Molecular gears represent fundamental archetypes of molecular machines as they provide crucial capacity in redirecting, translating, and rate-shifting of nanoscale motions. Most prevalent are thermally driven molecular bevel gears, while other architectures such as spur gears are much rarer owing to their specific requirement of parallel spatial alignment. More recently, implementation of additional control over gearing via a secondary stimulus has emerged as a new frontier, allowing one to build more sophisticated molecular machinery. In this work, we present a light-switchable molecular spur-gear setup, which allows one to engage and disengage a parallel-oriented gear system on command. Using hemithioindigo (HTI) as a photoswitchable central unit, the correlated motion of two parallel engaged triptycene gear wheels can be engaged and disengaged via light-induced double-bond isomerization. This molecular setup further paves the way toward realizing a light-driven and directional photogear motor as the engaging/disengaging motion can straightforwardly be coupled to the gearing motion.
CD4+ T cells play an important role in antitumor immunity due to their capacity to acquire highly functional effector states and cytotoxic-like programs in the tumor microenvironment. However, the mechanisms underlining this process remain largely undefined. Herein, we identify the medium chain fatty acid-sensing receptor GPR84 as a metabolic checkpoint that restricts the antitumor immunity mediated by CD4+ T cells. GPR84 upregulation was detected in tumor-infiltrating CD4+ T cells, and in the absence of GPR84, CD4+ T cells exhibited enhanced tumor control, associated with increase in their proliferation and survival, and with a reprogramming toward a more functionally competent state characterized by increased polyfunctional cytokine production and reduced expression of inhibitory receptors, without accumulation of regulatory T cells. In the tumor antigen-specific mouse model, GPR84 deficiency drastically improved the therapeutic efficacy of adoptively transferred CD4+ T cells. Mechanistically, without GPR84, CD4+ T cells, by upregulating mTORC1 signaling activity, metabolically enhance both glycolysis and mitochondrial activities, thereby gearing toward tumor-killing cytotoxic phenotypes. Importantly, pharmacologic inhibition of GPR84 drastically improves the effectiveness of both PD-1 blockade therapy and adoptive cell transfer. Together, these findings validate GPR84 as a key regulator of CD4+ T-cell metabolic fitness and establish the extracellular lipid sensing pathway as a targetable axis for improving the efficacy and responsiveness of cancer immunotherapies.
Social participation is significantly limited for children with neurodevelopmental conditions. Many social participation opportunities are derived from physical activities, which may be restricted for children with neurodevelopmental conditions. Adapted bikes play a crucial role in facilitating physical activity. This study aims to investigate the experience of children with neurodevelopmental conditions and the impact of adapted bike use on enabling physical activity and social participation. A qualitative descriptive approach was used to examine the experiences of seven children aged 6 to 14 with neurodevelopmental conditions and their parents. We conducted semi-structured interviews with the seven child-parent dyads and analysed the data using reflexive thematic analysis. Based on the analysis, five themes were identified and labelled as 1) Pedalling towards inclusion and participation 2) Gearing up, 3) Essential skills and gains from biking, 4) Riding on different paths, and 5) Resources for biking. Adapted bikes can enhance inclusion and social participation. Achieving this requires a proper bike fit, the development of biking skills, consideration of bikers' diverse backgrounds and contexts, and access to necessary resources. By implementing these elements, more opportunities for social participation can be created and inclusion promoted. This study highlighted that both parents and children identify adapted bike use as an effective way to empower children to participate socially. Considering a proper bike-biker fit, a child’s developmental situation, environment, and support network can contribute to a better bike experience. We encourage researchers, organisations, therapists, and families to advocate for increased biking opportunities, as this can help children develop essential skills and experience the numerous benefits of biking. The development of inclusive policies and practices that promote the use of adapted bikes in school settings, for instance, through biking clubs, can enhance children’s opportunities to engage in biking and participate alongside their peers.
For enhancing the tribological behavior of gear-driven systems, TA, AO, GNS, SiCf and Ti are used to prepare Ti-based composite foils that are subsequently combined with Ti2AlNb foils to prepare laminated samples for use in aviation gearing systems. Friction and wear tests are executed to demonstrate the optimum tribological behavior of TAGSTT, coupled with ideal reductions in the friction coefficient (57.89%) and wear rate (60.32%) relative to that of TT. These improved metrics are probably because the SiCf, GNS, TA and AO induce smaller nanocrystals in the lubrication film on the transition layer, which improves the self-healing ability of wear scars, prevents the wear interface from damage, and imparts excellent tribological behavior to the TAGSTT. These results provide a propagable method for the tribological design of drive-gear systems.
Here we show that large language models (LLMs) can be transformed via supervised fine-tuning of engineered prompts into SmileyLlama for exploring the chemical space of drug molecules. We benchmark SmileyLlama against pretrained LLMs and chemical language models trained from scratch for generating valid and novel drug-like molecules, and use direct preference optimization to both improve SmileyLlama's adherence to a prompt and as part of the iMiner reinforcement learning framework to predict molecules with optimized three-dimensional conformations and high binding affinity to drug targets. By training an LLM to speak directly as a chemical language model, while retaining most of its natural language capabilities, we show that SmileyLlama can reliably generate molecules with user-specified properties rather than acting only as a chatbot with knowledge of chemistry or as a virtual assistant. While SmileyLlama is geared toward drug discovery, the supervised fine-tuning/direct preference optimization/LLM framework can be extended to other chemical, biological and materials applications.
Behavioral and psychological symptoms of dementia (BPSD) are common, profoundly troubling to patients and caregivers, and difficult to treat, yet their molecular underpinnings remain poorly understood. Here, we generated a large brain proteomic dataset with nine BPSD domains assessed in life from 376 donors from three cohorts. Protein associations with BPSD were examined using complementary approaches - domain-specific BPSD, multi-domain BPSD, and latent factor modeling - and integrated via cross-cohort meta-analysis. Four proteins (NMT1, DCAKD, DNPH1, and HIBADH) were associated with anxiety in dementia and five proteins (ABL1, SAP18, PLXND1, CTRB2, and LDHD) with multi-domain BPSD or BPSD latent factors after adjusting for sex, age, and other covariates (FDR < 0.05). Additionally, eight protein co-expression networks were associated with BPSD across cohorts. Together, these results link BPSD to dysregulation of synaptic signaling, protein folding, and humoral immune response, providing a molecular framework for therapeutic discovery.
Objective: We examined illicit substance use (including and excluding marijuana), mental health, alcohol consumption, and binge-drinking among postsecondary institution students, by sexual orientation. Participants: Students that completed the 2022-2023 Healthy Minds Study (N = 76,406), with complete demographic, substance use, and mental health responses. Methods: Weighted logistic regression models assessed the relationship between sexual orientation and substance use and mental health. Results: Positive mental health and a sense of belonging were protective against past 30-day substance use reporting (excluding marijuana), but the same protection was not seen in past two-week alcohol consumption and binge-drinking behavior. Respondents older than 20 years old had significantly lower odds of binge-drinking. Conclusions: Campuses should continue devoting appropriate resources to programming geared toward underage students for the dangers of excessive alcohol consumption. Additional strategies bolstering students' sense of belonging on campuses may also be protective against students' use of illicit substances.
This study presents a systematic design approach for a multi-speed bicycle rear transmission hub, which consists of a gear speed-changing mechanism and a rotary-type gear-shifting mechanism to enhance functional performance and optimize space utilization. The design process encompasses structural synthesis, gear stage arrangement, gear teeth synthesis, and clutch configuration, ensuring optimal power transmission and seamless gear shifting. A 9-speed rear transmission hub is used as an example to illustrate the design process. A compound planetary gear train with a new permanent magnet assisted gear-shifting mechanism was presented to provide nine forward gears, including four underdrive gears, a direct drive gear and four overdrive gears. The proposed design was verified through computer simulations, confirming its functional feasibility and mechanical integrity. Key performance results demonstrate that the system achieves a speed ratio ranging from 0.56 to 1.80 with a step jump no greater than 20%. Furthermore, the design maintains a compact dimension within a diameter of 200 mm and an axial length not exceeding 190 mm, while keeping the total weight under 3 kg. The results indicate that the system effectively meets performance specifications while addressing limitations associated with traditional spring-based gear shifting mechanisms. This study contributes to the advancement of multi-speed transmission hubs, providing a structured framework for next-generation bicycle transmission systems.
The utility of Letters of Recommendation (LORs) in The Match has been questioned in recent years. Although programs across specialties have generally favored LORs, their use and value remains unclear. The aim of this study was to review all existing literature pertaining to LORs to better understand their strengths and limitations. We hypothesized despite overall support for LORs, the evidence may argue against their current use. This study was a scoping review conducted between October 17th, 2024, through January 25th, 2025, using a single database PubMed search term "Letter of Recommendation Residency". Articles were screened for relevancy, followed by full text review, including only primary research articles and non-applicant perspectives. Open ChatAI, a third-party AI platform, and Covidence, a third-party review platform was used to extract studies based on outcomes and characteristics. Our final review included 108 research articles. Among selected articles, three primary aims were appreciated including program opinions, content analysis, and predictive value. A majority of studies supported LORs (68.1%) despite a high prevalence of observed bias (82.4%) and low predictive value (56.5%). LORs remain a key part of the application materials among concerns in the literature for their limited predictive value and bias concerns (race, gender, title). This highlights the need for a novel tool geared toward objectivity and aptitude to improve the quality of The Match for both programs and applicants.
Hypertrophic cardiomyopathy (HCM) is driven by sarcomeric mutations that cause energetic failure and secondary inflammation. This study demonstrates that targeting this metabolic-inflammatory axis with pioglitazone or its peroxisome proliferator-activated receptor gamma inactive enantiomer, R-pioglitazone, reverses disease progression in a murine HCM model. Both agents restored mitochondrial function (including Mitochondrial Pyruvate Carrier 1 [MPC1] levels) and resolved inflammation. Notably, R-pioglitazone showed superior efficacy, reducing interstitial fibrosis by >95% and hypertrophy by 33% without affecting healthy control hearts. These findings identify R-pioglitazone as a promising, mechanism-based candidate for disease-modifying therapy in HCM.
This paper aims to develop an on-board shock absorber detection method for general aviation aircraft. The effects of common gas and oleo leakage are analyzed in this paper. Based on the principle of landing gear dynamics, it is found that gas leakage and oleo leakage would mainly affect air spring force of shock absorbers in various ways. A rigid-flexible coupled landing gear multi-body system (MBS) model is developed by considering strut flexibility, aiming to offer more accurate simulated responses. A database is developed that considers common leakage faults and typical landing conditions using the developed landing gear model. A deep learning model is proposed in this paper. The proposed model is trained and tested using the database simulated from the rigid-flexible coupling landing gear model. The proposed method demonstrates robust detection performance, achieving over 95% precision for most fault types. This work provides a practical, sensor-efficient solution for real-time health monitoring of landing gear shock absorbers, contributing to improved maintenance strategies and operational safety for general aviation aircraft. As this is a preliminary feasibility study, full validation requires future drop tests or instrumented flight tests.
This study introduces a comprehensive framework that integrates reliability assurance and quality control in the Laser Powder Bed Fusion (L-PBF) gear manufacturing process via the Reliability-Quality-Reliability (RQR) chain model. The framework highlights the reciprocal link among manufacturing system dependability, process quality, and product reliability, hence enhancing gear performance and operating efficiency. The examination of L-PBF gears indicated that internal flaws, including absence of fusion, balling, keyhole porosity, and residual stress, significantly compromise structural integrity, while exterior issues such as surface wear, hardness variation, and geometric deviation exacerbate reliability deterioration. Experimental reliability graphs shown a significant decrease from about unity to below 0.1 during extended operation when both fault types were analyzed. The assessment of essential quality attributes verified the general stability of the process, with slight variations in wear resistance and geometric precision. Process parameters, including laser power, scan speed, and layer thickness, were recognized as critical factors affecting microstructural integrity, fatigue life, and wear reliability, while post-processing treatments like HIP markedly enhanced performance. The suggested RQR-based performance matrix offers a systematic framework for iterative process optimization and system-wide improvements, facilitating defect reduction, enhanced fatigue and wear reliability, and sustainable, high-quality manufacturing of L-PBF-manufactured gears. The framework is demonstrated using independent peer-reviewed datasets and should be interpreted as a methodological and benchmark validation rather than experimental post-process validation. Future work will focus on independent experimental verification of the proposed framework.
Face gear drives exhibit smooth transmission, low noise, and insensitivity to pinion axial installation error. Nonorthogonal face gear pairs enable torque transmission and speed variation under diverse shaft intersection angles, thus expanding their engineering applicability. At present, mathematical modeling of face gears generally considers only the tooth flank surface, while neglecting the tooth bottom surface. This leads to missing data in partial regions of the accurate tooth geometry of face gears. This paper focuses on the precise modeling algorithm and grinding methodology for the full tooth surface of nonorthogonal face gears. The tooth surface generation principle is analyzed, and the meshing kinematics between the grinding wheel (acting as the generating gear) and the nonorthogonal face gear are established. The full tooth surface is divided into five regions, and boundary conditions are defined separately for each region. Mathematical expressions for the generating gear and the full tooth surface of the nonorthogonal face gear are derived. The parameter boundaries for dish-wheel grinding are determined to guarantee full-tooth-surface completion. According to the common gear grinding machine configuration, the kinematic coordinate system for dish-wheel grinding is formulated, and virtual machining and grinding test are implemented. Comparative results demonstrate that the theoretical tooth surface matches the virtual machining outcome without noticeable deviation, validating the accuracy of the full tooth surface modeling and grinding motion. In this study, the proposed grinding method overcomes the limitation that non-orthogonal face gear grinding can only be performed on a few dedicated machine tools, thereby further expanding the application scope of face gear grinding technologies.
Chondroitin sulfate (CS) is an essential sulfated glycan in the brain, but standard LC-MS/MS disaccharide analysis provides only limited quantitative accuracy for detecting CS structural changes under physiological and pathophysiological conditions. Here, we incorporated eight distinct 13C-labeled CS disaccharide calibrants into the analytical workflow. Using this enhanced approach, we identified structural alterations in both sulfation patterns and total CS abundance in pre-clinical and clinical Alzheimer's disease (AD) brain samples compared with controls. Analysis of cerebrospinal fluid (CSF) from AD patients further revealed elevated levels of the CS-E disaccharide and reduced levels of hyaluronic acid. Functionally, we found that synthetic CS-E 19-mer-but not other synthetic CS 19-mer subtypes-impaired neuronal growth, underscoring the need to pinpoint specific CS structures that contribute to neurodegeneration. Because CS abnormalities are detectable in the pre-clinical AD brain, our findings raise the possibility that CS glycans could serve as early biomarkers for AD.
Multiple primary cancer is a self-explanatory term, albeit very uncommon. In most instances, when patients have a malignancy, the possibility of metastasis should be considered. Renal cell carcinoma (RCC) is one such cancer. However, as unlikely as it is, there is always a chance that another separate, unrelated malignancy could be present. Here, we would like to discuss a unique case of a 66-year-old female who not only developed primary RCC but also primary invasive mucinous adenocarcinoma of the lung. This revelation prompted a change in management, resulting in the medical team treating the two malignancies separately via surgical intent as opposed to treating metastatic RCC, which is more geared toward systemic medical therapy.
The accuracy of gears is a determining factor for their functionality, reliability, and durability in various mechanical systems. Two widely used technologies for producing plastic gears are injection molding and 3D printing, each having its own advantages and limitations. Injection molding is a traditional method for mass production that offers high productivity but is sensitive to parameters such as temperature, pressure, and cooling, which can lead to shrinkage and dimensional instability. On the other hand, 3D printing is gaining popularity due to its flexibility, rapid prototyping capabilities, and the possibility of producing small series without the need for expensive tooling. In the present study, the accuracy of plastic gears with module 2 and module 3, manufactured using both technologies, was investigated and compared. Measurements were performed on three main parameters: span measurement, chordal tooth thickness, and measurement over pins. The obtained data were statistically analyzed and classified according to the DIN 3962/3963 and ISO 628 accuracy standards. 3D-printed gears demonstrated lower standard deviation (0.0079-0.0083 mm) and improved repeatability compared with injection-molded gears (0.0131-0.0189 mm), achieving DIN 10-14 accuracy classes. Unlike previous studies that compare different materials or technologies separately, this work directly compares both simultaneously under controlled conditions, revealing that material selection (CF-reinforced vs. unfilled POM) may influence dimensional outcomes as strongly as the manufacturing method. These findings provide practical guidance for selecting production routes for low-to-medium precision polymer gears under the tested conditions.
Asparagus stem blight, caused by Phomopsis asparagi, is a devastating disease leading to significant yield losses in asparagus cultivation. Current control methods, such as greenhouse cultivation or extensive pesticide use, are either costly or environmentally unsustainable. Endophytes, residing within healthy plant tissues, offer a promising biocontrol alternative due to their antagonistic activities against pathogens. This study investigated the diversity and biocontrol potential of endophytic fungi and bacteria in the stems of one cultivated variety (ATL) and three wild asparagus resources (NFY, YAY, YDL). We employed high-throughput sequencing to analyze endophytic community composition and diversity. We conducted predictive functional profiling to assess potential metabolic capabilities. Additionally, endophytic strains were isolated from stem tissues and screened for antagonistic activity against P. asparagi using dual-culture assays. High-throughput sequencing revealed distinct endophytic communities between cultivated (ATL) and wild (NFY, YAY, YDL) asparagus. Wild varieties exhibited significantly higher microbial diversity and more unique Operational Taxonomic Units (OTUs). Principal Coordinate Analysis (PCoA) confirmed separate clustering, with wild samples grouping apart from ATL. Community composition differed markedly: in fungi, Russula was abundant in NFY, while Incertae_sedis dominated others; in bacteria, Pseudomonadota prevailed in wild types versus Armatimonadota in ATL. Functional prediction showed wild endophytes enriched in genes for direct antagonism (e.g., chitinase), stress resistance, and competition (e.g., ABC transporters, quorum sensing). Cultivated endophytes were geared toward core metabolism. From wild stems, 14 endophytic strains were isolated. Four bacterial isolates strongly inhibited Phomopsis asparagi (> 90% inhibition), with one (YDJ119602) achieving 100% inhibition via fermentation broth. In conclusion, wild asparagus exhibits rich endophytic diversity and represents a promising source of biocontrol agents against stem blight, offering a sustainable disease management strategy.
Pd2L4 cages have been extensively investigated for a range of applications but are prone to disassembly under acidic conditions or in the presence of competing ligands. More recently, PtII analogues became more accessible and allow addressing some of the issues limiting the further development of M2L4 cage structures, in particular around the stability of the architectures. We explored a range of structurally analogous Pd- and Pt-based M2L4 structures as hosts for the binding of a range of neutral guest molecules. We selected the guests for their varying structural features to affect their binding to these cages. We characterized the latter by qualitative and quantitative means, as well as structurally by X-ray diffraction analysis and supported the interpretation of the data by modeling. We found that the Pt2L4 cages exhibited superior guest binding abilities when compared to their Pd analogues as they were less prone to disassembly, while the binding strengths of the cages with 2-hydroxy-1,4-naphthoquinone were similar. This allows the use of a wider range of guest molecules to be encapsulated into supramolecular architectures. The cages built from bridging phenyl-based ligands were found to form stronger host-guest complexes than those featuring a pyridyl unit.
Social media plays an increasing role in healthcare, influencing patient education, provider selection, and physician marketing. Previous studies show mixed results on its impact on physician review scores, and limited data exist within orthopedic oncology. The purpose of this study was to quantify social media utilization among Musculoskeletal Tumor Society (MSTS) members as well as identify any differences by physician sex or practice type. All active MSTS members were searched for common social media accounts. Account activity and engagement data were acquired. Publicly available ratings from popular physician review websites were compiled. Data were collected on each member's demographic details including sex, geographical location, type of practice, and h-index. The association between social media activity and online review scores was analyzed using chi-square tests for categorical data and t-tests for continuous variables. A total of 247 MSTS members, comprising 199 academic and 48 private surgeons, revealed significant differences in orthopedic surgeon social media engagement and online presence. At least 1 social media account was used by 178 (72.1%) of MSTS members with LinkedIn most used (57.9%) followed by ResearchGate (39.7%). Surgeons with 3 or more active social media accounts demonstrated significantly higher ratings on practice-affiliated scoring sites compared with those without any social media presence (4.88 ± 0.10 vs. 4.82 ± 0.13, p = 0.017), and a significant difference was observed in practice-affiliated scoring, with higher h-index surgeons receiving better ratings (4.84 ± 0.10 vs. 4.79 ± 0.11, p = 0.009). Most MSTS members do not have professional social media accounts geared toward the patient population (i.e. Instagram, TikTok). Although social media demonstrates benefits of patient engagement, education, and recruitment, there was only significant difference in ratings on practice-affiliated scoring sites with over 3 social media accounts compared with surgeons without any accounts. Level IV. See Instructions for Authors for a complete description of levels of evidence.
Nanoarchitectonics of small-scale molecular units into functional materials is a key strategy in materials science. The central challenge lies in assembling, integrating, and nanoarchitecting fundamental functional units, such as molecular machines and microrobots, to innovate materials. This review examines collective behaviours typical in molecular and biomolecular machines and microrobots. We categorize collective behaviours into six types: (i) small-scale units operating cooperatively or collaboratively (often seen in macroscopic objects such as crystals); (ii) free-moving units in the bulk material; (iii) mechanical coupling between units resulting in chain interactions (not unlike gears); (iv) assembly of units to generate macroscopic output functions; (v) macroscopic stimuli controlling individual units; and (vi) cooperation between different molecular species to generate functional flows within a single system. After categorizing collective behaviours in molecular machines, we consider examples of material systems exhibiting this behaviour, such as MOFs, COFs and crystals. Furthermore, we examine the collective behaviours of molecular machines at solid surfaces and liquid interfaces. Additionally, we highlight the behaviour of biomolecular machines and microrobots in separate sections. Each section identifies and discusses trends in the relevant examples. This approach to utilizing molecular machines is anticipated to create highly functional systems, realizing the ultimate goal of functional materials chemistry.