy-confirmed pCR. Without standardized pretreatment NLR and SII measurements, reverse causality cannot be excluded. Response associations and PFS findings based on 14 events require cautious interpretation and prospective validation. Full article

The occurrence of multidrug-resistant (MDR) bacteria in foods of animal origin is a public health concern that underscores the need to investigate natural antimicrobial alternatives. Although Syzygium aromaticum essential oil exhibits antibacterial activity, evidence regarding its bactericidal effects against MDR bacteria recovered from commercial eggs remains limited. This study evaluated the bactericidal activity of eugenol-rich S. aromaticum essential oil (SAEO) and explored its potential antibacterial mechanisms. SAEO was obtained by steam distillation and chemically characterized by gas chromatography–mass spectrometry (GC–MS). Its antibacterial activity was evaluated by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), bacterial growth kinetics, and changes in membrane permeability. Molecular docking was performed to examine the interactions of eugenol with dihydropteroate synthase (DHPS) and β-ketoacyl-acyl carrier protein synthase III (FabH). Eugenol was the predominant constituent (73.9%), followed by dihydroeugenyl acetate (14.1%) and β-caryophyllene (6.0%). SAEO exhibited bactericidal activity against all tested strains, with MIC and MBC values ranging from 0.125 to 0.25 mg/mL and from 0.25 to 0.50 mg/mL, respectively. SAEO also produced sustained bacterial growth inhibition and concentration-associated changes in membrane permeability. Molecular docking predicted favorable interactions of eugenol with DHPS and FabH; however, these interactions require experimental validation. Overall, the findings demonstrate the in vitro bactericidal activity of eugenol-rich SAEO against MDR bacteria recovered from commercial eggs and support further investigation of its potential application in food-safety interventions. Full article

Cancer remains a major global health challenge, and computational approaches can support the early-stage identification of peptide candidates for experimental evaluation. This study aimed to identify putative anticancer peptides (ACPs) encrypted within Lupinus albus β- and γ-conglutins using an in silico screening strategy. Protein sequences from two β-conglutins and two γ-conglutins were subjected to simulated enzymatic hydrolysis with pepsin, trypsin, and chymotrypsin. The resulting peptides were evaluated using PeptideRanker for bioactivity prediction, AntiCP 2.0 for anticancer peptide prediction, ToxinPred 3.0 for toxicity assessment, and ProtParam for physicochemical characterization. Simulated hydrolysis generated 1610 peptide fragments, of which 749 met the length criteria for downstream analysis. PeptideRanker identified 124 peptides with predicted bioactive potential, and AntiCP 2.0 classified 47 as putative ACPs. Toxicity screening reduced this number to 31 peptides predicted as non-toxic, resulting in 18 unique putative non-toxic ACP candidates after redundancy removal. Among these, 16 met the minimum sequence length required for complete ProtParam characterization. These findings indicate that L. albus conglutins may contain encrypted peptide sequences computationally prioritized as putative ACP candidates, whose activity, selectivity, toxicity, and safety require in vitro and/or in vivo validation. Full article

Dihydrocaffeic acid (DHCA) is a naturally occurring phenolic acid with recognized antioxidant and biological properties. However, its relatively high polarity limits its applicability in lipid-based systems. In this study, myrtenyl dihydrocaffeate was synthesized through lipase-catalyzed esterification of DHCA with myrtenol using immobilized Candida antarctica lipase B. The reaction conditions were optimized using response surface methodology based on a central composite design, yielding an experimental ester yield of 39.94 ± 1.16%. The synthesized ester was characterized by NMR spectroscopy and subsequently evaluated using a combination of experimental and in silico approaches. Antioxidant activity was determined by DPPH^• and ABTS^•+ radical scavenging assays, while oxidative stabilization of rapeseed oil was assessed by pressure differential scanning calorimetry (PDSC). Antimicrobial activity was evaluated using disk diffusion, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) assays. In silico studies included ADMET profiling, PASS bioactivity prediction, protein target prediction, and molecular docking. These computational analyses were used only as hypothesis-generating tools because the predicted protein targets had low target-probability scores and were not experimentally validated. Myrtenyl dihydrocaffeate retained substantial antioxidant activity and significantly improved the oxidative stability of rapeseed oil, exhibiting protection factors comparable to those of DHCA. The ester also demonstrated mild antimicrobial activity against selected Gram-positive bacteria. Overall, the results indicate that lipophilization of DHCA with myrtenol is an effective strategy for developing lipophilic antioxidant derivatives for lipid-based food, cosmetic, or topical formulations, while the predicted molecular targets require experimental validation. Full article

Aspartame is a widely used artificial sweetener, but its possible relationship with rheumatoid arthritis (RA) remains insufficiently understood. This study aimed to explore, rather than prove, potential molecular links between aspartame-related targets and RA-associated gene networks. Three public RA transcriptomic datasets (GSE55235, GSE55457, and GSE77298) from the Gene Expression Omnibus (GEO) database were integrated as discovery/training data. Because these datasets included different tissue origins, batch correction was used to reduce dataset-level technical variation, whereas tissue-origin-related biological variation was not assumed to be fully removable. After differential expression analysis, RA-associated differentially expressed genes (DEGs) were identified. The single-cell dataset GSE200815 was used for cell annotation and cellular expression visualization; because its comparator group consists of psoriatic arthritis (PsA) samples rather than healthy controls, single-cell results were interpreted as RA-vs-PsA observations and were not treated as disease-versus-healthy-control evidence. Potential targets of aspartame were retrieved from ChEMBL, SwissTargetPrediction, and the Similarity Ensemble Approach (SEA), and were intersected with RA-related DEGs to construct an aspartame-gene-RA regulatory network. Diagnostic models were developed using 113 machine-learning algorithm combinations to determine an optimal multigene model and its core genes. HLA-DRB1 was selected for exploratory scTenifoldKnk-based virtual knockout mainly because it was included in the optimal model and has a well-established role in RA immunogenetics; the single-cell analysis was used only to describe cellular distribution in the RA/PsA dataset. Molecular docking was then used to evaluate the possible interaction between aspartame and HLA-DRB1. Forty-four intersected genes linked the predicted aspartame targets with RA DEGs. The random forest plus partial least-squares generalized linear model (RF + plsRglm) identified 16 core genes. Network-level interpretation indicated that these genes were distributed across immune/antigen-processing, inflammatory-signaling, protease/extracellular-matrix-remodeling, adhesion, metabolic, and proliferation-related modules; therefore, HLA-DRB1 was treated as a prioritized immune-module candidate rather than as the sole driver of the network. Following virtual knockout of HLA-DRB1, affected genes were enriched in extracellular matrix organization, extracellular structure organization, extracellular matrix, collagen trimer, extracellular matrix structural constituent, and collagen binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included integrin signaling, focal adhesion, proteoglycans in cancer, cytoskeleton in muscle, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling. Molecular docking showed a minimum binding energy of −6.7 kcal/mol, which was more negative than the preset stability criterion of −5.0 kcal/mol, and the docking pose suggested contacts around ARG-146. This integrative analysis suggests a hypothesis-generating association between aspartame-related predicted targets and RA-relevant molecular networks involving HLA-DRB1 and other core genes. The findings do not establish causality and require experimental, epidemiological, biophysical, and tissue-stratified validation before any causal or clinical inference can be made. Full article

Mycobacterium abscessus subsp. massiliense (Mabs) is an emerging nontuberculous mycobacterium associated with difficult-to-treat infections due to intrinsic antimicrobial resistance, intracellular persistence, biofilm formation, and limited responsiveness to currently available therapeutic regimens. In this context, adjuvant strategies targeting iron-dependent metabolic pathways and metal homeostasis may enhance the efficacy of conventional antimicrobials. This study investigated deferoxamine (DFO), a clinically approved iron chelator, as a potential adjuvant against Mabs using integrated in vitro and in silico approaches. Cytocompatibility was assessed using an MTT assay in RAW 264.7 macrophages and a hemolysis assay in human erythrocytes. Antimicrobial activity was evaluated through minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays, while interactions with clarithromycin (CLA) and amikacin (AMK) were assessed using the checkerboard method. Effects on virulence-associated phenotypes were examined through biofilm formation assays and protein quantification in extracellular vesicle-enriched fractions. Intracellular activity and modulation of inflammatory mediator gene expression were investigated in Mabs-infected RAW 264.7 macrophages through colony-forming unit (CFU) recovery and reverse transcription quantitative polymerase chain reaction (qPCR). DFO exhibited low cytotoxicity and negligible hemolytic activity under the tested conditions. Direct antimicrobial testing revealed a predominantly bacteriostatic profile (MIC = 9.75 µg/mL; MBC > 10 mg/mL), whereas checkerboard analysis suggested a synergistic interaction with CLA (FICI = 0.047), which requires further confirmation by time-kill or CFU-based combination assays. Furthermore, DFO reduced biofilm biomass, decreased protein levels in vesicle-enriched fractions, lowered intracellular bacterial burden, and modulated cytokine gene expression in infected macrophages. Molecular docking, ADME/Tox, and PASS analyses generated exploratory hypotheses regarding potential molecular interactions and pharmacological properties. Overall, these findings support DFO as a promising experimental adjuvant candidate for further investigation against Mabs, particularly in combination with clarithromycin. However, confirmation of a putative iron-restriction-associated mechanism and its translational relevance will require validation in additional clinical isolates, iron-rescue experiments, mature biofilm models, and in vivo studies. Full article

Background/Objectives: Neisseria gonorrhoeae is a high-priority pathogen for the development of new therapeutic alternatives. Efflux pumps are attractive drug targets because their inactivation influences N. gonorrhoeae susceptibility to multiple antimicrobials. Since most gonococcal efflux systems are energy-dependent, interference with energy metabolism and membrane transport may indirectly compromise efflux activity. Efflux inhibitors may increase intracellular antibiotic concentration, although this requires validation in resistant strains. The most effective efflux inhibitors interfere with energy metabolism, affecting several physiological processes, including efflux. In this work, we used an in silico drug repurposing strategy targeting proteins involved in membrane transport and energy metabolism in N. gonorrhoeae. A subset of candidate drugs were subsequently evaluated in vitro using only the reference strain N. gonorrhoeae ATCC 49226. Methods: Predicted drug–target interactions were identified using publicly available databases such as DrugBank and STITCH. Minimum inhibitory concentrations (MICs) of selected drugs against N. gonorrhoeae were determined by microdilution. Changes in intracellular ethidium bromide accumulation were assessed by real-time fluorometry as an indirect indicator of possible efflux-related interference. Results: In silico analysis identified 32 predicted targets associated with 57 approved drugs. Triclabendazole and dequalinium showed the lowest MIC values of the tested compounds (2 and 4 mg/L, respectively). Ketotifen and verapamil demonstrated activity consistent with possible efflux interference, as indicated by increased ethidium bromide accumulation. Atovaquone showed adjuvant-like effects in combination assays, suggesting that mechanisms other than efflux-related interference may contribute to its activity. Conclusions: Overall, this preliminary study identifies approved drugs with antimicrobial or adjuvant activity against a single N. gonorrhoeae reference strain, supporting further investigation in clinically relevant and efflux-variant strains. Full article

This study evaluated the anti-virulence effect of AuraAqua (Aq), a natural mixture of organic acids, against Pseudomonas. fluorescens. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Aq against P. fluorescens were 0.5% and 1% (v/v), respectively. Growth curve analysis confirmed concentration-dependent inhibition of planktonic growth, while sub-inhibitory Aq (0.25%; 1/2 MIC) significantly reduced biofilm formation. Rhodamine-based assays revealed membrane depolarisation at both 0.25% and 0.5% Aq, with decreased intracellular protein levels, indicating impaired membrane integrity under the tested conditions. In fibronectin adherence assays, the presence of Aq during bacterial contact markedly reduced adherence, whereas short pre-treatment alone produced limited, non-persistent effects, suggesting that continuous exposure is required to interfere with host matrix binding. Supernatants and lysates from Aq-exposed P. fluorescens induced lower extracellular protease activity in a concentration-dependent manner and mitigated P. fluorescens-induced cytotoxicity in primary shrimp (SGP) and tilapia (TGP) gut cells, as measured by lactate dehydrogenase (LDH) release after exposure to bacterial supernatants and lysates. Aq treatment was associated with decreased P. fluorescens internalisation into SGP and TGP cells. Collectively, these data show that Aq exerts multi-target inhibitory and virulence-attenuating effects on P. fluorescens, supporting its potential use in aquaculture environments. Full article

Salmonella Enteritidis is a major threat to poultry health and food safety, underscoring the need for safe alternatives to conventional antibiotics. In this study, quercetin, a natural flavonoid with antibacterial and immunomodulatory properties, was evaluated using an integrated approach combining network pharmacology, molecular docking, in vitro antibacterial assays, and preliminary in vivo validation. Potential targets of quercetin and Salmonella Enteritidis were identified from the TCMSP and GeneCards databases, followed by protein–protein interaction analysis, topological screening, and GO/KEGG enrichment analyses. Five core targets, namely IL1B, IL6, STAT1, PTGS2, and IFNG, were identified and were mainly enriched in immune- and inflammation-related pathways. Molecular docking suggested favorable interactions between quercetin and these predicted targets. In vitro, quercetin showed moderate antibacterial activity against Salmonella Enteritidis, with a minimum inhibitory concentration of 256 μg/mL and a minimum bactericidal concentration of 512 μg/mL. In vivo, quercetin alleviated intestinal histopathological damage and reduced the transcriptional expression of the five target genes in infected chicks in a dose-dependent manner, with more evident effects at doses of 512 mg/kg or higher. These findings provide preliminary evidence that quercetin may exert both direct antibacterial and host-associated protective effects against Salmonella Enteritidis, although the underlying mechanisms require further validation. Full article

To address the issues of operational complexity, long duration association, and reliance on specialized equipment with existing detection methods for Vibrio parahaemolyticus, this study established a rapid detection method for V. parahaemolyticus in exported aquatic products based on the domestically developed Enzymatic Recombinase Amplification (ERA) technology. To target the thermolabile hemolysin gene (tlh) and the iron-regulated virulence regulatory protein gene (irgB) of V. parahaemolyticus, highly specific ERA primers and probes were designed and screened. Two detection platforms, a colorimetric method and a fluorescent method, were developed. Method validation results showed that this detection system achieved specific amplification for all 30 tested V. parahaemolyticus strains, with no cross-reactivity observed with 30 other common foodborne pathogenic bacteria. The detection sensitivity for both the fluorescent and colorimetric methods reached 10⁻¹ ng/μL, with a minimum detection limit of 10 CFU/25 g for artificially contaminated samples. The entire detection process, including sample preparation, requires only approximately 20 min—significantly faster than traditional culture (24–72 h) or even conventional PCR methods. Collaborative validation across five independent laboratories confirmed excellent reproducibility, with inter-laboratory agreement yielding a Kappa coefficient of 0.98. The ERA method operates at a low, constant temperature (37–39 °C), eliminating the need for thermal cyclers. When combined with portable isothermal amplification devices and visual (colorimetric) readout, it offers a distinct advantage in terms of speed, cost-effectiveness, and suitability for resource-limited or field settings compared to existing PCR-based or culture-based platforms. This method is simple to operate, rapid, sensitive, and highly suitable for on-site application, providing a reliable and practical technical solution for the rapid screening and risk monitoring of V. parahaemolyticus in exported aquatic products. Full article

The most recent National Research Council Nutrient Requirements for Sheep and Goats was published in 2007, one of the most consequential nutrient requirement recommendations for sheep and goats in the world. The enhancement of production efficiency, minimization of carbon footprint, and maximization of resource economy, among others, motivate the continuing discussion of nutrient utilization and refinement of nutrient requirements in sheep and goats that are increasingly important in various parts of the world. Progress has been made in the estimation of energy and protein requirements in sheep and goats, mainly utilizing empirical feeding experimentation, comparative slaughter techniques and minimum endogenous loss methods. In sheep, newer estimates of energy and protein requirements for maintenance and growth and partial efficiencies has been reported since 2007. There were suggestions that energy and protein requirements could have been affected by breed, wool growth, gender and size, with these reported values being similar or lower than the recommended values in international feeding systems such as NRC, ARC, INRA and AFRC. In goats, energy and protein requirements for growing goats were reported to be either higher or lower than the established recommendations, depending upon meat or dairy breeds. Effect of gender on energy requirement appeared to be related to the stage of growth or degree of maturity. Newer data also suggested that existing recommendations on nutrient requirements may not be adequate for non-pregnant and non-lactating pubertal females. In multiparous pregnant goats, energy and protein requirements for maintenance did not appear to be affected by days of pregnancy, but efficiencies of metabolizable energy and metabolizable protein utilization for pregnancy were. There were suggestions that metabolizable protein can be predicted from energy intake using equations that encompass both sheep and goats, but more data on goats were called for to account for specific differences in nutrition. In addition to sulfur, there has been progress made on the estimation of maintenance and growth requirements of calcium, phosphorus, potassium and magnesium in goats, with suggestions on the consideration of gender and breed differences. While conventional factors such as breeds and species, genotype, stage of maturity, gender, body composition, mobilization of tissue energy for production, and additional activity energy required due to resource limitation and acclimatization remain as important considerations for the estimation of nutrient requirements in sheep and goats, emerging factors such as climate change, heat stress, parasitism and secondary plant compounds that can affect nutrient utilization should also be considered in the estimation of nutrient requirements. Model equations and partial efficiencies used by NRC to predict energy and protein requirements for maintenance, growth, lactation, and fiber have been highlighted and discussed for the purpose of a more focus discussion and refinement for the future. Potential limitations of both traditional and emerging methodologies in determining the nutrient requirements in sheep and goats were discussed. The advancement in nutrigenomics can potentially move nutrient requirements beyond its population-based guidelines. To justify the research investment, emerging methodologies such as nutrigenomics will have to be linked more directly to the improvement of production efficiency via more precise prediction of nutrient requirement. With the assistance of artificial intelligence and more data obtained from sensor technology, precision nutrition has the potential to deliver nutrients precisely to individual animals and meet nutrient requirements in sheep and goats. Full article

Background: Vibrio harveyi is a major bacterial pathogen threatening turbot aquaculture, necessitating the development of more effective vaccines. Bacterial ghosts (BGs), which are empty bacterial envelopes with preserved surface antigens, offer a promising alternative to traditional formaldehyde-killed vaccines that often suffer from reduced immunogenicity. Methods: We developed an optimized BGs vaccine for V. harveyi by combining the nonionic surfactant NP-40 with sodium hydroxide (NaOH). This NP-40/NaOH combination demonstrated a synergistic lytic effect, halving the minimum inhibitory concentration of NaOH required for complete inactivation. Results: The resulting BGs exhibited intact cellular morphology with transmembrane pores, efficient removal of cytoplasmic contents, and significantly better preservation of lipopolysaccharide structure compared to NaOH-alone treatment. Vaccination trials in turbot demonstrated that the NP-40/NaOH BGs provided the highest relative percent survival (RPS = 58.8%) upon challenge, outperforming both NaOH-alone BGs (RPS = 55.0%) and a traditional formaldehyde-killed vaccine (RPS = 34.8%). The superior protection was correlated with the induction of a more robust and sustained immune response, characterized by significantly higher levels of specific IgM antibodies, elevated lysozyme activity, and increased total serum protein. Conclusions: This study establishes the NP-40/NaOH protocol as an effective strategy for producing high-quality BGs with enhanced immunogenicity, presenting a potent vaccine candidate for controlling vibriosis in aquaculture. Full article

Determining protein requirements (PRs) for dogs remains a longstanding challenge. During growth, the rapid rate of protein deposition increases the demand for amino acids. In adult dogs, differences in overall diet digestibility and lower energy requirements of domestic dogs have led to discrepancies between the minimum crude protein (CP) value proposed by the National Research Council (NRC; 80 g of CP/kg of diet) and the 180 g of CP/kg of diet proposed by the European Pet Food Industry Federation (FEDIAF) and the Association of American Feed Control Officials (AAFCO), although most commercially available adult dog feeds offer protein levels that exceed both recommendations. In elderly dogs, physiological changes such as sarcopenia and reduced energy intake indicate a potential increase in PR, although evidence remains scarce. A similar gap exists for pregnant and lactating bitches, since most recommendations rely on extrapolations from growth studies. Classical PR recommendations were based on body weight gain and nitrogen balance (NB), methods that present important limitations. Due to this, stable isotope methods—including ¹³C-leucine, ¹⁵N-glycine, and ¹³C-phenylalanine—have emerged as precise methodological tools, enabling a detailed and dynamic assessment of whole-body protein metabolism, protein quality, and more accurate determination of PR and recommended allowance across different life stages. Full article

Anti-Porphyromonas gingivalis mechanisms of Berberis hemsleyana bark extract remain to be elucidated, and the anti-inflammatory activity of its n-butanol fraction (BNB) in RAW264.7 cells—mediated through suppression of the NF-κB pathway—require further validation. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the crude extract from B. hemsleyana were determined against Candida albicans, Escherichia coli, Porphyromonas gingivalis, Staphylococcus aureus and Streptococcus mutans. Scanning electron microscopy (SEM) and bacterial protein leakage assays were used to evaluate its antibacterial activity against P. gingivalis. High-performance liquid chromatography-mass spectrometry (LC-MS) was applied to analyze the ethanol extract of B. hemsleyana bark, leading to the screening of 47 compounds. The antibacterial mechanisms of the compounds were predicted through Network Pharmacology analysis and Molecular docking. Anti-inflammatory activity mediated via the NF-κB pathway was verified using an LPS-induced RAW264.7 cell inflammatory model. Specifically, the BNB showed a significant antibacterial effect on P. gingivalis. Meanwhile, it was confirmed that this fraction damaged the bacterial cell membrane structure, leading to the leakage of intracellular proteins in bacteria and thus impairing their infectivity. Network pharmacology analysis and molecular docking results indicated that B. hemsleyana bark’s biologically active compounds (Calenduloside E, Limonin, Acanthoside B, Dihydroberberine) antibacterial activity by regulating cytokines and cell apoptosis, thereby coordinating the body’s microbial homeostasis and inflammation. Additionally, BNB significantly reduced the secretion of the inflammatory cytokines IL-1β, TNF-α and IL-6 in vitro via the NF-κB pathway. The crude extract from the bark of B. hemsleyana has antibacterial and Anti-inflammatory activity. The n-butanol fraction showed a significant antibacterial effect on P. gingivalis. Full article

Numerical simulations of protein folding enable the design of protein-based nanomachines and nanorobots by predicting folded three-dimensional protein structures with high accuracy and revealing the protein conformation transitions during folding and unfolding. In the kinetostatic compliance method (KCM) for folding simulations, protein molecules are represented as ensembles of rigid nano-linkages connected by chemical bonds, and the folding process is driven by the kinetostatic influence of nonlinear interatomic force fields until the system converges to a free-energy minimum of the protein. Despite its strengths, the conventional KCM framework demands an excessive number of iterations to reach folded protein conformations, with each iteration requiring costly computations of interatomic force fields. To address these limitations, this work introduces a family of sign gradient descent (SGD) algorithms for predicting folded protein structures. Unlike the heuristic-based iterations of the conventional KCM framework, the proposed SGD algorithms rely on the sign of the free-energy gradient to guide the kinetostatic folding process. Owing to their faster and more robust convergence, the proposed SGD-based algorithms reduce the computational burden of interatomic force field evaluations required to reach folded conformations. Their effectiveness is demonstrated through numerical simulations of KCM-based folding of protein backbone chains. Full article