Otitis media (OM) and its recurring (rAOM), effusive (OME), and chronic forms, represent a frequent clinical challenge. The middle ear, the mandible, and the temporomandibular joint (TMJ) share several embryological and anatomical connections. Despite that, the role of mandibular malposition and TMJ dysfunction is frequently overlooked in the management of otitis media. In this narrative review, we present current evidence supporting the etiopathogenetic role of a dysfunctional stomatognathic system in the onset of OM and the effectiveness of orthognathic treatment in preventing rAOM and OME. In particular, a focus on the influence of TMJ on Eustachian tube function is provided. Otitis media (OM) consists of inflammation in the middle ear. Subcategories include acute otitis media (AOM), otitis media with effusion (OME), recurrent acute otitis media (rAOM), and chronic suppurative otitis media (CSOM) . While tThe etiopathogenesis is still debated, though it is thought to be multifactorial, with a central role attributed to the Eustachian tube (ET) function . Other rThe pathogenetic role of the temporomandibular joint (TMJ) function, mandible position, and malocclusion has been hypothesized in this complex scenario . RelatioHere, we summarize the current knowledge on this topic, exploring the known relations between ear, TMJ, and dental occlusion, and evidence and hypothesis supporting the efficacy of gnathological treatment in preventing OM in its various forms.The review aims to collect current evidence about the impact of TMJ dysfunction and malocclusion on the onset and course of OM.The main objectives of the review were to: (I) Describe the embryological, anatomical, and functional relations between the stomatognathic system, the ear, and associated structures; (II) Summarize available evidence of the role of TMJ dysfunction, mandibular malposition. In addition, malocclusion on OM pathogenesis, and the effectiveness of gnathological therapies on preventing OM and ameliorating middle ear function and ventilation; (III) Discuss the actual knowledge on OM pathogenesis, risk factors, and associated comorbidities in light of the possible association with TMJ dysfunction and malocclusion.A narrative review was carried out. The searches were conducted using the PubMed database, using various combinations of the following keywords: (otitis OR otitis media OR acute otitis media OR recurrent acute otitis media OR otitis media with effusion OR Eustachian tube OR Eustachian tube function OR Eustachian tube dysfunction) AND . The search was conducted in October 2022.To be included in the review, articles had to meet the following criteria: (1) published in peer-reviewed journals; (2) written in English; (3) consider the role of TMJ function or malocclusion or orthognathic treatments in the clinical course of OM in its various form or Eustachian tube dysfunction; (4) only human subjects included.Titles and abstracts were viewed: the appropriate articles were reviewed, and the inappropriate ones were discarded. References in the selected articles were reviewed and included if not already listed. Further relevant papers were added from the authors’ libraries if not already included. The studies were then grouped according to their content and relevant findings described in narrative chapters.Details on study selection are summarized in The actual anatomy of the middle ear and TMJ structures derives from changes in the splanchno-cranium from reptile to mammal evolution. In reptiles, the mandible is composed of multiple bones, and there is a single bone in the ear. In the mammalian jaw, only the dentary bone was left. The bones of the old joint detached from the mandible and are part of the middle ear bone chain: the articular bone (mandible) became the malleus, and the quadrate bone (cranium) became the incus .In mammals, the maxillary and mandibular bones, the ET, the tympanic membrane, and most middle ear structures develop from the 1st pharyngeal arch . PharyngFinally, an indirect proof of this shared and interdependent embryologic development is the associated ear anomalies and mandibular dysplasia in the case of congenital malformations such as in congenital microtia, Treacher Collins syndrome, Turner syndrome, or 21 Trisomy. Such conditions also increases the risk of AOM, rAOM, OME, and CSOM ,22,23,24The TMJ is a diarthrosis formed by the union of the temporal bone cavity with the mandibular condyle. The articulation comprises a synovial cavity filled with synovial fluid, articular cartilage, and a capsule covering the same joint. A complex of ligaments and muscular tendons stabilizes and consents mandibular movement, forming a morpho-functional unit. The most relevant are the sphenomandibular ligament, the stylomandibular ligament, the pterygomandibular ligament, the discomalleolar ligament, and the collateral ligament. Among muscles, those which close the jaw are the masseter, temporal, and lateral pterygoid; those which open the jaw are the medial pterygoid, geniohyoideus, mylohyoideus, and digastric .The middle ear, the TMJ, and the mandible are anatomically related by their proximity and direct and indirect connections.The TMJ and the ear are anatomically close. The cranial surface of TMJ consists of the squamous area of the temporal bone; it is called the glenoid fossa and welcomes the condyle of the jaw. The posterior area of the fossa contains a bone portion called the postglenoid process, which contributes to forming the upper wall of the external acoustic meatus . The proThe most direct communication between the middle ear and the TMJ is the abovementioned petrotympanic fissure, which contains the anterior tympanic and deep auricular arteries, the chorda tympani and auriculotemporal nerve, and the disco-malleolar and anterior malleolar ligaments .However, the most relevant aspect in understanding OM pathogenesis is represented by the anatomical and functional relations between ET, TMJ, and mandible. The ET lies immediately below the skull base, runs anteriorly, medially, and inferiorly from the middle ear to the nasopharynx, and is formed of osseous  and cartilaginous  sections . It liesThe ET is collapsed at rest; the oval-shaped lumen opens during swallowing as the result of contraction of the para-tubal muscles on the cartilaginous portion of the Eustachian tube. The TVP muscle is the most important muscle in opening the ET ,29,30. OThe TVP consists of a lateral layer originating from the skull base and a medial layer arising from the lateral lamina of the tubal cartilage. The lateral layer pulls from the skull base to a small tendon going around the pterygoid hamulus and spreading into the aponeurosis of the soft palate. Between the tendon and the hamulus, there is a small bursa. The medial layer of the tensor is situated between the lateral lamina of the tubal cartilage and the medial lamina of the pterygoid process. There are two fasciae that cover the medial and the lateral surface of the TVP muscle. Laterally, there is the Weber-Liel fascia, which separates the TVP muscle from the medial pterygoid muscle. Medially, a fascia runs from the lateral lamina of the tubal cartilage along the lateral surface of the so-called lateral Ostmann fat pad to the salpingopharyngeal fascia, which is also called the von Tröltsch fascia .The function of the TVP muscle is complex for two reasons: (I) its contraction is completely isometric, meaning that the opening function depends on a system of levers that Leuwer et al. call hypomochlia; (II) both TVP layers have dissimilar effects on ET function: whereas contraction of the medial layer opens the eustachian tube by lateralization of the lateral lamina of the cartilage, the lateral layer compresses the lower portion of the tube. Thus, the medial layer supports ventilation, and the lateral layer supports drainage and protection . There aFinally, two masticatory muscles need to be cited to fully understand the relations between ET, TMJ, and the mandible: the medial and lateral pterygoid muscles. The medial pterygoid muscle is a chewing muscle that closes the mouth and helps protrude the mandible. Its contraction causes a posteromedial movement of the tensor toward the cartilage, increasing the tubal opening pressure. Inversely, the opening of the ET is facilitated by the relaxation of the medial pterygoid due to an anterolateral movement of the TVP while opening the mouth. Due to their connection via the Weber-Liel fascia, the TVP and medial pterygoid muscles form a mechanical functional unit. Simultaneous relaxation of the medial pterygoid muscle, as well as contraction of the TVP muscle by yawning, can be used as a maneuver for the physiologic active tubal opening during external pressure changes, such as the landing of an airplane. Morphological or functional alterations of the medial pterygoid muscle, for example, in craniomandibular disorders, may change the muscular compliance of the eustachian tube .The lateral pterygoid muscle is a single unit divided into two bellies: the superior belly inserts anteriorly on the infratemporal surface of the sphenoid bone’s greater wing and the pterygoid process lateral wing, and posteriorly on the TMJ disc and mandibular condyle; the inferior belly anteriorly attaches on the lateral area of the pterygoid process lateral wing, lateral area of the pyramidal process, and part of the maxillary bone tuberosity, and posteriorly to the mandibular condyle and TMJ capsule .In normal subjects, cine CT imaging acquired during a sequence of swallows demonstrated a discrete air bolus progressing superiorly toward the middle ear in a peristaltic-like movement with medial and lateral pterygoid muscle contractions . The latThe anatomical and physiological relations between middle ear structures, particularly ET, TMJ, and the mandible, and their interdependent development corroborate the role of the gnathic system in the pathogenesis of OM.The shortening and thickening of the mastication medial pterygoid muscle in over-closed jaw positions exert a lateral pulling force on the TVP muscle and the ET. An increase in medial pterygoid transverse volume can result from an open-closed position depending on muscle length and tension variation. Thus, the medial pterygoid muscle activity could change muscle tension direction together with another two structures contacting the TVP (pterygoid hamulus and Ostmann’s fatty tissue), which may influence middle-ear ventilation by Eustachian tube compliance . The musMcDonald et al. conducted a radiological study on 16 adults with or without ET dysfunction who have undergone a cine computed tomography during swallowing or other jaw movements. Images obtained from subjects with ET dysfunction displayed a smaller or absent air bolus passing through the ET and a little, if any, observable medial pterygoid movement. They conclude on the amplificatory role of the masticatory muscles on ET opening and closing .As electromyographic studies suggest, the activity of the masticatory muscles could be altered by a malocclusion. The involved side and muscular group depend on the type of malocclusion . A signiThese considerations could help evaluate eligibility for ET dilation with catheter ballooning, a procedure that has recently emerged to treat ET dysfunction. This procedure has shown good efficacy in updated metanalyses; however, 30 to 50% of subjects seem non-responding to this therapy at a medium-term follow-up . The motSeveral studies on the pediatric population support the relationship between stomatognathic structures and function and the risk of OM. In a study on 105 infants, McDonnell et al. found deep bite an independent risk factor for ET dysfunction, with a 2.8 times higher odds ratio compared to children with normal occlusion . In a siGreater alterations in the craniofacial morphology and in the mandibular-maxillary relation were found in children with rAOM younger than 4 years compared to healthy control in a study by Gremba et al. . SpecifiIf alterations in the stomatognathic system could increase the risk of OM, it is also possible that treating the predisposing conditions benefits ET function, preventing middle ear inflammations.In 1988 Marasa and Ham presented four cases of children affected by retrognathic bite and OME or rAOM, who resolved their otologic complaints after receiving orthodontic treatment . SimilarA study led by the first author (E.B.) assessed the effect of orthognathic treatment on children with rAOM . The cliThe beneficial effects of gnathological treatments on middle ear conditions are also stated in works considering maxillary expansion .Kilic et al. report significant hearing improvement and air-bone gap reduction after semi-rapid maxillary expansion in a group of 19 adolescents, and these changes remained relatively stable during the last two periods. Middle ear volume increased statistically significantly after maxillary expansion and continued to increase until the end of treatment. After maxillary expansion, the TVP muscle is stretched, and its contractible activity improves with consequent more effective vectorial forces . Singh eOtitis media in its various forms is a relevant clinical problem. Involved pathogens are well renowned, namely Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis, and Staphylococcus aureus. The introduction of vaccination against S. pneumoniae has been associated with a reduction in OM caused by these bacteria and a rise of the other pathogens as causative agents . The appFrom a preventive perspective, risk factors for AOM are classified as modifiable and unmodifiable. Vaccinations, xylitol, probiotics, and vitamin D supplementation show low evidence of efficacy ,52,53. IIn the pathogenetic ET-TMJ model discussed above, if a single episode of AOM could be attributed to a sporadic viral or bacterial colonization of the middle ear coming from the upper airway tract, rAOM or OME could be interpreted as a recurrent infection or persisting effusion due to relapsing or chronic TVP dysfunction, mediated by a dysfunctional bite . The midFrom this perspective, an orthognathic treatment could be seen as a form of primary, secondary, or tertiary prevention, depending on the time point it is administered in the natural history of OM: as primary prevention when malocclusion is intercepted before an episode of AOM take place; as secondary prevention to prevent relapses, chronicization, CSOM, and complications such as cholesteatoma or TMJ septic arthritis; as tertiary prevention to maintain the results of otological surgery when ventilation routes are restored or in case of radical procedures such as for extensive cholesteatomas ,56,57.This conceptual framework shed new light on renowned modifiable and unmodifiable risk factors with some changes to their classification.Age, male sex, Caucasian ethnicity, genetic factors, school-attending siblings, prematurity, immunological deficiency, atopy, and anatomical factors such as ET dysfunction and craniofacial anomalies are included among unmodifiable risk factors for AOM .As explained above, ET function can be influenced by the mandibular position and dental occlusion; therefore, it should be listed among the modifiable risk factors. The characteristic anatomy of the ET in childhood is thought to be the main reason for its dysfunction since it is shorter and with a shallower angle compared to adults . NeverthAs discussed in the “Relevant Sections”, craniofacial anomalies are frequently associated with rAOM and OME. Fortunately, cases of craniofacial malformations are rare. Contrariwise, abnormal facial shape and position of facial components are frequently seen in malocclusion, which can be adjusted with an orthognathic treatment. Therefore, most cases addressed as “unmodifiable” could be easily treated with non-invasive interventions .Genetic factors are implied in a familiar history of rAOM or OME, especially for homozygotic twins ,61. MoreObstructive sleep apnoea syndrome (OSAS), gastro-oesophageal reflux disease (GERD), school attendance, and exposure to smoke and air pollution are among the modifiable risk factors.Exogenous factors such as smoke and air pollution need an entryway to the nasopharynx, ET, and middle ear. Malocclusion may predispose to oral breathing due to difficulty in keeping the mouth closed and muscular fatigue . In the Speaking of OSAS, it is thought to increase the risk of rAOM and OME. However, the effectiveness of OSAS treatment on OM outcomes is still debated. Robison et al. showed an increased incidence of ET dysfunction in children with OSAS and a decreased need for myringotomy and tympanic tube placement after surgical interventions for treating OSAS . Ungar eFinally, GERD is listed among the potential risk factors for OM due to the inflammatory effects on ET. The prevalence of GERD in children with OME and rAOM may be higher than the overall prevalence for children. The presence of pepsin/pepsinogen in the middle ear could be related to physiologic reflux. Nevertheless, a cause-effect relationship between pepsin/pepsinogen in the middle ear and OM is unclear, and anti-reflux therapy for OM cannot be endorsed based on existing research . ObstrucRandomized controlled trials are advocated to determine the quantitative contribution of malocclusion in the onset of OM and the effectiveness of orthognathic treatment in preventing relapses and chronicization. Groups that are homogeneous for confounding factors and stratified for ages would be recommended.Current research is not evaluable with metanalysis due to variable endpoints, non-standardized treatments, and lack of uniformity in defining fundamental features such as ET dysfunction. When solid evidence is collected, a clear profile of risk should be included in guidelines to provide physicians with practical tools to screen for possible malocclusion predisposing to or sustaining OM. This would aim to recognize the orthodontist’s role and include the gnathological evaluation and treatment in the integrated management of OM.the external and middle ear, the TMJ, the mandible, the ET, and associated musculature and ligaments share interdependent embryogenesis and development;these structures have multiple anatomical connections. In particular, ET, TMJ, and masticatory muscles are strictly connected;ET function is influenced by the mandibular position and masticatory muscles function; the role of the medial pterygoid muscle is particularly emphasized;mandibular position and malocclusion are related to a higher risk of AOM and rAOM; this is particularly evident in children with a deep bite and a crossbite;the studies on the effectiveness of orthognathic treatments in preventing rAOM show encouraging results;TMJ dysfunction and malocclusion are strongly related to known predisposing factors for AOM, rAOM, and OME; addressing them could further protect the patient from ear inflammations.The sequent key points emerge from our review:The current literature supports malocclusion with mandibular malposition and TMJ dysfunction as a predisposing factor to ET dysfunction due to alterations of TVP activity. This persisting condition could lead to rAOM, OME, and potential chronicization of OM. Gnathological, conservative treatments with removable oral appliances improve TVP and ET function, consenting middle ear ventilation and preventing relapsing or persistent forms of OM. Otolaryngologists, pediatricians, and physicians should evaluate the occlusal status of patients, especially when recurrent inflammations are present. Otitis media should be regarded as a multidisciplinary pathology requiring multidisciplinary management.


By improving the diameter of nanoparticles This study aimed to analyze the momentum and thermal transport of a rotating dusty Maxwell nanofluid flow on a magnetohydrodynamic Darcy–Forchheimer porous medium with conducting dust particles. Nanouids are the most important source of effective heat source, having many applications in scientific and technological processes. The dust nanoparticles with superior thermal characteristics offer a wide range of uses in chemical and mechanical engineering eras and modern technology. In addition, nanofluid Cu-water is used as the heat-carrying fluid. The governing equations for the two phases model are partial differential equations later transmuted into ordinary ones via similarity transforms. An efficient code for the Runge–Kutta technique with a shooting tool is constructed in MATLAB script to obtain numeric results. The study is compared to previously published work and determined to be perfect. It is observed that the rising strength of the rotating and magnetic parameters cause to recede the  Non-Newtonian fluids do not follow Newton’s viscosity law, having continuous viscosity regardless of stress. Non-Newtonian nanofluids are employed in various technological, vehicle, and typical housekeeping machinery applications. When external forces influence non-Newtonian fluids, their density might change, resulting in more fluids or solids. To develop innovative non-Newtonian nanofluid features, mathematicians worldwide are exploring novel research models throughout all periods of every day and night. Firstly, Powell and Trying introduced non-Newtonian fluid in 1944. Wang et al.  deliberaNanoparticles are tiny particles with a diameter range of (1–100) nm. For the human eye, these are invisible, having chemical and physical properties that differ significantly from their bigger material counterparts. Experts in thermal engineering have embraced the effectiveness of nanofluids due to improvements in heat transmission throughout fluid movement. The nature of the base fluid and nanoparticles underpins the previously described progress. Physical features include nanoparticle concentration and temperature impacts on the mass-to-density ratio and viscosity. Thermal conductivity, specific heat capacity at various concentrations of nanoparticles, and nanoparticles’ size and temperature are some of the thermal characteristics. According to Jama et al. , the nanResearchers in thermal engineering have embraced the effectiveness of nanofluids due to improvements in heat transmission throughout fluid movement. The nature of the base fluid and nanoparticles underpins the previously described progress. Physical features include nanoparticle concentration and temperature impacts on the mass-to-density ratio and viscosity, thermal conductivity, specific heat capacity at various concentrations of nanoparticles, and the size and temperature of nanoparticles. Nanofluids have multiple features, including nanoparticle concentration, pressure drop, friction factor, and nanoparticle radius.Because of its unique thermo-physical features and heat transmission efficiency, various researchers and analysts have been driven to examine the magnetohydrodynamic flow of viscous particles across a stretched surface due to its beneficial applications in daily life. Magnetohydrodynamic characteristics of metallic materials, such as plasma, metals, seawater, liquid, and electrolytes, are determined. Magnetic medicines, astrophysical detection, and engineering applications may benefit from MHD. Zhang et al.  investigDue to its wide-ranging uses in sophisticated technologies, engineering, and other branches of science, the flow across a spinning disc has become an advanced subject of research for investigators and engineers. Centrifugal pumps, aeronautical science, engineering areas such as rotating machinery, gas turbine rotors, thermal power-producing systems, air vacuuming devices, and medical equipment are only a few real-world applications. For the very first time, Von Karman studied flow by a rotating disk. Khan et al.  discusseTwo-phase fluid flow has become more important in the industrial and engineering sectors. One phase is assumed to be dust, while the other is fluid. Large-scale industrial and engineering applications have used dusty nanofluids made of dust substances. As a result, multiple researchers have studied the dusty fluid flow over various surfaces while suspending nanoparticles. Mahanthesh et al.  investigBy analyzing the above literature survey, we deduce that no research has been carried out on the MHD rotating flow of Maxwell fluid with dust particles and nanoparticle radius. Therefore, the prime purpose of the present investigation is to study the outcomes of nanoparticle diameter on the dynamic of Maxwell dusty fluid. Thus, this study explores the consequence of magnetic and Coriolis force effects on dusty fluid flow across extending sheets. The related nonlinear partial differential equations are converted to a system of coupled nonlinear ordinary differential equations by utilizing appropriate similarity modifications. The numerical outcome of the local skin friction coefficient and the local Nusselt number are examined in graphical and tabular form for different physical parameters. The inclusion of dust and nanoparticles with base fluid formed the dusty nanofluid. This numerical report has enormous applications in chemical and mechanical engineering, and others areas, such as the cooling of nuclear reactors, heat exchangers, retrieval of crude oil, waste water treatment, and power technology.z-axis. Fluid rotates about the z-axis with constant velocity A three-dimensional laminar rotating flow of incompressible dusty Maxwell, the dynamics of water conveying copper nanoparticles over a stretching sheet, is assumed. The sheet is stretched in the For dusty particle flowThe dimensional boundary conditions areBy introducing similarity transform (10)u^=aEquation  is identFor dusty phaseThe important physical quantities of interest are discussed in this section. The Nusselt coefficients The local Reynolds number A system of ordinary differential equations represents the flow model. Algorithms (11)–(16) are numerically solved using the effectiveness and strength of numerical computing in the Runge-Kutta approach using MATLAB. Refs. ,53 proviThe corresponding boundary conditions are as follows:This research aims to investigate Maxwell nanofluid flow and melting thermal transport across a stretched surface with fluid–particle suspension. The Runge–Kutta approach solves the governed highly nonlinear expressions with associated conditions coded in MATLAB. The numerical code validation is obtained by comparing the numerical outcomes of the current and past results of skin friction ,48 and Nx-direction for the fluid phase, and x-direction for the dust phase, respectively. It can be seen that the velocity lowered while the temperature boundary layer rose with improving the M inputs. The influence of a magnetic field on an electrically conducting fluid causes the resistive force that tends to reduce the momentum while increasing the thermal boundary layer. Because of this, the magnetic field impact has a wide range of control-based applications, including magnetohydrodynamic ion propulsion, electromagnetic metal casting, magnetohydrodynamic power production, etc. The velocity and thermal boundary layer for different inputs of the diameter of nanoparticles are portrayed in x-axis while y-axis for the fluid phase, and x-axis while y-axis for the dust particles, respectively. It is observed that the momentum profile decreased. The reduced viscosity of water-based nanofluid caused due to a larger copper nanoparticles radius leads to a rise in momentum at all levels of energy flow due to the concentration gradient. When the energy flow owing to the concentration gradient is sufficient in magnitude, a drop occurs in temperature distribution over the domain. The other side shows the impact of the rotation parameter x-direction declines and in the y-direction, it enhances fluid and dust particles with improving M and M, From diagrams a,b that Throughout all levels of energy flux caused to the concentration gradient, a decrease in the viscosity of water-based nanofluid due to a larger radius of copper nanoparticles produces an increase in the momentum boundary layer.x and y axis velocities in the two phase fluid to recede, but the temperature function exhibits an opposite trend.It is observed that the growing strength of the rotating and magnetic parameters cause the x- and y-axis velocities in the two-phase fluid, but the temperature is upgraded.The higher input in the porosity and Forchheimer number causes a decline in the magnitude of the A significant decline in the thermal boundary layer over the domain, caused due to enhancing the radius of Copper nanoparticles, is feasible when the heat flux caused to the concentration gradient is sufficiently higher in magnitude.The inclusion of dust particles or nanoparticles both cause to decline the primary and secondary velocities of fluid, and also dust particles decrease the temperature, but nanoparticles enhance the base fluid temperature.The Nusselt number is decreased negatively against higher values for higher values of The present results are compared with the past literature to validate the results.An effort has been made to investigate the importance of raising the radius of nanoparticles and heat flux due to the thermal boundary gradient in the dynamic of the Maxwell nanofluid across the stretched sheet. The non-dimensional boundary value problem is resolved numerically. The code of the Runge–Kutta method is developed in a MATLAB script. Based on the results, it is reasonable to conclude the following:


Tubal factor is an important contributor to female infertility, and the current diagnostic approaches cannot correctly identify many subtle causes of tubal dysfunction. While it is known that the most common cause of tubal factor infertility is pelvic inflammatory disease (PID), creating critical alterations of the tubal epithelium, little attention has been devoted to understanding the tubal modifications caused by the resident microbial population and their interaction with the surrounding tubal epithelium. Furthermore, most of these samples are obtained by traumatic procedures such as direct sampling during laparoscopy using a cytobrush. However, as in any other organ of the female genital tract, the microbiota environment of the fallopian tube plays an essential role in maintaining tubal functioning, counteracting the pathogenic effect of acquired microbes. Consequentially, to better analyze the tubal microbiota without causing anatomical and/or functional alteration of the fallopian tube and preserving fertility, the hysteroscopic approach might be the method of choice, guarantying maximal integrity of the uterine cavity and tubal lumen. Here we describe our plan for using atraumatic hysteroscopic sampling methods to investigate the correlation between tubal microbiota and female infertility. Chlamydia trachomatis, Neisseria gonorrhoeae, Escherichia coli, Mycoplasma hominis, Mobiluncus, Bacteroides and Ureolyticus) cause ultrastructural changes consisting of sloughing and/or destroying of ciliated cells, with subsequent cessation of ciliary activity, disruption of cell junctions and apoptosis of epithelial cells. These are the consequences of several pathogenic mechanisms such as direct cytotoxic effect, immune response, secretion of chemokines, and cytokines [Tubal factor causes 30% of all female infertility and generally occurs secondary to tubal obstruction, distortion, or intrinsic dysfunction of the epithelium . The mosytokines ,6.Several studies have confirmed that each organ of the female genital tract is characterized by the presence of a specific microbial population that plays a pivotal role in maintaining the normal reproductive function, and preventing dismicrobisms and infections ,8.Similar to what happens in the vagina and the endometrium, it could be argued that the microbiota, as a result of a delicate balance of the all-female genital tract organs, also plays a prominent role in the tubal function and, therefore, in female fertility opposing to pathogenic microbes. With this in mind, a few authors have focused their efforts on the direct evaluation of microbe’s effect on the tubal lumen, assessing, incidentally, only the detection of the most common pathogens.The majority of data currently available in the literature come from studies obtained by laparoscopic access, specifically by salpingectomy . Other sTo maintain the anatomical and functional integrity of the whole female genital tract and obtain a cytological and microbiological sample of the tubal epithelium, finding a non-invasive technique becomes mandatory. In this perspective, the hysteroscopic approach could be the method of choice for an indirect tubal integrity evaluation . Currently, hysteroscopy is considered the ideal diagnostic procedure for assessing the vaginal walls, cervical canal, uterine cavity, endometrium, and tubal ostia ,12,13. MSome authors have used the hysteroscope to obtain fallopian tissue samples to determine the etiologic diagnosis of salpingitis using a cytobrush inserted through the working channel . The hysAlthough hysteroscopy seems the most appropriate minimally invasive method to examine the tubal factor, scanty and inconsistent data are currently available in the literature to support its use.In conclusion, the tubal infertility factors remain an enigmatic dilemma waiting to be discovered entirely, and the microbiota, with its changes, could be a milestone in the understanding of tubal factor infertility. Although vaginal and endometrial microbiota are extensively studied in the literature ,8, scantFor this purpose, alternative microbiological and cytological sampling methods should be encouraged without the potential methodological bias described above. Thus, large multicentre well-designed studies using hysteroscopic sampling methods are necessary to elucidate the relationship between tubal microbiota and female infertility.


Pigs utilize multimodal communication for reproductive and other behaviors, and chemical communication is one of the key components. The success of reproduction relies on chemical communication favored by the steroid pheromones from boar saliva. These steroids were proven to be involved in advancing puberty in gilts (the boar effect) and in promoting estrus behaviors in gilts/sows, thereby helping to detect estrus and facilitating the timing of artificial insemination. The steroid pheromones bound with carrier proteins are evidenced in the mandibular (submandibular) salivary secretions of the boar. These salivary steroids bind with carrier proteins in the nasal mucus and vomeronasal organ (VNO) of the sows, eventually triggering a cascade of activities at the olfactory and endocrine levels. Besides steroid pheromones, pig appeasing pheromones (from mammary skin secretions of sows) have also been demonstrated to bind with carrier proteins in the nasal mucus and VNO of the piglets. Thus far, four different proteins have been identified and confirmed in the nasal mucus and VNO of pigs, including odorant binding proteins (OBPs), salivary lipocalin (SAL), pheromaxein, and Von Ebner's Gland Protein (VEGP). The critical roles of the chemosensory systems, main olfactory systems and VNO, have been comprehensively reported for pigs. This review summarizes the current knowledge on pheromones, their receptor proteins, and the olfactory systems of porcine species. Pheromonal signals in pigs are perceived and processed through various components, in that binding protein and the olfactory systems [main olfactory system (MOS) and Vomeronasal organ (VNO)] are pivotal. The binding proteins and olfactory systems were extensively investigated during the past three decades. In particular, molecular studies revealed novel binding proteins and elucidated the structural and functional aspects of the olfactory systems. Put together, these research results improved our understanding of pig chemical communication; however, a comprehensive and updated review on these topics is yet to be available. While we recently reviewed the pheromonal communication of pigs , in thisPheromones are species-specific chemical moieties secreted in various body fluids that elicit specific behavioral and/or neuroendocrinological changes in the receiving individual of the same species. In many animals, various body secretions such as urine, feces, saliva, glandular secretions, and tears have been shown to be sources of pheromones. In pigs, boar saliva and sow mammary skin secretions have been documented as key sources of pheromones. Saliva contains steroid pheromones  that induce the boar effect in gilts, i.e., advancing the onset of puberty. In common with rodents, an immediate increase in LH pulse frequency was seen in prepubertal gilts exposed to a boar, but only in those destined to show an earlier puberty . An incrBoar salivary steroid pheromones were proven to induce estrus behaviors in sows and so help to detect estrus. Unlike boars, there are no reports of salivary pheromones in sows although non-steroid pheromones were reported in their mammary skin secretion. Briefly, these non-steroid pheromones (a mixture of fatty acids) potentially reduce aggression between the piglets. In addition to the steroid pheromones, saliva contains specific proteins that are believed to act as carrier molecules for the steroid pheromones.via the blood circulatory system, stored in adipose tissues, and in part secreted through the saliva  gland, secrete the saliva that carries the steroid pheromones. These pheromones are primarily produced in the testes, transported e saliva . The prie saliva . In the e saliva . These ae saliva  reportede saliva  reportede saliva . Neverthe saliva , and 3β-e saliva , while te saliva , 10. TheRecently, a synthetic mixture including androstenone, androstenol, and quinoline as a boar saliva analog was shown to elicit estrus behaviors in sows and, potentially, to reduce their weaning-to-estrus intervals , and to In addition to steroid sex pheromones, non-steroid pheromones  were identified in the mammary skin secretions of suckling sows , 15. ExpPigs rely heavily on their sense of smell and are an excellent model system to investigate olfaction . The olfThe detailed analysis of sensory systems in other animals led to the discovery of the Grueneberg ganglion that expresses odorant olfactory receptors. Grueneberg ganglia are involved in the detection of odors and alarm pheromones . FurtherMany soluble binding proteins are present in the body exudates and olfactory systems of animals to deliver and receive volatile pheromones . For insThe VNO and nasal mucosa of both boar and sow contain odorant binding proteins (OBPs), Von Ebner's Gland Protein (VEGP), and salivary lipocalin (SAL). In addition, SAL and pheromaxein were reported in the mandibular gland of boars. Bound ligands (5α-androst-16-en-3-one and 5α-androst-16-en-3α-ol) were also identified in the sex-specific binding proteins of the mandibular gland of adult boar . HoweverThe mandibular gland in boars is the key organ in the secretion of frothy saliva that contains active steroid pheromones and induces sexual behaviors in sows. The presence of two different carrier proteins (SAL and pheromaxein) in the mandibular gland with similar functions makes pig an interesting chemosensory research model. Even though SAL and pheromaxein belong to different protein families , both revealed steroid pheromones as bound ligands, suggesting an indispensable role in the chemical communication of pigs. Hitherto, the presence of SAL and pheromaxein in the mandibular gland has been reported by separate studies, and no report for both the proteins in a single study is available. The two proteins may exhibit differential binding affinity toward steroids and so comparative analysis of SAL and pheromaxein in the same boar is recommended, which may shed light on pheromonal communication in pigs.The 16-androstene binding protein, pheromaxein, was identified in the saliva and mandibular gland of Gottingen miniature pigs . SubsequBesides pheromaxein, a large amount of a binding protein that possessed a lipocalin signature (-G-X-W-) was found in the mandibular gland of mature boars. This protein of molecular mass of approximately 22 kDa was identified as SAL . Unlike The porcine OBP was identified as a dimer with a β-barrel structure, which is formed of aromatic or aliphatic chains in addition to a few polar non-charged residues. This β barrel structure is linked to an α-helical domain, but there were no conformational changes upon binding with the odorants . The ligHancock et al.  tested tThe binding proteins identified in boars and sows are illustrated in E. coli and was used together with native SAL purified from mandibular glands in fluorescent-based binding assays and the two proteins displayed comparable affinities for the tested ligands. This was surprising because native SAL bears N-glycans that are absent from the bacterial recombinant counterpart. Indeed, glycosylation is known to modify the function of the proteins. Such a result could indicate that SAL N-glycosylation is not involved in the internal binding of ligands, but more likely in interactions at the surface of the protein, such as dimer formation or interaction with olfactory receptors.OBP and VEGP N-terminal sequences are characterized by the cyclization of the first residue Glu1 in pyroglutamic acid (Gln1) that makes the protein refractory to Edman sequencing . The N-tO-N-acetylglucosaminylation (O-GlcNAcylation)  , 49. In ylation)  whilst tylation) . Mappingylation) . Indeed,It is apparent from the above literature that pigs use different soluble proteins to carry/release and to receive various ligands, including steroid pheromones and fatty acids of PAP. However, the presence of the same proteins in the nasal mucus and VNO of both sexes is intriguing and suggests functions of the proteins in the chemical communication of pigs. The sex-specific expression and presence of pheromaxein in boars and their bound ligands confirm the pivotal role of these proteins in carrying the steroid pheromones to the receiver.MacLeod et al.  revealedThe VNO is crucial for chemical communication in many animals. It connects to both nasal and oral mucus, thereby facilitating the effective transfer of odorant molecules. In order to demonstrate the importance of VNO in the detection of pheromone, Dorries et al.  used surIn common with rodents, gilts demonstrate acceleration of puberty when exposed to boars (Vandenbergh effect) as well as increased variability of estrous cycle length when maintained in all-gilt groups (Lee Boot effect). However, unlike in rodents, only a few studies have reported the molecular components of olfactory system and VNO in pigs. Nguyen et al.  reportedStefanczyk-Krzymowska et al.  used trivia blood circulatory system to various brain areas and the hypothalamus, bypassing the systemic circulation and avoiding hepatic clearance. Further, repeated intramuscular injections of this steroid into cycling follicular phase gilts resulted in reduced mean plasma LH and estradiol concentrations (via kisspeptin release with more than 90% of the KNDy neuron afferents originating from within the arcuate nucleus (The mechanisms involved remain to be fully elucidated but as detailed by Stefanczyk-Krzymowska et al. , 5α-andrtrations , reflect nucleus . Further nucleus , and and nucleus . Steroid nucleus .Although a recent study has documented the habituation and dishabituation paradigm of boar pheromone , direct Baldwin and Cooper  confirmein silico or other related approaches to decipher the role of newer compounds in pig chemical communication.Recent studies have reported various molecules potentially involved in pig chemical communication. These compounds, in part, were shown to elicit behavioral changes in pigs. For instance, quinoline was found to elicit erected ears in sows during the assessment of sexual behavioral scores . Also, aThe pig is an immensely important food animal that relies heavily on olfaction for reproduction, social interaction, survival and feeding. The reproduction of pigs, in part, is mediated through chemical communication. However, unlike rodents, the chemosensory systems and their related components have been sparsely investigated in pigs. Despite studies on the effect of pheromones at the behavioral level, deciphering the interaction between the pheromone and the cognate receptor of the olfactory system is less categorical and remains elusive in pigs. In order to decipher the chemical communication system of pigs, a complete understanding of pheromones, carriers or binding proteins, and the potential molecular action of pheromones in olfactory systems/subsystems are required. Given the knowledge gaps, advancements in basic research are needed in pigs to establish the roles of pheromones and to discriminate the general odorant and putative pheromones.DS and RK perceived the idea and drafted the first version of the manuscript. PN-L revised the first draft of the manuscript. JA, SA, and GA critically revised the manuscript and drafted the final version. All authors contributed to the article and approved the submitted version.The authors declare that the review was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Plant toxins constitute an effective defense against herbivorous animals. However, many herbivores have evolved adaptations to cope with dietary toxins through detoxification, excretion, sequestration, target site insensitivity and/or via behavioral avoidance. While these adaptations are often directly encoded in herbivore genomes, evidence is accumulating that microbial symbionts can reduce the dose of plant toxins by metabolizing or sequestering them prior to absorption by the herbivore. Here, we describe a few well-studied examples to assess such symbiont-mediated detoxification and showcase different approaches that have been used for their analyses. These include: (i) a host phenotypic route in which the symbiotic association is manipulated to reveal host fitness costs upon toxin exposure in the presence/absence of detoxifying symbionts, including function restoration after symbiont re-infection, (ii) a molecular microbiological approach that focuses on the identification and characterization of microbial genes involved in plant toxin metabolism, and (iii) an analytical chemical route that aims to characterize the conversion of the toxin to less harmful metabolites in vivo and link conversion to the activities of a detoxifying symbiont. The advantages and challenges of each approach are discussed, and it is argued that a multi-pronged strategy combining phenotypic, molecular, and chemical evidence is needed to unambiguously demonstrate microbial contributions to plant toxin reduction and the importance of these processes for host fitness. Given the interdisciplinary nature of the topic, we aim to provide a guideline to researchers interested in symbiont-mediated detoxification and hope to encourage future studies that contribute to a more comprehensive and mechanistic understanding of detoxification in herbivores and their symbionts. In nature, caffeine likely serves as an anti-herbivory defense molecule, given its deterrent and toxic effects on arthropods. While many insect species occasionally feed on parts of coffee plants, the coffee berry borer  is the only known species to complete its entire life cycle solely on coffee beans, apparently thriving on the high concentrations of caffeine in their diet. In an elegant study, Ceja-Navarro et al.  derivatives. Mimosine is produced in high quantities by leucaena, , a fast growing shrub commonly used as forage in tropical areas despite its strong antimitotic effect on cell division in mammals , to improve outcomes for livestock fed leucaena through symbiont-mediated detoxification. This effort was based on preliminary observations of differential tolerances to mimosine poisoning among ruminants from different regions  in symbiont(s) responsible for detoxification coupled with identification of the dietary compounds on which the symbiont acts.Removal of the gene/symbiont of interest, followed by the introduction of a genetically modified gene/symbiont that can carry out the detoxification reaction into the host, and then measuring the physiological consequences on the host without and with the modified gene/symbiontBelow we outline the various approaches that have been taken, and the advantages and limitations of each (summarized in Box 2). We end with a set of criteria that we feel necessary to clearly document symbiont-mediated detoxification.Generally, researchers have employed one or two of the three different approaches described below to address symbiont-mediated detoxification in animals, with the choice usually based on the available expertise and equipment, as well as the properties of the study system. All three approaches require that the negative impact of the plant toxin of interest be demonstrated in ecologically relevant concentrations. While this may seem trivial, it can in practice present considerable challenges. After all, if a toxin is indeed detoxified by the host or its symbiont, the host is likely to suffer little or no deleterious effects, so the toxicity will go unnoticed. Thus, to demonstrate that a plant metabolite is indeed a toxin, its activity should be assessed either in bioassays with non-specialist herbivores closely related to the animal of interest, or in conjunction with targeted manipulation of the mechanism for detoxification in the target species. Once the toxin is identified, symbiont-mediated detoxification can be evaluated from the phenotypic, the molecular/microbiological, and/or the chemical side (Box 2).This approach relies on the manipulation of the symbiosis and the assessment of its effects in the presence and absence of the toxin, respectively. It usually starts with a culture-dependent and/or culture-independent characterization of the microbial community associated with the host, followed by manipulation via antibiotic treatment or disruption of the natural route of vertical or horizontal symbiont transmission or acquisition from the environment  it is technically less demanding than the other two approaches, and (ii) it yields important information on the fitness consequences of detoxification, and thereby, provides insights into the ecological and evolutionary implications of the symbiosis. On the downside, however, detoxification is difficult to demonstrate via the phenotypic route if symbionts confer additional benefits, and it is impossible to distinguish direct and indirect effects, i.e., to assess whether the microbes really detoxify or enable the host to cope with the toxin by alternative mechanisms. Furthermore, this approach requires that (i) the animal host can be reared under controlled conditions, (ii) the toxin is available for experimentation in sufficient quantities , (iii) a toxin-free diet either artificial or natural for the animal is available, (iv) the toxin can be delivered to the animal in the diet, (v) the relevant microbial taxa can be removed from the animal, and (vi) re-infection of the animal with the relevant microbes is possible .The second approach relies on molecular methods to identify and manipulate detoxification genes in the symbiont. It starts with a thorough taxonomic and functional characterization of the microbial community associated with the host animal by cultivation-based approaches in combination with full-genome sequencing of the isolates or meta-genomics or meta-transcriptomics of the microbial community. Identification of putative detoxifying symbionts can be accelerated by using selective toxin-containing media for microbial isolations  the culturability of the symbiont in vitro, (ii) the ability to identify candidate detoxification genes, and, crucially, (iii) the genetic tractability of the symbiont. In reality, most reported studies using this approach end after isolation of the microbes and demonstration of their detoxifying ability in vitro, with further genetic manipulation and characterization rarely included.The third route takes a chemical approach, i.e., characterization of the conversion of the toxin to less harmful metabolite(s) in vivo. Classically, this can be achieved by following isotopically-labeled precursors or quantifying known catabolites in well-characterized detoxification pathways by mass spectrometry  used in order to establish symbiont-mediated detoxification, although its virtue in unambiguously establishing toxin catabolism and ability to follow toxin break-down products is undeniable. A major downside of this approach are difficulties in obtaining labeled toxin or its precursors required for assessing the chemical conversions. Furthermore, linking toxin break-down to a particular member within the host-microbiome can be extremely difficult without experimental manipulation of the community, especially given the challenges in localizing toxin break-down products in situ.Most existing studies on symbiont-mediated detoxification use one of these approaches or parts thereof. Ideally, however, a multi-level approach should be used toward unravelling symbiont-mediated detoxification that combines aspects of all three approaches. In particular, research should include a thorough phenotypic characterization of the benefits provided by the symbiont to the host by quantifying proxies of fitness such as growth rate, developmental time, body mass, survival, or reproductive output. In addition, molecular and/or chemical evidence for the symbiont-mediated detoxification pathway should be provided. Together, such results would provide causal evidence for symbiont mediated detoxification. However, as each of the three approaches presents different challenges and comes with different requirements for the study system, a comprehensive characterization and unambiguous demonstration of symbiont-mediated detoxification has rarely been achieved.Burkholderia gut symbiont sets a high standard for establishing symbiont-mediated detoxification that has yet to be realized for the symbiotic break-down of a natural plant toxin  of aspen (Populus tremuloides) acquires bacteria associated with aspen foliage that are able to degrade the phenolic toxins of aspen leaves and thus improve herbivore performance (Mason et al. This example illustrates another key point with respect to symbiont-mediated detoxification in herbivores, i.e., the acquisition of microbes from the environment. Many studies focus on identifying microbes found either in or on the herbivore; however, the plant tissues fed on by herbivores may be a good source of microbes capable of metabolizing the major toxins present in these plants (Mason et al. In summary, this is an exciting time for exploring symbiont-mediated detoxification in herbivores. Many promising natural systems have been identified, and current tools and technology including metagenomics and microscopy, coupled with culture-based approaches allow for rigorous investigation. However, demonstration of symbiont-mediated symbiosis remains challenging and requires a range of tools and skills. A clear demonstration of these interactions will likely need to draw on a diversity of approaches and expertise. Expanding on the knowledge of symbiont-mediated detoxification in the future will undoubtedly advance our understanding of microbial symbionts as important sources of ecological innovation and shed light on their role in enabling herbivory across vertebrate and invertebrate hosts.


In vitro bioimaging based on CDs in different cells and important organelles. (2) The distribution, imaging and application of CDs in mice and zebrafish. In addition, this review also points out the potential advantages and future development directions of CDs for bioimaging, which may promote the development of CDs in the field of bioimaging.As a new type of “zero-dimensional” fluorescent carbon nanomaterials, carbon dots (CDs) have some unique optical and chemical properties, they are being explored for a variety of applications in bio-related fields, such as bioimaging, biosensors, and therapy. This review mainly summarizes the recent progress of CDs in bioimaging. The overview of this review can be roughly divided into two categories: (1)  Among tin vitro bioimaging of CDs, such as imaging of cancer cells and nerve cells, etc. In this review, we survey the latest research on the application of CDs in the rapidly evolving bioimaging field, especially in vitro bioimaging of important organelles  and in vivo bioimaging . This review aims to provide readers with the latest, most exciting and influential research in this field. What’s more, the opportunities and challenges of carbon dots in bioimaging applications in the future are briefly discussed. Eventually, we hope to provide some new ideas for developing bioimaging based on CDs.In recent years, several reviews have been summarized on applications of CDs for neurological treatment, biosensors, photocatalysis, bioimaging, and so on . At presin vivo bioimaging, which hope to promote the development of cell imaging techniques.CDs have shown excellent potential in the field of bioimaging due to the CDs have good dispersibility, the ability to specifically bind to target units, high near-infrared absorption and photoluminescence efficiency, good chemical stability and photostability . As knowCancer is one of the greatest challenges facing humanity today, and many people die from cancer every year, early diagnosis of cancer and prevention of malignant tumors are extremely important. Currently, CDs can penetrate a variety of cancer cells, what’s more due to the stable optical properties and excellent biocompatibility of CDs, cancer cells can be detected by fluorescence imaging of CDs . Gudimelin situ imaging of miR-9 in living neurons and brain tissue of AD mice. It was found that the M9 fluorescent probe easily entered neuron cells and distributed them in the cytoplasm of neuron cells. These results shed light on understanding the genetic basis of AD and hold great promise for the early diagnosis of cancer and neurological disorders . A large accumulation of CDs was observed in the cytoplasm and nucleus, which indicated that CDs have good permeability of cell membrane and other intracellular organelle membranes. It could be applied to biological imaging of brain cells in the future . Besidesisorders . In concNowadays, fluorescence imaging technology is becoming more and more mature, and more and more fluorescent probes for biological imaging have been developed, but the bioimaging of subcellular and organelles still needs further efforts to track changes in cell morphology or function. Biomaging of cell nuclei is crucial for revealing nuclear morphology and its role in cell metabolism, growth, differentiation, and inheritance . Zhang ein situ by simple microwave-assisted synthesis. Due to electrostatic interactions, positively charged CDs tend to accumulate in mitochondria with high negative MMPs in healthy cells. When cells are damaged with a concomitant decrease in MMP levels, CDs migrate from the mitochondria to the nucleolus due to their binding affinity to nucleic acids. Once the cellular state is restored, MMP levels are again highly reduced, and the CDs are reversed back to the mitochondria. Therefore, the viability of cells can be easily observed through the different spatiotemporal distribution of CDs in living cells. The discovery of CDs has great potential in the study of cell survival  for in vivo imaging in mice. The CDs were injected into mice and detected Fn-CDs in mice at different periods. At different periods, different parts of the mice appeared fluorescence successively. After that, the fluorescence intensity of Fn-CDs gradually decreased, indicating that Fn-CDs may have entered the blood circulation. What’s more, the fluorescence disappeared after 24 h, which manifesting that Fn-CDs can be excreted through digestive system metabolism, making Fn-CDs an excellent candidate for in vivo bioimaging and biosensing  is one of the most important factors limiting the development of treatments for neurological diseases and brain cancer. Many drugs cannot directly penetrate the BBB, resulting in very limited drug delivery systems (DDS) for the treatment of central nervous system-related diseases and brain cancer. Therefore, the development of new DDS is very necessary. CDs-mediated DDS has received extensive attention due to its penetration of the blood-brain barrier . A fluorin vivo optical fluorescent agents, which in addition to their excellent optical properties, also possess excellent 808 nm laser-induced photothermal properties, photothermal therapy (PTT) for cancer and CD has a good biological function  were taken for fluorescent bioimaging of fluorescence-specific parameters of PDA-CDs. Normal mouse PDA-CDs mainly accumulated in the liver and kidney. In AKI mice, PDA-CDs mainly accumulated in the liver and kidney  emission as function . These sfunction . Due to formance . Acute kd kidney , and aftd kidney .in vivo bioimaging based on CDs have broad application, the above work validates the ability of CDs to have potent chemotherapeutic effects, which can provide a strategy for the potential clinical application of CDs in image-guided tumor therapy, renal disease treatment and other diseases.In a short, in vitro bioimaging of important organelles  and in vivo bioimaging . Although the CDs have shown many advantages in bioimaging, there are still some challenges: (1) How to synthesize CDs with excellent fluorescent properties by a simple synthesis method and explain the synthesis mechanism? (2) More experimental and theoretical studies should be carried out to elucidate the fluorescent mechanism of the CDs. (3) CDs with red or near-IR fluorescent emission are more suitable for bioimaging in vitro/vivo, it is very important to prepare CDs with red or near-IR fluorescent emission which have high quantum yield and excellent bioimaging performance. (4) With the advancement of bioimaging methods and equipment, efficient tissue penetration and in vivo bioimaging under low background fluorescence will continue to be achieved, which will further promote the development of CDs in bioimaging. We believe that with the continuous development of the field, the practical application of CDs in bioimaging will be greatly improved.Till now, CDs have already proven to be an intriguing class of nanoparticles, which have made significant achievements in the field of bioimaging due to their excellent fluorescence properties, good biocompatibility, low toxicity, high sensitivity, and easy surface functionalization. This review mainly summarizes recent advances in the field of CDs-based bioimaging in two aspects : in vitr


Lassa fever (LF) is a rodent-borne disease that threatens human health in the sub-region of West Africa where the zoonotic host of Lassa virus (LASV) is predominant. Currently, treatment options for LF are limited and since no preventive vaccine is approved for its infectivity, there is a high mortality rate in endemic areas. This narrative review explores the transmission, pathogenicity of LASV, advances, and challenges of different treatment options. Our findings indicate that genetic diversity among the different strains of LASV and their ability to circumvent the immune system poses a critical challenge to the development of LASV vaccines/therapeutics. Thus, understanding the biochemistry, physiology and genetic polymorphism of LASV, mechanism of evading host immunity are essential for development of effective LASV vaccines/therapeutics to combat this lethal viral disease. The LASV nucleoprotein (NP) is a novel target for therapeutics as it functions significantly in several aspects of the viral life cycle. Consequently, LASV NP inhibitors could be employed as effective therapeutics as they will potentially inhibit LASV replication. Effective preventive control measures, vaccine development, target validation, and repurposing of existing drugs, such as ribavirin, using activity or in silico-based and computational bioinformatics, would aid in the development of novel drugs for LF management. Lassa fever (LF) is an acute viral hemorrhagic fever ailment that can degenerate into neurological diseases . ReportsMastomys natalensis, the animal which serves as LASV reservoir and vector is more abundantly seen in these regions , MV-LASV (V182-001) [that is in phase 1 clinical trials], adenovirus vector-based , live-attenuated (ML29 and rLASV-GPC/CD), VSV-based, recombinant vaccinia-based (VAC-LASV), as well as RNA replicon LF candidate vaccines. The challenge with many of the vaccines in preclinical development is that many of them require the usage of more than one dose of vaccination. Several vaccination doses pose a challenge in underdeveloped countries as there is inadequate resources as well as lack of access to health care facility, and/or personal motivation Accumulating evidence suggest that there exist numerous LF candidate vaccines in preclinical stage of development, although no FDA-approved vaccines is currently in use for human LF treatment. There was emphasis by the 2017 WHO Target Product Profile (TPP) for LF vaccines stating that a high priority for prophylactic vaccines development, optimal candidates should meet acceptable standard for safety/reactogenicity as stipulated by WHO, including being single-dose as well as greater than or equal to 70% efficacy in preventing infection or disease orchestrated by the LASV lineages I-IV. Besides, it should be long lasting (≥5 years) ,130. MajOne of the candidate vaccines in clinical trial is INO-4500. It is a DNA-based vaccine candidate which expresses the LASV GPC and is based on the Schwarz strain of the measles virus (MV) ,136. It Furthermore, MV-LASV  is another vaccine candidate which has been developed using the Schwarz MV vaccine platform besides INO-4500. It expresses the LASV GPC, Z, and/or NP (Josiah strain). Literature opined that those vaccines that expresses either GPC or NP alone furnishes the best protection level in cynomolgus macaques against a homologous virus challenge  ,137. In Moreso, tremendous progress has been made in adenovirus vector-based platforms development  as vaccine vectors, that can express antigens of several different pathogens including influenza and lASV, with few entering clinical trials in human ,140. TheAdditionally, there was creation of RNA vaccine, a live attenuated ML29 vaccine by reassortment of the genomic RNA segments of Mopeia virus (MOPV) and LASV  has equally been developed. The Codon deoptimization (CD) is a method which reduces expression of gene through swapping out the wild-type codons with less-preferred codons across the entire coding sequence of the target gene . This teEven though ML29, rLASV-GPC/CD, and other live-attenuated vaccines show promising outcomes, a challenge with some LASV live-attenuated vaccine candidates is that a relatively high dosage is required to be efficacious. Significant negative effect can be observed using these high dosages of the LASV live-attenuated vaccines ,149 as wDrug development beginning from screening stages to modulatory approval stage is costly and a time-demanding exercise that might take twelve to fifteen years and the cost has been evaluated to be more than $1 billion . NotablyValidation of target is critical and crucial in the process of drug discovery as drug development against a definite target is a huge commitment with respect to finance and time. Thus, experimental models are required to investigate if the selected target is contributory/involved in the concerned disease in humans. In vitro systems offer the prospect of testing and validating targets prior to the commitment of huge financial and transient resources to a promising lead compound. These systems allow the usage of reversible strategies that involves the regulation of gene expression in the concerned gene(s) and the monitoring of its action on the effectiveness of the candidate drug employing a myriad of biochemical and molecular endpoints. Consequently, this will furnish proof-of concept data which will precisely indicate if the promising target is involved in the drug action, hence reinforcing credence and lowering the possibility of costly failures of careless chosen candidatesDrug repurposing also referred to as drug repositioning can be explained as a technique that involves the identification of pharmacological indications from old/earlier marketed/FDA licensed drugs and the use of redesigned drugs in the treatment of ailments apart from the drug’s original/intended therapeutic application. This entails the establishment of novel treatment for existing drugs, in addition to approved, discontinued, abandoned, and experimental drugs ,155,156.Following the evolution of cheminformatics/bioinformatics tools and accessibility of vast biological and structural repositories, repurposing of drugs has remarkably led to a reduction in the duration and financial burden associated with drug manufacturing with diminution in failure rates. Currently, the application of in silico methods as well as the evolution of structure-based drug design (SBDD) and artificial intelligence (AI) has further quickened the process of drug repurposing ,160.There are two approaches to drug repurposing viz: experiment-based method and in silico-dependent method. The experimental-dependent method also referred to as activity-based repurposing involves the screening of existing medications for a novel pharmacologic activity using investigations based on experiments. In this approach, target-based protein screening and cell/organism-based screen in ex vivo and/or in vivo disease models excluding any knowledge about the structure of proteins target are involved. Different methods of repositioning include target cell assay technique, screening technique, zoonotic model, and clinical approaches ,162. In In silico technique has been accepted widely and recorded successes have been remarkable in drug discovery programs over the past years. In silico tools and techniques have been successfully used by several drug manufacturing companies and research laboratories in the discovery of a novel drug that differs in structure from various chemical spaces since substantial amounts of data on the structural chemistry of the biologically active compounds, pharmacophore models and protein’s structure are obtainable free online. Additionally, in silico repositioning has reduced time and financial burden associated with development as well as reduced risk of failure, unlike experimental-based approach ,164.Consequently, target validation and repurposing of existing drugs used in the management of LF such as ribavirin could be harnessed for the development of better therapeutics for curtailment of LF infection. At present, some cellular proteins likely to play a role in the replication and spread of LASV have been identified. For example, GSPT1 cellular protein currently identified might be a potential drug target, as CC-90009, a drug that specifically targets and degrades GSPT1, exhibited antiviral activity against LASV without cytotoxicity. Currently, CC-90009 is in phase 1 clinical development for the treatment of acute myeloid leukemia, raising the possibility of its repurposing as an antiviral against LASV . AdditioThe major clinical challenge in the management of LF is attributed to its high virulence and fatality rate that is further aggravated by the unspecific means of presentation (having similar signs like other fevers). Consequently, clinical investigation/diagnosis is mostly not plausible, particularly in our remote villages in the early presentation of this disease. The contagious nature of this disease creates a huge challenge for health workers and other caregivers mostly exposed to this ailment without protection before diagnoses and the establishment of barrier nursing. Its mode of contraction via fomite and aerosol poses another critical problem to all who have close contact with infected individuals . It is aAnother source of worry is the threat of complications that people who survived and those not having noticeable signs might suffer from. Robust evidence has indicated that subjects who survived and developed serious sensorineural hearing losses had distinctive poor speech differentiation and were not manageable using hearing aids . HoweverLack of standard and inaccessibility of personal protective materials (PPM) particularly during the inception of the breakout of disease were critical challenges. This perhaps added immensely to the hospital-acquired spreading of the LASV to other medical personnel involved in the management of infected individuals. Thus, there is an urgent need to ensure that standard PPM is made available particularly masks, goggles and gloves to be put on during outbreak situations.Furthermore, lack of proper awareness of the illness betwixt the people and medical personnel is another problem confronting the management of this disease culminating in fear of contracting the ailment. Consequently, this culminates in fear and tension among clinical personnel involved in the management of infected individuals. Difficulty in contact tracing is another challenge in combating this illness. There is a problem in tracing the origin of the disease to know the source of infection .LF is a severe viral hemorrhagic illness characterized by life-challenging, multiple organ failure. The lack of licensed medical countermeasures accentuates the need for the development of safe and efficacious treatment and prophylactics. Experiments using monoclonal antibodies and convalescent immunoglobulin formulations indicate that antibody-based treatment serves as an efficacious method of LF treatment . The annThe curtailment of human contact with the zoonotic vector of LF is a crucial index in the prevention of LF, however, such extensive contact control seems impracticable currently in the West Africa endemic zones. Thus, the provision of vaccines for usage in communities and hospitals is of public health importance because vaccination is mostly the feasible control measure . MountinThe LASV genome’s high rate of heterogenicity poses a serious problem in the manufacture of an efficacious pan-LASV vaccine and immunotherapeutic curtailment regimen. Ideally, any vaccination or antibody-dependent therapeutic should give defense against all strains of LASV. Previous studies indicated that four strains of LASV have been established, three is found in Nigeria which includes Lineages I, II, and III, while lineage IV is seen in many other West African countries including Sierra Leone, Guinea, and Liberia . AdditioEnvironmental factors have been reported to have serious impacts on the control of LF ailment, although the exact course of LASV transmission is yet to be decisively confirmed. For example, studies on environmental samples of LASV are scarce in order to point out the interface with the greatest challenge in transmissibility between rats and humans. The comprehension of the factors that promote the tenacity and spreading of LASV via the external environment would be better appreciated .Although several works have been conducted on Lassa genetics and epidemiology, little attention has been paid to the impact of the environment and ecosystem on Lassa transmissibility. The spreading, maintenance, and continuation of LASV are linked to conditions of the environment that are related to the zoonotic vector . The ratThe high cost of accommodation, house rents, and student hostels in urban areas results in overcrowding owing to insufficient accommodation, particularly in less developed and developing countries. This makes individuals more prone and at greater threat of harboring the zoonotic host of LASV infection. Lack of personal and environmental sanitation and improper disposal of solid waste promotes the infection of LASV, with a huge risk for later spreading and preservation of LASV . FurtherTaking into consideration the increasing incidence of LF in the endemic areas, it is expedient to contemplate the manufacture of a substitute and more efficacious countermeasures opposed to LASV infection via necessary and coordinated public-health methods that will earmark all Lassa possible routes of transmission and maintenance. Subsequent outbreaks and spreading of Lassa to regions previously with no record of Lassa can be tracked following scientific experiences and lessons garnered from the different breakout of Lassa and current progress in throughput genomics and mathematical modeling. Hamam and colleagues have documented different mathematical modelling for the control of L epidemic disease including the Stochastic Modelling . LiteratIndisputably, this review has established that LF is a critical rodent-borne ailment that has witnessed epidemiological proportion and progression in the West Africa sub-region wherein soaring endemicity had been reported. The importance of this in public health cannot be overemphasized. The remarkable rise in the transborder traffic and international travels increases the likelihood of the transmission of the LASV to other zones within Africa and beyond the continent besides the probable periodic outbreaks of the disease within the region. The political instability and limited resources available for the health care delivery system characteristic of West African countries might continue to be a setback to the management of both emerging and currently devastating contagious ailments in the zone. Notwithstanding, the provision of properly furnished infectious disease laboratories and research centers including sufficient training of health care workers and other medical personnel would help in the quick investigation and treatment of highly infectious ailments such as LF and would thus help in preventing probable outbreaks. Additionally, in the endemic region, ribavirin should be provided in hospitals and health centers especially in the rural communities as this would be of assistance in the control of LF disease particularly at onset. This study is important because it x-rayed the pathogenesis and epidemiology of LF, its management and appraises the associated health challenges and the hurdles in combating the disease. Besides, effective preventive control measures, vaccine development, as well as repurposing of the existing drug like ribavirin using in silico-based approach have been suggested as plausible means of curtailing the dreaded disease.


Editorial on the Research TopicBariatric surgery—its influence on the development, diagnosis, and treatment of tumorsMetabolic bariatric surgery (MBS) has been shown to be safe , 2, effeThe influence of obesity on the development of many tumor types . A subgroup analysis showed that females showed a higher decrease in NLR than male patients . Chi et al. presented changes in the NLR in 100 patients and reported a significant decrease already at 3 months post operation . While these data confidently report optimization of the systemic inflammatory state after MBS, the underlying physiologic mechanism and its role on oncogenesis is yet to be investigated.The assessment of systemic inflammation, especially the changes of the neutrophil-to-lymphocyte ratio (NLR) following laparoscopic sleeve gastrectomy, was the focus of two original research articles. The NLR in the peripheral blood is a well-known indicator of subclinical inflammation and has been associated with poorer prognoses in ischemic coronary disease, heart failure, peripheral vascular disease, and patients with obesity . Zhou etRoss et al. published a state-of-the art review focusing on the relationship between MBS and endometrial cancer. They reported that among different types of cancers, endometrial cancer had the strongest association with obesity, and weight loss may lead to a regression of premalignant pathology. The authors gathered evidence supporting that a decreased incidence of hormonally responsive cancers  was associated with MBS. Therefore, they pledged for well-designed, prospective, and mechanistic studies to clarify the most appropriate candidates and time for MBS in patients with obesity and early-stage endometrial cancer.Mehdorn et al. performed a retrospective double center study in patients with obesity and MAFLD-related Child A liver cirrhosis who underwent MBS. They reported ambiguous outcomes, with some patients presenting a postbariatric aggravation of their liver function and others showing improvement that resulted in un-listing from the liver transplantation waiting list. Nevertheless, according to the 2022 IFSO/ASMBS guidelines, with parsimonious patient selection and a multidisciplinary surgical pre-habilitation pathway, MBS has the potential to improve the candidacy for transplantation in patients with an end-stage organ disease ( disease .Taken together, these findings highlight the role of MBS in the reduction of systemic inflammation and, consequently, the risk of cancer, but they also showcase the need for more extensive basic and clinical research in the field. The main limitation of our Research Topic is the lack of original research publication in the field of bariatric oncology, leaving the primary aims of the Research Topic unmet. However, we are confident that all the selected studies in our Research Topic pave the way for further scientific interest aiming to better diagnose, prevent, and treat cancer in patients with obesity and/or history of MBS.


Since the beginning of the twenty-first century, a number of novel emerging and re-emerging viruses, largely of zoonotic origin, have spread from wildlife reservoirs to human population, instigating deadly outbreaks of global concern  transmission, a rabies virus-based pseudovirus neutralization assay for the detection of neutralizing antibodies against Marburg virus, the epidemiology and pathogenicity assessment of ferret badger-associated rabies viruses, and the role of long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in limiting Hantaan virus propagation.This Research Topic, titled “via different transmission routes. Therefore, understanding the transmission routes of viruses, whether direct or indirect, as well as their molecular evolutionary dynamics, forms an integral and primary component in formulating the guidelines for effective control and prevention of viral zoonoses, as well as assessing the public health risks. In contrast to the most frequently documented method of transmission, which involves direct contact with infected animals or fomites, Ma et al. identified the saliva and milk of asymptomatic goats as a potential novel source of Orf virus infection in humans. By using comprehensive genome and co-evolutionary approaches, Chu et al. highlighted the potential contribution of migratory birds to the transmission of δ-CoVs and forecasted frequent host-switching events among birds as well as interspecies transmission to a few mammalian species. Similarly, Ye et al. showed how wild birds contributed to the spread of H5N8 viruses among poultry, and how several reassortment events controlled the evolutionary dynamics of influenza viruses.For a successful perpetuation of zoonotic viruses, they must be efficient in crossing the species barrier in order to enter, replicate, and disseminate within a suitable host, and/or be transmitted to the same or a new host Diaz-Cánova et al. demonstrated a Norwegian human Cowpox virus (CPXV) isolate carrying multiple genes from orthopoxviruses that originated from the Old World, including Ectromelia virus (ECTV) and Vaccinia virus, and North America, Alaskapox virus (AKPV), through multiple reassortment events. Four distinct lineages of ferret badger-associated rabies viruses with minimal pathogenicity in mice, beagles, and humans were found in China in a longitudinal analysis by Miao et al. These studies emphasize the importance of continuous monitoring of virus genetic variants and assessing the associated public health risks.Furthermore, in order to overcome host selective pressures and adapt to a new host, viruses preferably undergo recombination, reassortment or acquire adaptive mutations. This allows for the generation of new genetic variants with altered transmissibility, virulence, and host switching capacity , a volatile substance present in fruits and food additives, was shown by Olasunkanmi et al. to have antiviral activity against Coxsackievirus group B (CVB) both in vitro and in vivo. These studies offer the safe therapeutic avenues for the development of antiviral drugs for emerging viral infections.Significant progress has been made toward delivering potent vaccines and antiviral drugs (through drug repurposing) in short span of time. However, in order to effectively combat future pandemics, it is essential to initiate proactive preparedness programs at the global level. These programs should enhance the capacity for surveillance, rapid testing of available and new antiviral drugs, as well as generation of safe, efficacious and affordable vaccines (Belay et al., Lessons learned from the emerging and re-emerging zoonotic viruses underscore the need for a more holistic and integrated strategy to averting future pandemics taking into the account of the health of humans and animals, and their shared environment; i.e., “one health approach.” The “one health approach” may be challenging to implement practically given the dramatic changes in the anthropogenic and environmental factors. However, if we implement large-scale intensive genomic surveillance programs along with the metagenomic surveillance at the animal-human interface, limit ecological space sharing with wildlife, and raise stakeholder awareness of “one health,” we can reduce the risk of future zoonotic spillover events. This Research Topic demonstrates the diverse spectrum of emerging and re-emerging viral zoonoses, and the need for understanding the evolutionary dynamics of viruses, complex host-pathogen interactions, and effective prophylactic measures. These aspects will ensure our preparedness for future pandemics.All of the listed authors contributed significantly to the work and gave their consent for publishing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.