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The fibroblast growth factor receptor (FGFR) is a crucial receptor tyrosine kinase involved in essential biological processes, including growth, development, and tissue repair. However, FGFR gene mutations, including amplification, fusion, and mutation, can disrupt epigenetics, transcriptional regulation, and tumor microenvironment interactions, leading to cancer development. Targeting these kinase mutations with small molecule drugs or antibodies has shown clinical benefits. For example, erdafitinib is approved for treating locally advanced or metastatic urothelial cancer patients with FGFR2/FGFR3 mutations, and pemigatinib is approved for treating cholangiocarcinoma with FGFR2 fusion/rearrangement. Effective screening of FGFR variant patients is crucial for the clinical application of FGFR inhibitors. Various detection methods, such as polymerase chain reaction, next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry, are available, and their selection should be based on diagnostic and treatment decision-making needs. Our developed expert consensus aims to standardize the diagnosis and treatment process for FGFR gene mutations and facilitate the practical application of FGFR inhibitors in clinical practice.

Abstract Surface charge patchiness of different charge types can influence the solution behaviours of colloidal particles and globular proteins. Herein, coiled-coil ‘bundlemer’ nanoparticles that display only a single type of surface charge (SC) are computationally designed to compare their solution behaviours to mixed charge-type (MC) counterparts with both positively and negatively charged side chains. Nematic and columnar liquid crystal phases are discovered in low concentrations of SC particles, indicative of particle end-to-end stacking into columns combined with lateral electrostatic repulsion between columns, while MC particles with the same net charge and particle shape produced only amorphous, soluble aggregates. Similarly, porous lattices are formed in mixtures of SC/MC particles of opposite charges while MC/MC mixtures of opposite charges produce only amorphous aggregates. The lattice structure is inferred with a machine learning optimization approach. The differences between SC and MC particle behaviours directly show the importance of surface electrostatic patchiness.

Abstract The development of thermoelectric devices provides an ideal solution for self-sustaining Internet of Things (IoT) applications. However, existing thermoelectric devices face issues such as low integration levels and poor stability. To address these challenges, this paper presents a novel method for fabricating flexible thermoelectric devices using Ag2Se/MgAgSb, which combines MEMS lithographic lift-off techniques to achieve precise control over the dimensions of the thermoelectric functional layer while also reducing fabrication costs. The optimal cell dimensions were identified through simulations. The device achieved an open circuit voltage of 0.49 mV at a temperature difference of 50 K. Additionally, the output power density of the Ag₂Se/MgAgSb flexible Y-type thermoelectric device reached 3.39 µW/m² at a temperature difference of 5 K. The device also demonstrated excellent flexibility; even after being bent 800 times around a glass rod with a diameter of 4 mm, its conductivity decreased by only 12%. Furthermore, it maintained stability under high humidity conditions. This work offers a novel strategy for the miniaturization and large-area controllable fabrication of flexible and reliable thermoelectric devices, as well as an enhancement in their reliability.

Abstract Bovine parainfluenza virus type 3 (BPIV3) is a viral respiratory pathogen that infects cattle and causes significant economic losses. We generated a recombinant adenovirus called rHAd5-F + HN by expressing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein of BPIV3 using the human adenovirus serotype 5 (rHAd5). We evaluated its effects on humoral and cellular immune responses in mice (n = 45) and calves (n = 9). Serum antibody responses were assessed by enzyme-linked immunosorbent assay (ELISA), hemagglutination inhibition (HI), and neutralising antibodies (NAb). After boosting immunity with rHAd5-F + HN, mice produced significantly higher levels of antibodies against the BPIV3 genotype A and genotype C strains. The production of antibodies exceeded those produced by adenoviruses rHAd5-F and rHAd5-HN, which express the F and HN glycoprotein, respectively. The percentages of splenic CD3+/CD8+T lymphocytes and IL-4+ cytokines in rHAd5-F + HN mice were considerably higher than those in the control group. Mice immunised with rHAd5-F + HN exhibited much lower viral loads in the lungs and tracheas compared to the control group. Additionally, the lungs of mice vaccinated with rHAd5-F + HN showed no notable histopathological changes. On the other hand, rHAd5-F + HN produced a humoral immune response in calves. Following the booster intramuscular injection with the rHAd5-F + HN, the serum antibody levels against BPIV3 genotype C strain were 1:20 452, 1:1024, and 1:426 in calves, as detected by ELISA, HI, and NAb, respectively. The HI and NAb levels against the BPIV3 genotype A strain were 1:213 and 1:85 in calves, respectively. These results indicate that rHAd5-F + HN effectively induced immunity against BPIV3 infection.

Abstract The traditional diagnostic markers for mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are synaptophysin (SYP), chromogranin A (CHGA) and CD56. However, there is still a lack of a large series of article focused on the expression of insulinoma-associated protein 1 (INSM1) in gastrointestinal and pancreatic MiNENs. This study compared the expression of INSM1 and traditional neuroendocrine markers in MiNENs. In this study, we collected 46 cases of gastrointestinal and pancreatic MiNENs and performed immunohistochemical staining for INSM1, SYP, CHGA, and CD56. Histologically, the neuroendocrine components of MiNENs were all neuroendocrine carcinomas, with small cell neuroendocrine carcinomas accounting for 15.2% (7/46) and large cell neuroendocrine carcinomas accounting for 84.8% (39/46). With respect to immunohistochemical expression, the overall sensitivity of INSM1 was 80.4% (37/46), which was lower than that of SYP (100%, 46/46), but comparable to that of CHGA (67.4%, 31/46) or CD56 (73.9%, 34/46). The overall specificity of INSM1 was 91.3% (42/46), which was greater than that of SYP (63.0%, 29/46) and CD56 (69.6, 32/46), but was not significantly different from that of CHGA (82.6%, 38/46). The proportion of 3 + staining for SYP (100%, 46/46) was greater than that of INSM1 (71.7, 33/46), while the proportion of 3 + staining for CHGA (10.9, 5/46) or CD56 (21.7, 10/46) was lower than that of INSM1. In conclusion, INSM1 exhibited high sensitivity and specificity in the diagnosis of gastrointestinal and pancreatic MiNENs.

Abstract An acellular bovine bone matrix modified to release Magnesium ions (Mg2+) (ABBM-Mg) was prepared and evaluated for its potential in osteogenesis and mandibular defect repair. Mg2+ was incorporated into ABBM using an ion exchange method. The microstructure and mechanical properties of both ABBM and ABBM-Mg were analyzed using SEM and a biomechanical testing machine. Cytocompatibility, cell adhesion, and osteogenic differentiation were assessed using various methods including CCK-8, Live/Dead staining, SEM, ALP staining, and qPCR analysis in MC3T3-E1 cells. Additionally, a mandibular defect model in rats was established. The bone defect repair outcomes were evaluated using Micro-CT, histological HE staining, and Masson staining. The study showed that mineralization containing magnesium was redeposited on the surface of the three-dimensional porous ABBM, and the ABBM-Mg scaffold promoted cell proliferation and osteogenic differentiation compared to the ABBM scaffold. In the rat mandibular defect model, the ABBM-Mg scaffold demonstrated superior bone repair ability. This study successfully incorporated Mg2+ into ABBM without significantly affecting its microstructure and compressive strength. Furthermore, ABBM-Mg showed sustained release of Mg2+ which enhanced cell proliferation, adhesion, and osteogenic differentiation in vitro, and promoted mandibular defect healing in rats. This research opens up new possibilities for the clinical application of functionalized acellular bone matrix. Graphical Abstract

Abstract Background Spinal cord injury (SCI) is a severe traumatic spinal condition with a poor prognosis. In this study, a scaffold called linearly ordered collagen aggregates (LOCAS) was created and loaded with induced pluripotent stem cells (iPSCs)-derived neural stem cells (NSCs) from human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) to treat SCI in a rat model. Methods The rats underwent a complete transection SCI resulting in a 3-mm break at either the T9 or T10 level of the spinal cord. Results Scanning electron microscope analysis revealed a uniform pore structure on the coronal plane of the scaffold. The LOCAS had a porosity of 88.52% and a water absorption of 1161.67%. Its compressive modulus and stress were measured at 4.1 MPa and 205 kPa, respectively, with a degradation time of 10 weeks. After 12 weeks, rats in the LOCAS-iPSCs-NSCs group exhibited significantly higher BBB scores (8.6) compared to the LOCAS-iPSCs-NSCs group (5.6) and the Model group (4.2). The CatWalk analysis showed improved motion trajectory, regularity index (RI), and swing speed in the LOCAS-iPSCs-NSCs group compared to the other groups. Motor evoked potentials latency was lower and amplitude was higher in the LOCAS-iPSCs-NSCs group, indicating better neural function recovery. Histological analysis demonstrated enhanced neuronal differentiation of NSCs and nerve fiber regeneration promoted by LOCAS-iPSCs-NSCs, leading to improved motor function recovery in rats. The LOCAS scaffold facilitated ordered neurofilament extension and guided nerve regeneration. Conclusions The combination of LOCAS and iPSCs-NSCs demonstrated a positive therapeutic impact on motor function recovery and tissue repair in rats with SCI. This development offers a more resilient bionic microenvironment and presents novel possibilities for clinical SCI repair.

Abstract Arterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptor–ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbβ3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patient’s pathological profile.

Abstract Antibacterial bone cements (ABCs), such as antibiotic-loaded bone cements (ALBCs), have been widely utilized in clinical treatments. Currently, bone cements loaded with vancomycin, gentamicin, tobramycin, or clindamycin are approved by the US Food and Drug Administration. However, traditional ALBCs exhibit drawbacks like burst release and bacterial resistance. Therefore, there is a demand for the development of antibacterial bone cements containing novel agents to address these defects. In this review, we provide an overview and prospect of the new antibacterial agents that can be used or have the potential to be applied in bone cement, including metallic antibacterial agents, pH-switchable antibacterial agents, cationic polymers, N-halamines, non-leaching acrylic monomers, antimicrobial peptides and enzymes. Additionally, we have conducted a preliminary assessment of the feasibility of bone cement containing N-halamine, which has demonstrated good antibacterial activities. The conclusion of this review is that the research and utilization of bone cement containing novel antibacterial agents contribute to addressing the limitations of ALBCs. Therefore, it is necessary to continue expanding the research and use of bone cement incorporating novel antibacterial agents. This review offers a novel perspectives for designing ABCs and treating bone infections. Graphical abstract

Abstract To tackle the clinical challenge of noninvasively assessing immunotherapy efficacy in patients, here we used positron emission tomography (PET) with 68Ga-grazytracer, which targets granzyme B, a crucial effector molecule secreted by activated CD8+ T cells. In this phase 1/2 clinical trial (NCT05000372) involving a diverse cohort of 24 patients with solid tumors and lymphomas who received immunotherapies, including immune checkpoint inhibitors (either alone or with chemotherapies) and chimeric antigen receptor-T cell therapy, we examined the in vivo behaviors of 68Ga-grazytracer. Primary endpoints were safety, biodistribution, granzyme B specificity, and the predictive utility of 68Ga-grazytracer, while secondary endpoint was the relationship between 68Ga-grazytracer uptake and tumor immune phenotype. 68Ga-grazytracer exhibited a safe profile and specifically targeted granzyme B in patients. 68Ga-grazytracer PET showed superior predictive value for short-term prognosis and progression-free survival than those of conventional assessment criteria, including RECIST 1.1 and PERCIST. Moreover, the uptake of 68Ga-grazytracer in tumors was significantly higher in those with a “non-desert” immune phenotype than those with an immune “desert” phenotype, thereby meeting the primary and secondary endpoints of this trial. Collectively, we successfully visualized CD8+ T cell effector function in humans using 68Ga-grazytracer PET, offering insights for enhancing immunotherapy assessment, patient stratification and treatment planning.

Abstract Background Cervical cancer is the fourth leading cause of cancer-related death among women worldwide, and effective therapeutic strategies for its treatment are limited. Recent studies have indicated that ferroptosis, a form of regulated cell death, is a promising therapeutic strategy. KLF14 has been shown to regulate both cell proliferation and apoptosis in cervical cancer. However, its role in modulating lipid peroxidation and ferroptosis remains largely unexplored and enigmatic. Methods SiHa and HeLa cells were transduced with lentiviral vectors to overexpress KLF14. Protein levels were analyzed via western blotting and immunohistochemistry (IHC). LDH assays, calcein-AM/propidium iodide (PI) staining, and generation of cell growth curves using a real-time cell analysis (RTCA) system were used to detect cell damage and proliferation. Cellular ROS, lipid ROS, transmission electron microscopy (TEM), and Fe2+ assays and a xenograft mouse model were used to measure the level of ferroptosis. Proteomics combined with bioinformatics methods was used to screen target genes regulated by KLF14, and CUT&Tag and dual-luciferase assays confirmed the repression of GPX4 by KLF14 via direct binding to its promoter. Results KLF14 is abnormally expressed in various tumors and downregulated in cervical cancer. Overexpression of KLF14 induced ferroptosis and inhibited cell proliferation in vitro as well as xenograft tumorigenicity in vivo. Mechanistic studies revealed that KLF14 binds to the promoter of GPX4, suppressing its transcriptional activity and thereby decreasing its expression, which contributes to the induction of ferroptosis. Truncation and point mutation analyses of the GPX4 promoter revealed multiple binding sites for KLF14 within the − 1000 bp to + 35 bp region, which are responsible for its inhibitory effect on GPX4 transcription. Additionally, deletion of the zinc finger motif in KLF14 abolished its inhibitory effect on GPX4 promoter activity and cell proliferation. Conclusion Our data revealed a previously unidentified function of KLF14 in promoting ferroptosis, which results in the suppression of cell proliferation. Mechanistically, we revealed a novel regulatory mechanism by which KLF14 targets GPX4. These findings suggest a novel strategy to induce ferroptosis through the targeting of KLF14 in human cervical cancer cells.

Abstract Metal nanoparticles have extraordinary properties, but their integration into mesostructures has been challenging. Producing uniformly dispersed nanoparticles attached to substrates in industrial quantities is difficult. Herein, a “plasmashock” method was developed to synthesize metal nanoparticles anchored on different types of carbonaceous substrates using liquid salt solution precursors. These self-supporting, nanoparticle-loaded carbon fabrics are mechanically robust and have been tested as antibacterial substrates and electrocatalysts for reducing carbon dioxide and nitrite. A piece of silver–carbon nanotube paper with a silver loading of ~0.13 mg cm−2 treated after a few-second plasmashock presents good antibacterial and electrocatalytic properties in wastewater, even after 20 bactericidal immersion cycles, due to the strong bonding of the nanoparticles to the substrate. The results prove the effectiveness of this plasmashock method in creating free-standing functional composite films or membranes.

Abstract Background Coronary artery disease (CAD) is a major global cardiovascular health threat and the leading cause of death in many countries. The disease has a significant impact in China, where it has become the leading cause of death. There is an urgent need to develop non-invasive, rapid, cost-effective, and reliable techniques for the early detection of CAD using machine learning (ML). Methods Six hundred eight participants were divided into three groups: healthy, hypertensive, and CAD. The raw data of pulse wave from those participants was collected. The data were de-noised, normalized, and analyzed using several applications. Seven ML classifiers were used to model the processed data, including Decision Tree (DT), Random Forest (RF), Gradient Boosting Decision Tree (GBDT), Extra Trees (ET), Extreme Gradient Boosting (XGBoost), Light Gradient Boosting (LightGBM), and Unbiased Boosting with Categorical Features (CatBoost). Results The Extra Trees classifier demonstrated the best classification performance. After tunning, the results performance evaluation on test set are: 0.8579 accuracy, 0.9361 AUC, 0.8561 recall, 0.8581 precision, 0.8571 F1 score, 0.7859 kappa coefficient, and 0.7867 MCC. The top 10 feature importances of ET model are w/t 1, t 3/t max , t max , t 3/t 1, As, h f/3, t f/3/t max , t f/5, w and t f/3/t 1. Conclusion Radial artery pulse wave can be used to identify healthy, hypertensive and CAD participants by using Extra Trees Classifier. This method provides a potential pathway to recognize CAD patients by using a simple, non-invasive, and cost-effective technique.

Abstract The temporal stability of aboveground net primary productivity is generally regulated by plant community structure and species diversity. There are recurring debates on the mechanisms by which environmental changes impact productivity stability in semiarid steppes. Here we revealed that plant community structure, rather than species diversity, regulates productivity stability in a semiarid Steppe. We conducted a decade-long in situ warming and precipitation addition experiment in a semiarid steppe in Inner Mongolia, China, to monitor plant productivity, species asynchrony, species diversity, and stability. We found that Leymus chinensis productivity increased and the Shannon–Wiener decreased under warming conditions, while Stipa krylovii productivity decreased under precipitation addition. Warming reduced the stability of Stipa krylovii and the plant community stability, whereas it did not affect the stability of L. chinensis. These results deepen our understanding of the regulatory role played by community structure and species diversity regarding productivity stability in semiarid steppes.

Abstract Background Insect-based food and feed are increasingly attracting attention. As a domesticated insect, the silkworm (Bombyx mori) has a highly nutritious pupa that can be easily raised in large quantities through large-scale farming, making it a highly promising source of food. The ratio of pupa to cocoon (RPC) refers to the proportion of the weight of the cocoon that is attributed to pupae, and is of significant value for edible utilization, as a higher RPC means a higher ratio of conversion of mulberry leaves to pupa. In silkworm production, there is a trade-off between RPC and cocoon shell ratiao(CSR), which refers the ratio of silk protein to the entire cocoon, during metamorphosis process. Understanding the genetic basis of this balance is crucial for breeding edible strains with a high RPC and further advancing its use as feed. Results Using QTL-seq, we identified a quantitative trait locus (QTL) for the balance between RPC and CSR that is located on chromosome 11 and covers a 9,773,115-bp region. This locus is an artificial selection hot spot that contains ten non-overlapping genomic regions under selection that were involved in the domestication and genetic breeding processes. These regions include 17 genes, nine of which are highly expressed in the silk gland, which is a vital component in the trade-off between RPC and CSR. These genes are annotate with function related with epigenetic modifications and the regulation of DNA replication et al. We identified one and two single nucleotide polymorphisms (SNPs) in the exons of teh KWMTBOMO06541 and KWMTBOMO06485 genes that result in amino acid changes in the protein domains. These SNPs have been strongly selected for during the domestication process. The KWMTBOMO06485 gene encodes the Bombyx mori (Bm) tRNA methyltransferase (BmDnmt2) and its knockout results in a significant change in the trade-off between CSR and RPC in both sexes. Conclusions Taken together, our results contribute to a better understanding of the genetic basis of RPC and CSR. The identified QTL and genes that affect RPC can be used for marker-assisted and genomic selection of silkworm strains with a high RPC. This will further enhance the production efficiency of silkworms and of closely-related insects for edible and feed purposes.

Abstract Patients with spinal cord injury (SCI) have permanent devastating motor and sensory disabilities. Secondary SCI is known for its complex progression and presents with sophisticated aberrant inflammation, vascular changes, and secondary cellular dysfunction, which aggravate the primary damage. Since their initial discovery, the potent neuroprotective effects and powerful delivery abilities of exosomes (Exos) have been reported in different research fields, including SCI. In this study, we summarize therapeutic advances related to the application of Exos in preclinical animal studies. Subsequently, we discuss the mechanisms of action of Exos derived from diverse cell types, including neurogenesis, angiogenesis, blood–spinal cord barrier preservation, anti-apoptosis, and anti-inflammatory potential. We also evaluate the relationship between the Exo delivery cargo and signaling pathways. Finally, we discuss the challenges and advantages of using Exos to offer innovative insights regarding the development of efficient clinical strategies for SCI.

Abstract Background Intra-lobar (ILS) and extra-lobar lung (ELS) sequestrations represent rare congenital lung malformations. Despite their benign nature, the lesions pose risks such as recurrent pulmonary infections, hemoptysis, congestive heart failure, and tumor development. Pulmonary sequestration (PS) typically manifests in two forms, ILS and ELS, with bilateral occurrence being exceptionally rare and mostly requiring bilateral thoracic surgery. Case presentation A 9-year-old child, who initially presented with bilateral lung lesions without respiratory symptoms, was diagnosed with PS following a chest computed tomography scan. The surgical approach was determined based on the absence of inflammation and the clear demarcation of the lesions from normal lung tissue, highlighted by a unique tissue connection between the ILS and ELS across the chest cavities. We used a novel method wherein the left ELS was successfully pulled into the right chest cavity and both sequestrations were concurrently resected. Postoperative recovery was smooth, with no complications or residual lesions. Conclusions Our findings highlight the importance of thorough preoperative planning with enhanced computed tomography. Simultaneous unilateral thoracoscopic surgery can be a viable, less invasive option for treating bilateral PS, offering benefits such as reduced recovery time and better cosmetic outcomes.

Abstract Objective To evaluate the potential utility of 18F-FDG PET/CT to assess response to neoadjuvant immunochemotherapy in patients with resectable NSCLC, and the ability to screen patients who may benefit from neoadjuvant immunochemotherapy. Methods Fifty one resectable NSCLC (stage IA–IIIB) patients were analyzed, who received two-three cycles neoadjuvant immunochemotherapy.18F-FDG PET/CT was carried out at baseline(scan-1) and prior to radical resection(scan-2). SULmax, SULpeak, MTV, TLG, T/N ratio, ΔSULmax%,ΔSULpeak%, ΔMTV%, ΔTLG%,ΔT/N ratio% were calculated. 18F-FDG PET/CT responses were classified using PERCIST. We then compared the RECIST 1.1 and PERCIST criteria for response assessment.With surgical pathology of primary lesions as the gold standard, the correlation between metabolic parameters of 18F-FDG PET/CT and major pathologic response (MPR) was analyzed. All metabolic parameters were compared to treatment response and correlated to PFS and OS. Results In total of fifty one patients, MPR was achieved in 25(49%, 25/51) patients after neoadjuvant therapy. The metabolic parameters of Scan-1 were not correlated with MPR.The degree of pathological regression was negatively correlated with SULmax, SULpeak, MTV, TLG, T/N ratio of scan-2, and the percentage changes of the ΔSULmax%, ΔSULpeak%, ΔMTV%,ΔTLG%,ΔT/N ratio% after neoadjuvant therapy (p

Abstract Background Bi-allelic variants in DNAH11 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on human sperm flagellar and their involvement in male infertility remain largely unknown. Methods A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 variants. Results In this study, we identified seven novel variants in the DNAH11 gene in four asthenoteratozoospermia subjects. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated, instead of inner dynein arms (IDA) proteins DNAH1 and DNAH6. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11, resulting in the aberrant assembly of sperm flagella and contributing to asthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.