Renal cell carcinoma (RCC) is the most common and the most lethal urogenital malignancy, and can metastasize rapidly via hematogenous spread. Even so, RCC metastasis within the breast is extremely rare and may appear deceptively benign on screening mammograms. In this article, we present a rare case of RCC that remained undiagnosed until an intra-mammary metastasis was detected on a routine screening mammogram. Further imaging workup and core needle biopsy of the mass ultimately confirmed a new diagnosis of metastatic clear cell RCC. Given that the presence of an RCC breast metastasis indicated advanced-stage RCC, the patient in this case underwent treatment with systemic immunotherapy. This case report describes key imaging features of metastatic RCC on common breast imaging modalities. It underscores the vital role that screening mammography can play in the initial detection of clinically silent, extra-mammary malignancies, including RCC. Thorough imaging workup and tissue biopsy are essential to distinguish a primary breast lesion from intra-mammary metastatic disease, to inform the management plan, and to prevent lumpectomy or mastectomy when it does not benefit the patient.  Renal cell carcinoma (RCC) is the seventh most common malignancy in the Western world, and is both the most common and the most lethal urogenital malignancy . RCC is A 76-year-old female patient presented to the breast imaging center for her annual screening mammogram. Her past medical history included hypothyroidism, bilateral simple renal cysts, stage III chronic kidney disease, and chronic hypertension. She had no history of prior tobacco use. Her family history included pancreatic cancer in her maternal grandmother but was otherwise negative for malignancy. At the time of her presentation for screening mammogram, she voiced no complaints; however, she was quite overdue for mammographic screening, having not undergone an annual mammogram for three years. The screening mammogram demonstrated fatty breasts, with a small, 2.5 mm mass observed in the medial left breast at eight o’clock, that had not appeared on any of her previous mammograms Figure . AlthougThe patient returned one month later, at which time a diagnostic mammogram and targeted left breast ultrasound were performed to further evaluate the left breast focal asymmetry. On the diagnostic mammogram, it was noted that the previously visualized medial left breast mass had doubled in size, and now measured 5 mm in greatest dimension Figure . Its borThree weeks later, the patient returned to the breast imaging center for an ultrasound-guided left breast biopsy. During her conversation with the radiologist prior to the biopsy, the patient mentioned that for approximately one to two years prior to this time, she had noticed multiple small nodules developing under her skin in multiple areas throughout her body, and had recently noticed a new palpable lump in her left axilla. The radiologist physically examined the area and noted a palpable, superficial, mobile nodule, which was subtly bluish in gross appearance. Ultrasound examination of this left axillary mass revealed a superficial, extremely vascular, non-parallel, fairly circumscribed mass with posterior acoustic shadowing Figure . It someShe underwent the ultrasound-guided biopsy of her medial left breast mass, which notably bled rather significantly during the biopsy and, despite appropriate compression of the left breast after the biopsy, developed a small post-biopsy hematoma. The final pathology of the left breast mass biopsy demonstrated clear cell carcinoma compatible with metastatic clear cell renal carcinoma Figure .The patient was promptly referred for medical and surgical oncology management. She underwent contrast-enhanced computed tomography (CT) scanning of the chest, abdomen, and pelvis for further staging. This revealed a large, heterogeneously enhancing lesion involving the lower pole of the left kidney. No left renal vein invasion, no retroperitoneal lymphadenopathy, and no involvement of the left renal pelvis was observed. A metastatic lesion was visualized involving the left breast, in addition to numerous additional lesions within the lungs, subcutaneous tissues, and even skeletal muscle Figure . Given tRCC is the most common urogenital malignancy and is also the most lethal, with a 76% five-year relative survival rate. The survivability of this disease depends largely on the disease stage at the time of diagnosis; the five-year survival drops from 93% in the setting of stage 1, localized disease down to 12% in patients with stage IV metastatic disease. Men are more commonly affected than women; two-thirds of all cases are diagnosed in men. RCC is most typically found in older patients, with an average age of 64 years at the time of diagnosis, although it may occur at younger ages in patients with hereditary renal cell cancer syndromes such as von Hippel-Lindau syndrome or tuberous sclerosis. Other, modifiable risk factors for RCC include tobacco use, obesity, chronic hypertension, and certain occupational exposures such as trichloroethylene [Clinically, RCC may present in a classic symptom triad of hematuria, flank pain, and palpable renal masses . HoweverImaging findings on mammography and ultrasound can be somewhat non-specific, sharing certain features with other types of intra-mammary metastases and with benign breast masses -14. On mDefinitive diagnosis of RCC is accomplished with tissue biopsy. Histologic examination differentiates several RCC subtypes, including clear cell, type 1 and 2 papillary, chromophobe, collecting duct, or medullary -20. CleaThe prompt and accurate diagnosis of RCC metastasis in the breast is vital for deciding on a suitable treatment plan; while resection of a primary breast mass with lumpectomy or mastectomy is appropriate, surgical resection of an RCC metastasis in the breast may result in unnecessary surgical morbidity without providing a meaningful therapeutic benefit ,2. ApproRCC is an insidious neoplasm that can spread to every organ system via hematogenous spread, but metastasis to the breast is extremely uncommon, and breast imaging findings in the setting of metastatic RCC can be somewhat non-specific, necessitating tissue biopsy for definitive diagnosis. In this case report, we presented and discussed key imaging findings that are typically observed in metastatic RCC lesions within the breast; these imaging features are often similar amongst metastatic breast lesions from many different extramammary sources. The confirmation of RCC metastasis within the breast heralds advanced disease and indicates the need for systemic therapy, including targeted therapy with anti-angiogenics and/or immunotherapy. Prompt imaging workup and tissue biopsy are essential to distinguish a primary breast malignancy from intra-mammary metastasis, to inform the management plan, and to prevent lumpectomy or mastectomy when it does not benefit the patient.


Although titanium allergies are not commonly diagnosed, they can present with a variety of conditions years after the implantation of titanium-containing medical devices. Furthermore, there are few options to effectively manage the long-term outcomes of these conditions. We present the case of a 41-year-old female who experienced neck swelling, pain, and difficulty swallowing 16 years after a right thyroid lobectomy for benign follicular adenoma, requiring the implantation of titanium-containing surgical clips in her neck. This was accompanied by an extensive symptomatic history, and the patient showed mild reactivity to nickel and titanium on a metal lymphocyte transformation test analysis. X-ray and computed tomography of the neck later confirmed the location of 18 surgical clips. The patient was diagnosed with a chronic immune disease including immune complex disease and mast cell activation-related symptoms. Symptoms were managed with low-dose naltrexone until the surgical clips were removed. Further research is needed to identify more accurate testing methods to diagnose titanium hypersensitivity. Alternative treatment methods should be explored to reduce disease burden and complications related to titanium-containing implants. Nickel, cobalt, chromium, and titanium are just some of the many metallic elements used widely in dental and surgical implants. While nickel has a well-documented history of causing hypersensitivity reactions, with an estimated prevalence of 17% in women and 3% in men in some studies, titanium allergies are less frequently diagnosed . MetalliPrior notable cases of suspected metal reactions encountered include a 61-year-old female who had complaints of nonspecific symptoms following surgical clip placement during cholecystectomy. This patient had a history of a localized allergic reaction to titanium plates after ankle surgery. A review of medical records showed her memory lymphocyte immunostimulation assay (MELISA) had equivocal results for titanium allergy . Also enChief complaintA 41-year-old female presented to her primary care physician (PCP) in August 2021 complaining of worsening neck pain, swelling, and difficulty swallowing at the site of a previous partial thyroidectomy  scan in October 2021 due to suspicion of delayed hypersensitivity reaction to surgical clip implantation in her neck. Imaging revealed 18 surgical clips that were implanted in her neck during a right thyroid lobectomy for the removal of a benign follicular adenoma in 2005.The patient reported a majority of her symptoms occurred in 2015 or later that were described by her PCP as a “mono-like” syndrome, although she had negative mononucleosis antibody titers when evaluated. She first experienced extreme fatigue and general malaise associated with difficulty ambulating and speaking, as well as general left-sided abdominal pain. Additional symptoms experienced by the patient over the last 10 years include but are not limited to memory loss, difficulty concentrating, severe shortness of breath, hot and cold flashes, metallic taste in the mouth, halitosis, change in body odor, abdominal bloating, decreased libido, joint and body aches, muscle pain and tightness, bruxism, insomnia, dizziness, sudden-onset nausea, diarrhea, constipation, blurred vision, hair loss, skin rash, dermatitis, tachycardia, palpitations, weight gain, mood swings, coarse facial hair growth, increasing frequency of asthma exacerbations, paresthesia of extremities, migraines, acne, anovulation, lymphadenopathy with associated pain, swelling of hands and feet, mild fevers, sore throat, cough, laryngitis without a sore throat, thyroid swelling, tinnitus, and fecal incontinence. She reported an episode of syncope in 2019 and described brain fog and episodic fasciculations throughout 2020. At the time of the encounter, the patient reported her current symptomatology consistent with her chief complaint while awaiting surgical removal of the implanted clips.Past medical historyThe patient’s past medical history consisted of type 2 diabetes, mixed hyperlipidemia, nonalcoholic steatohepatitis, pancreatitis, splenomegaly, and autonomic neuropathy. The patient was also diagnosed with atypical depression and was prescribed mirtazapine which temporarily relieved her insomnia. However, when the depression symptoms returned, mirtazapine was discontinued. The patient was currently on 15 mg of melatonin to aid with sleep. The patient’s past surgical history included bilateral tubal ligation with Filshie clip placement in 2010 as well as laparoscopic cholecystectomy with surgical clip placement in 2005. The patient’s social history was insignificant, with no smoking and occasional alcohol consumption. The patient had no known history of allergic reactions or allergies to metals or other substances.InvestigationsLaboratory InvestigationsThe patient had positive laboratory results for inflammation between 2016 and 2021  implanted in the right thyroid bed/parapharyngeal space causing a hypersensitivity reaction resulting in immune complex disease and mast cell activation-related symptoms.TreatmentThe patient was prescribed 0.1 mg fludrocortisone after being diagnosed with autonomic neuropathy in 2021 which helped regulate her blood pressure and decreased thyroid pain. After consultation with a rheumatologist in July 2022, the patient was started on LDN therapy of 1.5 mg twice daily to minimize immune activation prior to surgery. This led to an improvement of most autonomic symptoms , as well as neck swelling. Removal of 18 surgical clips from the previous right thyroid bed/paratracheal space was performed in December 2022 with one clip remaining due to the inability to properly identify it on X-ray/CT scan prior to the procedure Figures , 5.Postoperative diagnosisHypersensitivity reaction to surgical clips causing suspected immune-related disease inclusive of immune complex disease and mast cell activation-related symptoms.Outcome/ProgressThe patient reported resolution of most symptoms within one week of surgical clip removal, complicated by a self-resolving seroma at the incisional site Figure . At the The challenges presented in patients with complex presentations of hypersensitivity reactions to metallic ions include a lack of availability of validated tools for a reliable diagnosis of these diseases and management of symptoms prior to definitive surgical intervention.A possible reason for the inaccuracy of current testing methods may be the impurity or variability in the composition of surgically implanted metal devices. Different metallic ions can provide a multitude of immunogenic molecules that induce allergic reactions . CurrentNonsurgical management of symptoms in patients experiencing metal hypersensitivity reactions has traditionally been with the use of corticosteroids to reduce inflammation but LDN is emerging as an alternative to reduce inflammation without as much concern for harmful side effects. LDN is thought to reduce inflammation by antagonizing mu-opioid receptors paradoxically increasing endogenous endorphin production. Endorphins modulate the function of T-regulatory cells which reduces the production of proinflammatory cytokines and immunoglobulins by T and B cells, respectively. This therapy has been shown to be an effective long-term alternative to surgery or traditional medications in a variety of autoimmune and inflammatory diseases related to immune cell activation, which may allow improved function for patients .Our approach to patients with suspected metal allergies should consider both the patient’s exposure to metal implants and their history of symptoms. This, however, proves to be challenging when considering the variability of clinical presentations of metal hypersensitivity reactions. Clinical suspicion of these conditions should be able to further guide when to utilize available diagnostic tools. The need to develop more reliable and accurate testing for diagnosis is an important concern in clinical practice with the increasing prevalence of metal allergies, specifically in the fields of dentistry and surgery.When managing symptoms of patients with confirmed or suspected metal hypersensitivity reactions and related conditions, physicians should consider a multidisciplinary approach utilizing both medical and surgical interventions when appropriate to improve the overall health and outcome for these patients.


Cisplatin (cis-diamminedichloroplatinum (II)) is one of the most broadly used chemotherapies worldwide. Since the unexpected discovery of its antitumor effects, huge strides have been made toward the comprehension of key determinants of the antitumoral mechanism. Despite decades of research proving that cisplatin antitumor activity is linked to DNA adduct formation and reactive oxygen species (ROS) production, the important role of inflammation is becoming increasingly apparent . The useThe aim of this Special Issue is to highlight the emerging based-platinum strategies to maintain anticancer activity, avoid adverse effects and overcome cisplatin resistance.Many different drugs and natural products reduce cisplatin toxicity ,5. A recMany efforts are being made to counteract cisplatin toxicities; on the other hand, extensive research has been devoted to increasing cisplatin’s effects. To achieve this goal, many formulation and delivery approaches have been developed. It has been demonstrated that nano-based cisplatin delivery systems delay drug release, extend half-life, and decrease systemic toxicity, while nanocapsules, nanogels and hydrogels improve cisplatin uptake by cancer cells . In this


Mitochondria are energy-generated organelles and take an important part in biological metabolism. Mitochondria could be transferred between cells, which serves as a new intercellular communication. Mitochondrial transfer improves mitochondrial defects, restores the biological functions of recipient cells, and maintains the high metabolic requirements of tumor cells as well as drug resistance. In recent years, it has been reported mitochondrial transfer between cells of bone marrow microenvironment and hematological malignant cells play a critical role in the disease progression and resistance during chemotherapy. In this review, we discuss the patterns and mechanisms on mitochondrial transfer and their engagement in different pathophysiological contexts and outline the latest knowledge on intercellular transport of mitochondria in hematological malignancies. Besides, we briefly outline the drug resistance mechanisms caused by mitochondrial transfer in cells during chemotherapy. Our review demonstrates a theoretical basis for mitochondrial transfer as a prospective therapeutic target to increase the treatment efficiency in hematological malignancies and improve the prognosis of patients. Mitochondria are highly dynamic double-membraned organelles found in the majority of eukaryotic cells . They coMitochondrial malfunction has been involved in a broad spectrum of human illnesses. Since energy production is closely linked to mitochondria, mitochondrial dysfunction may be the initiating link in many diseases such as neuronal degeneration. For example, oxidative stress can lead to impairment of mitochondrial structure and function, and consequently synaptic damage and neuronal apoptosis, thus promoting the progression of Alzheimer’s disease . Also, tMitochondria were formerly assumed to be permanently housed in their somatic cell, however, recently they have been reported to be transported between cells –10. ThisMitochondrial intercellular transfer enhances mitochondrial integration to the endogenous web of recipient cells, leading to a significant change in the bio-energetic state and other functions in the receptor ones, and also generates changes associated with cell differentiation, cell survival, and even drug resistance . TherefoRecently, mitochondrial transfer has been observed in several kinds of hematological malignancies involving acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. In these hematological diseases, mitochondrial transfer seems to promote tumor progression and result in chemotherapy resistance –22, implThere have been a few mechanisms described to mediate transcellular mitochondrial transfer. Among them, tunneling nanotubes (TNTs) are the primary means of mitochondrial transport, and multiple TNTs are able to be built between cells to interconnect, constituting a complex regulatory network for intercellular substance and signaling . Other tTNTs appear to represent a novel route of intercellular communication, indicating the ability to swap organelles for mammalian cells . As is kTNT formulation is mediated by two main pathways. The former mechanism relies extremely on cell mobility. When two cells approach each other spatially and then separate after close contact, the remaining membrane pores form TNTs , 32. TheTNTs have a cytoskeleton consisting mainly of cell membranes as well as fibrillar actin and microtubulin . BesidesA number of molecular mediators of actin-driven TNT synthesis have been reported. –39. LeukSeveral other pathways have been reported to affect the synthesis of TNTs. Under oxidative stress, the cellular expression of p53 is elevated and activation of AKT-PI3K-mTOR signal pathway is achieved, controlling the protrusion and growth of nanotubes . MeanwhiMitochondrial transfer is regulated by actin motors and Milton adaptor proteins , 45. MirIt is known that Miro1 functions in neurons as well as among other kinds of cells –51. MiroMiro2 protein (encoded by RHOT2) is also the main connector for intracellular transport of mitochondria. In the presence of Miro1, it seems somewhat redundant for Miro2 in that it does not fully compensate for the loss of Miro1. Surprisingly, the two Miro proteins modulate kinesin-based motion, with Miro2 playing a dominating part in short-distance transmission  and moreIn general, a diverse population of vesicles are discharged from the internal into extracellular environment, and the vesicles are named EVs. They are globular structures enclosed by a phospholipid bilayer membrane which encases many cellular proteins, nucleic acids, chemicals, and structural components –55. BaseEVs can carry multiple substances over long distance to alter the fate of host cells and organismal functions , 58. BesMany types of cells, such as astrocytes and MSCs, can secrete mitochondria-carrying EVs , 63, 64 +, K+, Ca2+, etc.), second messengers ,and other small molecules to be exchanged across cells [GJs are another important ways for mitochondrial transfer, though there are fewer studies about GJs compared with TNTs due to that TNTs are easily observed in in vitro co-culture systems . GJs conss cells . Therefoss cells . Studiesss cells , 74 and ss cells .17. GJs play important roles in mediating mitochondrial transfer via Cx43 and other proteins.In a study examining the protected effects of mitochondrial exchange of BMSCs in lung tissue, BMSCs release vesicles encapsulating mitochondria to reach alveolar epithelial cells via GJs, which are subsequently taken up by endocytosis . This miExcept for TNTs, EVs and GJs, cell fusion is another proposed method of mitochondrial transport in cell-to-cell communication. As cell fusion is rarely found in higher eukaryotes under normal physiologic conditions, it is not the main mechanism for mitochondrial transfer.Cell fusion is the process whereby the membranes of two or several cells unit together and partake organelles and cytoplasmic components. The process may be triggered when injury and inflammation occur . ParticuAs for the form of cell fusion, it occurs both by partial cell fusion formed by TNTs and by full cell fusion. When co-cultured human MSC with transgenic mouse cardiomyocytes, the transfer of mitochondria can be identified at full fusion of MSCs with cardiomyoblasts with mitochondrial damage . Yet, miStress conditions, like infections or inflammations, hypoxia, x-rays, and ultraviolet, can trigger early signals for mitochondrial transfer , 85–91. Functionally normal mitochondria are able to be transmitted from MSCs into receptor cells, while injured mitochondria in recipient cells under stress can also be transferred to MSCs via TNTs and be cleared by mitophagy . In thisNF-κB signaling presents in most cells, and is involved in inflammatory and other diseases . DysreguAlthough most studies demonstrated that mitochondrial transfer occurs via intercellular mechanisms, more and more evidence indicate that mitochondria could be freed to the extracellular environment and then transmitted to donor cells . As prevIt has been proven that cells could leave some elastic fibers behind during migration, and little vesicles grow at the top or intersection of the elastic fiber, which are named migrasomes . During These external mitochondrial interactions with other cells open up a novel field of research where mitochondria transcend the roles as cellular powerhouses and act as signal organelles –107. EluMitochondrial transfer may preserve metabolic homeostasis and cell-to-cell interaction in the microenvironment in response to metabolic and oxidative stressors. It alters the functional status of recipient cells, and takes a critical part in the progression and viability of neoplastic cells as well as in the repair of damaged cells.Through TNT-mediated mitochondrial transport, the energy metabolism of recipient cells has been changed, with the increased production of OXPHOS and ATP and thereby maintaining metabolic homeostasis in a variety of cells .As is reported, mitochondrial transmission from MSCs to adenocarcinoma cells has caused a series of changes of the latter in energy metabolism, including decreased extracellular lactate and ROS, and increase in extracellular ATP, membrane potential and oxygen consumption, indicating a complete recovery of mitochondrial activity after being co-cultured. Similarly, osteosarcoma cells, after co-culture with MSCs, displayed the higher mitochondrial activity by boosting intracellular ATP and oxygen consumption rates . Also, dThe progression of tumors requires interaction between tumor cells and neoplastic microenvironments. In normal conditions, mitochondrial transfer can induce cellular reprogramming. It has been demonstrated that co-culture of fully-differentiated cardiomyocytes and MSCs caused the mitochondrial transfer from MSCs into cardiomyocytes, promoting a progenitor-like state of the latter . As for Meanwhile, mitochondrial transmission has been shown to mediate chemotherapy resistance  in many Mitochondrial transfer could promote wound healing and might be implemented in the repair of impaired tissue. Mitochondrial transfer has been proven to take a protective part in the vascular system. Mitochondria transferred between endothelial progenitor cells via a TNT pattern could promote regeneration and repair of damaged myocardium . In addiIntercellular mitochondrial transfer is also reported to be involved in the maintenance of homeostatic of lung tissue. Mitochondrial transfer was observed from BMSCs to alveolar epithelial cells in a murine model of acute lung damage treated with LPS, and resulted in increased alveolar ATP levels . This miIn serious corneal injury situations, corneal stem cell transplantation has become an emerging tactic for corneal regeneration and scar formation prevention. The rate of bioenergetic parameters such as ATP production and maximal respiration rate were inferior in rotenone-treated corneal epithelial cells in comparison to healthy corneal epithelial cells. All these indices showed significant improvement in corneal epithelial cells co-cultured with MSCs, suggesting that mitochondrial transmission in MSCs is a crucial mechanism of MSC treatment for corneal impairment . In addiMitochondrial transfer has been observed in normal hematopoiesis. Upon exposure to bacterial infection, hematopoietic stem cells (HSCs) expanded quickly in response to stress stimulation and the immune system underwent a rapid granulocytic response associated with acute bacterial infection. At this time, mitochondria were transferred from BMSCs to HSCs via GJs under the regulation of ROS. As a result, the mitochondrial mass of HSCs increased, leading to a metabolic shift from glycolysis to OXPHOS. Mechanistically, ROS-induced oxidative stress regulated phosphatidylinositol 3-kinase (PI3K) activation to mediate the opening of connexin channels, thereby permitting transport to occur. Here, HSCs act as recipients of transfer to acquire mitochondria in response to acute bacterial infection .In another discovery, mitochondrial transfer was found to occur in the opposite direction, i.e., from hematopoietic stem and progenitor cells (HSPCs) to MSCs. After radiation prior to bone marrow transplantation (BMT), the mitochondria of MSCs were dramatically impaired. HSPCs transferred healthy mitochondria to the stromal microenvironment (ME) via HSPC Cx43-mediated cell contact, thereby improving mitochondrial activity in recipient MSCs. As a result, supportive stromal ME was restored and hematopoietic compartment reconstruction was improved. Understanding the mechanisms that regulate stromal recovery after myeloablative stress is highly clinically relevant for optimizing BMT procedures and emphasizing the importance of adjuvant non-HSC accelerated hematopoietic transplantation .Moreover, after injecting erythroblast island (EBI) macrophages into mice that suffered from multiple modes of anemia stress, it could be found that mitochondrial transfer occurred from EBI macrophages to early erythroblasts via direct uptake. At the early erythropoietic stage, mitochondrial transfer alters the bioenergetic profile of recipient cells through CD47-Sirpα interactions, promoting their proliferation, protein synthesis, and energy generation, thereby driving the recovery of erythroid lineage cells in response to stress. This finding provides evidence for a supportive role of splenic and bone marrow EBI macrophages in erythropoiesis during erythrocyte stress and confirms the essential mediating role of mitochondrial transfer .These above findings suggest that mitochondrial transfer occurs in normal hematopoiesis under infection, radiation and stress, and involves various cell types and different directions of transport. These transfers alter the metabolic state and physiological functions of the recipient cells, and facilitate the body’s adaptation to and recovery from stress.Hematological malignancies define a highly heterogeneous disorder with strongly variant prognoses that continuously relapse after therapies. Hematological malignancies have the leading morbidity and mortality and seriously affect human health . BecauseAML is featured by the invasion of clonal and inadequately differentiated hematopoietic cells in bone marrow . Via WarIt has been found that the proteins associated with cell energy metabolism are up-regulated in AML cells after cocultured with BMSCs . DespiteMitochondrial exchange between BMSCs and AML cells has already been observed in co-culture conditions both by lentiviral transfection and fluorescent staining of BMSCs mitochondria, which was also shown in vivo . A high As mentioned before, AML cells rely on OXPHOS for ATP production. Another study explored the mechanisms whereby the bone marrow microenvironment promotes secondary resistance of AML cells to OXPHOS repression. They utilized IACS-010759 to treat AML cells, a newly complex I OXPHOS inhibitor, and discovered that direct contact with BMSCs induced the compensation of AML cells by activating mitochondrial respiration and developing tolerance to OXPHOS suppression. In terms of mechanism, suppression of OXPHOS inspired mitochondrial transport from MSCs towards AML cells through TNTs under direct-contact co-culture circumstances. Additionally, in AML cells, this inhibition induced mitochondrial division, an increase in functional mitochondria, and mitochondrial phagocytosis. Moreover, it was demonstrated that mitochondrial transmission of MSCs to AML cells induced by OXPHOS suppression was further strengthened by Ara-C . These fClinical observational trials using Venetoclax combined with hypomethylating agents targeting BCL2, an important modulator in mitochondrial apoptosis pathway, have shown a tolerable safety profile and good overall remission rates in elderly AML patients . TherefoCurrent studies demonstrate that mitochondria transfer between AML cells and BMSCs via TNTs or endocytic pathways. AML receptor cells have enhanced metabolic capacity and resistance to chemotherapeutic agents. Mitochondrial transfer become a promising target in AML therapy. In combination with existing chemotherapeutic regimens, it can increase the killing power of chemotherapeutic agents on AML cells by inhibiting mitochondrial transport, which is expected to be widely applied in the clinic.CML is a myeloproliferative neoplasm and manifests increased peripheral blood leukocytes. CML is triggered by reciprocal chromosome translocations, which results in a BCR-ABL fusion gene . The annIn conclusion, mitochondrial trafficking between CML cells and BMSCs by TNTs increases resistance towards chemotherapeutic drugs and decreases the apoptosis rate of CML cells. This could be considered a therapeutic tool when leukemic cells develop drug resistance or when individuals fail to obtain a complete cytogenetic response.T-ALL is one of the most invasive hematologic malignancies. It originates from the malignant conversion of T-cell progenitors. The cure rate of T-ALL has improved to about 50% in adults with the treatment of high-dose multi-agent chemotherapy . HoweverBMSCs have been shown to have an impact on cellular mitochondrial dynamics of T-ALL and affect the chemo-resistance of leukemia cells. In a study, MSCs were shown to provide protection against chemotherapeutic cell mortality and cytotoxicity in T-ALL under both indirect and direct co-culture conditions . The celThe important role of mitochondrial metabolism in the maintenance of bioenergetic and metabolic homeostasis makes it an interesting therapeutic target. T-ALL cells have oxidative stress and metabolic disruption, which is a frequent hallmark of cancer cells. The level of ROS in T-ALL cells is much higher than that in normal cells. As excessive ROS causes leukemic cell death, it has been shown that inducing intracellular oxidative stress is an essential anticancer machinery of leukemia chemotherapy . ALL celIn summary, mitochondrial transport from T-ALL cells to MSCs is mainly regulated by TNTs, which reduces the level of mitochondrial ROS in the cells and induces drug resistance. Clinical disruption of the communication between leukemia and stromal cells could provide a novel therapeutic method in combination with conventional chemotherapeutic agents.Mitochondrial transfer is also present in B-ALL. It has been shown that primary B-cell precursor ALL (BCP-ALL) cells utilize TNTs to communicate with MSCs. The signaling led to the secreting of pro-survival cytokines, induced stroma-mediated prednisolone resistance, and increased the viability of B-ALL cells. Suppression of TNTs significantly inhibited this process and made BCP-ALL cells re-sensitized to a vital anti-leukemic medicine prednisolone. The discovery of TNT signals in ALL-MSC interaction sheds light on the pathobiology of ALL and brings novel opportunities for developing more efficient treatments . AnotherMM is a hematological malignant tumor that features abnormal clonal plasma cells in bone marrow . The gro64. In MM cells, CD38 was shown to be highly expressed [It is recognized that MM cells typically utilize a non-mitochondria-based glycolytic process to produce their ATP and be sensitive to glycolytic inhibitors . The depxpressed , while sxpressed . Thus, tIt was reported that myeloma MSCs are less dependent upon mitochondrial metabolism than healthy ones, exhibiting significantly higher glycolytic rates such as decreased NAD+/NADH ratios and increased intracellular lactate . The metIn conclusion, the role of mitochondrial trafficking in BM microenvironment is crucial for the pathogenesis, progression and drug resistance of hematological tumors Table . Most ofHere, we offer an overview of intercellular mitochondrial transfer, and discuss the modes and mechanisms underlying the process in diverse illnesses. Mitochondrial transfer has multiple different effects. The main reason is that mitochondria with reduced membrane potential can be released from cells of injured tissues, thus maintaining cellular homeostasis. In addition, mitochondria can also rescue metabolically damaged neighboring cells more altruistically, so as to promote the repair of cellular damage in a variety of tissues and apply to the treatment of many diseases. At the same time, cancer cells receive mitochondria from their neighbors to restore energy metabolism and increase proliferation, invasion and metastasis as well as resistance to chemotherapy. The above evidence suggests that mitochondria could be used as therapeutic targets in future therapy. This knowledge raises significant potential for modulating mitochondrial transfer to enhance normal cellular homeostasis and energy dynamics or to disturb the pathologic adaptations of tumor cells.To date, it has been found that intercellular mitochondrial transfer plays a major role in the tumorigenesis, progression and drug resistance of hematological malignancies like AML and ALL. In other hematological malignancies, mitochondria are also targeted to enhance sensitivity to chemotherapeutic agents. All these findings could pave the way for a novel approach to the treatment of hematological malignancies in days to come. The current treatment by blocking TNTs can inhibit mitochondrial transfer and has worked well. Although the mechanism of mitochondrial transport is still not well understood, it may be related to key molecules such as CD38, motor protein KIF5B, and Cx43. These molecules could provide molecular targets for targeted therapy of hematological malignancies. At the same time, the key challenge relating to mitochondrial transfer therapy is their dual role in normal hematopoiesis and malignant diseases. As mentioned earlier, BMSCs under stress conditions provide mitochondria to HSCs. Therefore, during the targeting mitochondrial transfer therapy, it is of vital importance to consider the specific selection of recipients of mitochondrial transport between HSCs and hematopoietic malignant cells as well as the accurate regulation of the direction of transfer. It is not yet known whether the transfer of mitochondria from stromal cells to HSCs or malignant cells will have any effect during chemotherapy. Moreover, in normal hematopoiesis and malignant diseases, the differences in the intensity or types of the stress, as well as the diversities in the BM stromal microenvironment may have an effect on the bias of mitochondrial transfer. Therefore, when blocking mitochondrial transfer for hematological malignancies therapy, we should try to avoid the impact of off-target effects and make effort to develop more specific targeting molecules.Nonetheless, additional research is required to cross knowledge gaps, eliminate clinical application challenges, and address ethical concerns related to the therapy.


Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation have led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations, and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion. et al. argue that further improvements in technology mean that lesions may be making a comeback in the treatment of brain disease.Historically, lesions were fundamental to localizing and treating neurological symptoms; however, their use decreased with the adoption of techniques such as functional imaging and electrical neuromodulation. Joutsa  Historically, pathological lesions played a key role in localization and therapeutic lesions in treatment of neurological and psychiatric symptoms . Over tiin vivo.6 However, by the 1980s, lesion-based studies were on the decline, in part due to functional neuroimaging technologies like PET and functional MRI (fMRI). These technologies allowed for localization of brain function in patients without brain lesions and helped overcome some of the challenges of lesion studies such as difficulty recruiting sufficient numbers of patients with similar symptoms or lesion locations, lack of statistical power and biological variability of spontaneous lesions in size and pathological process . Owing to this added flexibility, functional neuroimaging studies soon became the dominant tool for localization of human brain function, greatly exceeding the number of lesion-based studies.8 Advances in invasive animal studies, including large consortia  and new techniques (such as optogenetics), together with increasing use of computational models  may have further contributed to the decline in lesion studies.Brain lesions have been used to localize and treat neurological and psychiatric symptoms for well over a century . Early l9 Parkinson’s disease  and psychiatric disorders (leucotomy or lobotomy).10 Many of these early procedures were limited in efficacy, associated with unacceptable side-effects, and led to ethical concerns, especially in the case of psychosurgery.11 Serendipitous findings, such as improvement in tremor following an accidental iatrogenic thalamic lesion,12 and adoption of the stereotactic frame led to more reproducible lesions with fewer side effects. Randomized controlled trials soon validated the efficacy of therapeutic lesions for movement disorders.13 However, by the 1980s, lesion-based treatments were on the decline, in part due to the development of better pharmacological treatments15 and the finding that similar therapeutic benefit could obtained by electrical stimulation of traditional lesion targets.16 The latter finding led to the development of deep brain stimulation (DBS), which had the advantage of reversibility and tunability with less side-effects compared to therapeutic lesions, especially for bilateral interventions.16 A head to head trial of DBS versus thalamotomy for tremor highlighted these advantages, and by 2010, the number of DBS procedures greatly exceeded the number of lesion procedures for movement disorders.17Therapeutic lesions were also leveraged for treatment across psychiatric and neurological conditions . In the 18 and fMRI,19 these tools have dominated efforts to map symptoms to human neuroanatomy. The number of studies utilizing these technologies has dwarfed the number of lesion-based studies in the past few decades.Since the introduction of functional neuroimaging techniques such as PET20 This weakness of functional neuroimaging has been referred to as the ‘causality gap’ and may limit the ability to translate neuroimaging findings into therapeutic targets.21-23 A return to lesion-based localization may help address this weakness, allowing for stronger causal inference in symptom localization.20 For example, finding that a lesion of structure X impairs process Y shows that lesioning X is sufficient to cause impairment of Y. However, it should be noted that this does not mean that lesion of X is necessary for causing deficits of Y.20However, lesion studies have one important advantage over functional neuroimaging in that they can allow for causal links between the location of the lesion and the resulting symptoms.25 If the results do not align between these two complementary approaches, we need to rethink the data and its interpretation. However, these two approaches provide complementary information as lesion studies can identify brain regions essential to function whereas neuroimaging studies identify regions that are involved in, but not necessarily essential to, a particular brain function.Lesions are also valuable to critically test and validate neuroimaging findings, and vice versa.27 For example, a recent study of nearly 500 stroke patients showed that language deficits could be linked to damage of specific locations in the right hemisphere, not just the left hemisphere.28 As methods and sample sizes have improved, it has become clear that lesion-induced deficits often fail to map onto single brain regions. For example, amnesia can be caused by lesions outside the hippocampus, hemichorea by lesions outside the subthalamic nucleus, and hemiparkinsonism by lesions outside the nigrostriatal tract.29 In these cases, lesion-based localization can benefit from incorporating information about brain connectivity.29The causal inference allowed by lesion studies is bolstered by recent advances in lesion mapping. While early lesion-based localization was based on individual patients, modern lesion studies often include hundreds of patients, enabled by the interconnected age of information technology, and the use of advanced statistics to better map lesion-induced deficits to neuroanatomy.30-32 Using these circuit maps, one can map lesion-induced effects to specific white matter connections or functionally connected brain networks, rather than individual brain regions. Referred to as lesion network mapping29 or disconnection mapping,34 this approach has proven valuable across a wide range of neurological and psychiatric symptoms. For example, lesions causing amnesia, hemichorea and parkinsonism all fail to map to single brain regions but do map to specific brain networks.29Atlases of human brain connectivity are now available, built from thousands of subjects scanned with techniques such as resting state functional connectivity MRI and diffusion tensor imaging.35 Although rare, spontaneous brain lesions have been reported to improve drug addiction,36 movement disorders,37 stuttering,38 pain,39 tinnitus40 and even foreign accent syndrome.41 These spontaneous but beneficial brain lesions might help identify lesion-based treatment targets.35 For example, a proof-of-concept study examined eleven lesion locations resulting in tremor improvement. These lesions occurred in different brain locations, but they were all part of a single connected brain circuit with a hub in the ventral intermediate nucleus of thalamus. This hub aligned perfectly with the primary lesion and DBS target for treating tremor -DBS to thalamotomy for treatment of tremor found that both are similarly effective, but VIM-DBS resulted in fewer side-effects.17Although therapeutic lesions have been used as a treatment for a variety of neurological and psychiatric conditions , many eal-DOPA can cause dyskinesias.57 DBS is relatively expensive, requires specialized centres, and includes frequent doctor visits, permanent indwelling hardware, battery charging or surgical battery replacements, and risks of intracranial haemorrhage, infection and device malfunctions, which can even lead to severe and sudden clinical deteorioration.58 Ethical considerations include possible future financial issues preventing/delaying replacement of the pulse generator and a lifelong reliance on individuals in the companies producing the devices.59 Although DBS is currently the dominant technique in functional neurosurgery and the risk/benefit ratio of DBS is expected to continue improving, lesions have remained an option for selected patients and has motivated ongoing research into lesion-based treatments.61 Use of traditional therapeutic lesioning where DBS is not available or logistically or financially feasible might also allow more patients to benefit from functional neurosurgery.Despite the advantages and major benefits of medications and DBS, they are not without their own drawbacks. Antipsychotics can cause extrapyramidal side effects and 63 These latter advances are a major improvement over ventriculography, the targeting technology used in the landmark head-to-head trial of DBS versus lesion therapy.17 More refined surgical tools to create lesions such as radiofrequency (RF) ablations, laser ablations and gamma knife can help minimize tissue damage and the invasiveness of lesion-based procedures.64-66 A recent advance in lesion treatments is magnetic resonance-guided focused ultrasound (MRgFUS), which may have advantages relative to other lesion-based therapies.67 Unlike RF ablations, MRgFUS can be used to create lesions under direct MRI guidance without skin incision or opening the skull.69 This leads to reduced risk of infection or bleeding, reduced pain, and more rapid surgical recovery.69 MRgFUS can also be used to create a transient test lesion with immediate clinical effects, an advantage compared to gamma knife in which clinical effects may not appear until months after the treatment.67 As such, there has been a consistent increase in the number of MRgFUS operations for each of the past 7 years .74The efficacy of MRgFUS thermoablation of the VIM to treat essential tremor has been confirmed in a large prospective randomized controlled trial (RCT).74-78 There also are ongoing studies investigating MRgFUS in dystonic tremor , dystonia , Parkinson’s dyskinesias , obsessive-compulsive disorder (anterior capsulotomy), epilepsy , depression (anterior capsulotomy) and chronic pain   approval of bilateral thalamotomy in essential tremor and suggested benefit of unilateral lesions for motor symptoms in Parkinson’s disease patients who were not eligible for DBS .amotomy) .6879 Comparing response rates between different trials targeting VIM, tremor improvement may be less robust and side effects may be more common following MRgFUS versus DBS.80 As such, MRgFUS has so far been only offered unilaterally and often for patients who have contraindications for DBS, do not want DBS, or for whom repeated DBS tuning visits or hardware/battery maintenance could prove challenging.79 However, trials of bilateral lesioning using MRgFUS are already being conducted and staged bilateral thalamotomy has just received approval from the US FDA for treatment of essential tremor.78To date, there have been no head-to-head trials comparing MRgFUS to RF ablations, gamma knife or DBS.68 Skull thickness and morphology prevent use of MRgFUS in approximately one fifth of patients with a low skull density ratio because of not reaching high enough temperatures at the target, tissue heating related side-effects and a higher risk of complications.82 In addition, MRgFUS can currently only be used to lesion structures near the centre of the brain, as efficiency and accuracy diminishes the further one gets from the centre of the brain.68 MRgFUS generates an ellipsoid lesion, but there is limited ability to rotate, refine or shape this ellipse to best match the surgical target.68 Currently, MRgFUS is still limited in reaching sufficient accuracy to target specific parts of small nuclei, such as the subthalamic nucleus (STN), where sensorimotor or somatotopic representation of the targeted circuits are located.83 Similarly, optimal control of the expansion of the thermal lesion is still an ongoing challenge.68While MRgFUS can achieve high accuracy in placing lesions, it has technical restrictions that currently limit its use.85MRgFUS is currently available only in specialized centres and expensive compared to RF ablations and gamma knife, which are more available worldwide. These techniques provide an important alternative for MRgFUS, reaching larger populations and allowing more patients to benefit from functional neurosurgery. As such, RF ablation also has regained scientific interest with recent papers showing e.g. clinical benefit with bilateral thalamotomy in essential tremor and unilateral pallidotomy in dystonia.86 should allow us to better map lesion-induced effects to brain regions and brain circuits. The latter will benefit from improved atlases of brain connectivity.87-89 Second, therapeutic targets may become more precise as we shift from diagnosis-based targets to symptom-specific targets. For example, different targets are already used for different symptoms of Parkinson’s disease such as tremor (VIM), rigidity [STN or globus pallidus interna (GPi)] or dyskinesias (GPi),90 while new targets are being investigated for refractory symptoms such as freezing of gait.91 Similar symptom-specific targets may prove valuable in other diseases such as depression.92 Third, we may be able to reduce side effects as we identify brain circuits to be avoided  may improve our ability to identify therapeutic targets in individual patients.96-98Moving forward, we expect that therapeutic targets will continue to become more precise. First, ongoing efforts to collect large, prospective datasets of spontaneously occurring brain lesions or iatrogenic lesions avoided .93 For e68 Other technological advances may allow for lesioning of specific cell types or specific projections, as well as novel approaches to lesioning in general, such as delivery of cytotoxic agents across the temporarily permeabilized blood–brain barrier.68 Finally, ongoing research aims to improve our ability to create transient lesions using hyperthermia, mechanosensitive ion channels, cell membrane capacitance or blood–brain barrier disruption.99 The ability to create a transient lesion and control the duration of the lesion could allow one to pilot clinical effects prior to a permanent lesion, which would greatly facilitate experimental lesions for new indications.We also expect that our ability to accurately lesion a target anywhere in the brain will also continue to improve. New advances in MRgFUS design are underway to enlarge the workspace in which lesions can be generated.Given recent advances in lesion mapping, identifying therapeutic targets, and accurately placing lesions at these targets, we are likely to see a continued increase in the use of lesion-based therapies moving forward. These advances may change the benefit-risk ratio of therapeutic lesions relative to competing technologies such as DBS . If a pr100 With permanent lesions, it is important to acknowledge that brain structure and functional organization have interindividual variability and, therefore, a group-level optimal target may not be suitable for all patients.101 We also need to learn from the history of lesion-based therapies to avoid repeating the same mistakes.11 First, we need to ensure our lesion-based targets are as precise as possible.100 Although MRgFUS of the VIM is a US FDA approved therapy for tremor, targeting is usually only based on anatomical landmarks to approximate the location of VIM, and there is debate regarding whether VIM or a different structure near VIM is the ideal target for tremor.52 Tunable technologies such as DBS can compensate for some of this uncertainty postoperatively, while lesion-based treatments cannot. Second, we need to ensure that we are minimizing lesion-based side effects. Although acute side effects are often readily apparent, delayed-onset side effects can occur years after surgery. For example, delayed onset ataxia can occur following VIM DBS,103 and delayed onset cognitive decline can occur following STN DBS.104 Both of these side effects can be alleviated with DBS-reprogramming. If these side-effects are associated with the therapeutic target, they might also occur following therapeutic lesions where adjustment is not possible. Finally, informed consent for lesion-based therapies, especially experimental therapies, is critical and should only be conducted under the guidance of independent review panels.Although lesions appear to be making a comeback, caution is warranted, especially when using irreversible lesions that could be associated with side effects, or when pursuing psychiatric indications.8 but it has re-emerged as a tool for causal localization of symptoms and identification of therapeutic targets. Although there are limitations to lesion-based treatments, new technologies are improving the accuracy, safety, and convenience of therapeutic lesioning. Combined, these developments may facilitate the return of the lesion, complementing the currently available neuroimaging and brain stimulation techniques for localization and therapy.Lesion-based localization has sometimes been considered a relic of the past,awad123_Supplementary_DataClick here for additional data file.


Ipomoea batatas) is an economically important food crop that is grown primarily for its edible storage roots. Several researchers have consequently been conducting studies to increase sweet potato yield, and an important aspect of this research involves understanding how storage root initiation occurs. Although significant progress has been made, several challenges associated with studying this crop have resulted in lagging progress compared to other crops and thus sweet potato storage root initiation is not clearly understood. This article highlights the most important aspects of the hormone signalling processes during storage root initiation that needs to be investigated further and suggests candidate genes that should be prioritized for further study, based on their importance in storage organ formation in other crops. Lastly, ways of overcoming the challenges associated with studying this crop are suggested.Sweet potato ( This article reviews the current understanding of the hormone signalling pathways involved in the initiation of the growth of sweet potatoes. It highlights the gaps in the current knowledge of genes involved in the process and suggests future directions to overcome the challenges associated with studying sweet potatoes. This is important for researchers trying to improve sweet potato yields. Ipomoea batatas) has been ranked sixth in importance (Tubers and storage roots (SRs) form a significant contribution to the world’s food supply. Among these crops, sweet potato  that initiates tuberization, if the mechanism is similar to that in better-studied tuber crops (such as potato) and how hormones regulate tuberization at the molecular level. If these questions can be answered, this would be useful for researchers to identify what genetically affects sweet potato yield and thus develop better-yielding varieties faster by selecting new biomarkers, than what is presently available.Previous reviews  TFs. Auxin response factors are upregulated during SR initiation in potato and cassava  proteins (that inhibit ARFs at low auxin concentrations), Small auxin upregulated proteins  and Gretchen-Hagen 3 proteins (which inactivate auxin). Several studies have shown that some members of these gene families are differentially expressed during storage organ formation in potato, cassava and sweet potato (cis-zeatin (cZ), trans-zeatin (tZ), cis-zeatin riboside (cZR) and trans-zeatin riboside (tZR)  . Other atZR, was proposed to have vital roles in SR initiation by developing and activating the primary cambium  genes and hormone signalling pathways  and upregulating CKs , is a target of DELLA  and FLOWERING LOCUS T suppressors  TR, callus-expressing factor, ethylene response factor 4, AP2/EREBP TR ERF-2, dehydration-responsive element-binding protein and ethylene-responsive TR 3) were found to be upregulated in FRs but not SRs . HoweverA. thaliana roots (Brassinosteroids (BRs) are involved in various aspects of plant development, including root growth, thermotolerance, drought tolerance, and light responses . Some ofin vivo, even though SA can promote potato tuberization in vitro  signalling is a central hub that integrates environmental signals with hormone and nutrient signalling , which identifies TF-binding targets. However, this technique is very challenging to perform, thus making it prone to experimental error and artefacts (Another one of these techniques is single-cell RNA-seq (scRNA-seq). The ability to analyse transcriptomic data to the resolution of different cell types would be indispensable to determine how different cellular fates arise, particularly that of the adventitious roots at emergence which can lead to FRs or SRs. However, the application of this technique is limited in plants due to the presence of the cell wall preventing the dissociation of tissues into individual cells during protoplast formation  to determine plant phytohormone levels at various stages of development and map phytohormone-dependent protein interactions  by measuring the changes in the expression of important genes.Another challenge to investigating SR initiation in sweet potato is the difficulty associated with growing SRs http://sweetpotato.uga.edu/sweetgains_beauregard_v1_asm_anno.shtml). This genome, along with better versions in the future, will facilitate more genome-wide analyses of gene families to understand their roles in SR initiation. Transcription factors belong to large gene families, such as the MADS-box gene family, which has been widely studied to understand their importance in SR formation  between tuberizing and non-tuberizing sweet potato tissue and these DEGs have given invaluable insight into which processes are regulated and how they are regulated during tuberization. These comparisons include SR versus FR (The experimental suggestions described above will complement the existing studies conducted on individual genes to determine their roles in SR formation.Sweet potato SR initiation is a complex process that involves the interplay of several signalling pathways that involve various hormones, TFs and miRNAs. Prior to the release of a high-quality genome reference, progress in elucidating these pathways lagged in comparison to other well-studied storage organs, such as potato and cassava. It is expected that sweet potato research will accelerate with the availability of improved databases and experimental resources. While the present era of research on SR formation in sweet potato is largely based on transcriptomic data, it is expected that more proteomic and metabolomic data will complement these studies. This will lead to the improvement in our knowledge on these complex regulatory pathways and this should translate into producing better-yielding sweet potato varieties.


Dear Editor,Intramuscular lipoma is a deep-seated soft tissue lipoma that arises in muscle tissue, and is benign and relatively rare. Although multiple reports exist regarding intramuscular lipomas, their clinical and imaging characteristics are still not very well-known by clinicians. In general, we believe that there are three subtypes of intramuscular lipomas, which can define some of their imaging differences. These subtypes are infiltrative, well-defined/encapsulated and mixed, or partially well-defined/partially encapsulated (with areas of infiltration and well-defined areas).Sao Paulo Medical Journal.,Recently, we read the very interesting article by Balabram et al. named “Intramuscular lipoma of the subscapularis muscle” published in the On MRI, intramuscular lipomas are round or fusiform with occasional dumbbell-shaped masses. In contrast, well-differentiated liposarcomas have oblong or oval shape, with the dumbbell shape relatively frequent and crescent-shaped and fusiform masses less common. Intramuscular lipomas may vary between less than 3 cm and more than 15 cm. In general, well-differentiated liposarcomas are larger but the size alone is not significant enough to differentiate between them.,,Although some intramuscular lipomas  may be composed of homogenously pure fatty tissue similar to superficial lipomas, heterogeneity due to intermingled fat and muscle fibers is very common and is not a sign of malignancy. Interdigitation with skeletal muscle, creating a very typical striated appearance, is characteristic of intramuscular lipomas. This feature has not been described in well-differentiated liposarcomas and allows confident diagnosis of intramuscular lipoma. Well-differentiated liposarcomas are also heterogeneous. While tumor tissue other than muscle fibers exists in liposarcomas, the tumor tissue can easily be distinguished from muscle fibers, since the latter maintain their original structure and are usually isointense with normal muscle on both T1- and T2-weighted images. Nodular and patchy signal intensities different from fat (non-adipose components) have been commonly noted in well-differentiated liposarcomas. Entrapped muscle fibers  have been reported in some cases of well-differentiated liposarcomas. However, this matter is still controversial and requires more research in order to define the significance of this finding on MRI.Intramuscular lipomas may present with well-defined or irregular margins, or both. Completely irregular margins are a feature of intramuscular lipoma rather than well-differentiated liposarcomas.,Most intramuscular lipomas are unilobular, however bilobular lipomas have been described as well.Variable thicknesses of streaky structures (septa) have been observed inside the lesions and between the lobes (if bilobular) in the majority of patients with intramuscular lipomas. Thick linear structures within the nodules, which have been recognized not only in well-differentiated liposarcomas but also in intramuscular lipoma, may not be pathognomonic.Mild enhancement of the mass and streaky structures in intramuscular lipomas after contrast material administration can be observed occasionally. This is in contrast to well-differentiated liposarcomas, where the septa and globular areas of the tumor tend to be enhanced more prominently.In conclusion, a single MRI characteristic of intramuscular lipomas may not be sufficient for the diagnosis. However, considering all MRI features together and careful examination of the images may often afford almost pathognomonic evidence and help in selecting appropriate surgery. Future studies should directly compare MRI features of intramuscular lipomas with deep-seated well-differentiated liposarcomas, with additional histological and cytogenetic correlations for better accuracy. ,We thank you for further describing the specific characteristics of deep-seated intramuscular lipomas and citing references not present in our article,,However, we would like to point out that the main goal of our case report was to describe the unusual presentation of a deep-seated lipoma as an axillary mass. Since the patient was 58-year-old at the time of presentation, it was important to rule out metastatic breast cancer as well as other malignant diseases.


Plant respiration is one of the greatest global metabolic fluxes, but rates of respiration vary massively both within different cell types as well as between different individuals and different species. Whilst this is well known, few studies have detailed population-level variation of respiration until recently. The last 20 years have seen a renaissance in studies of natural variance. In this review, we describe how experimental breeding populations and collections of large populations of accessions can be used to determine the genetic architecture of plant traits. We further detail how these approaches have been used to study the rate of respiration per se as well as traits that are intimately associated with respiration. The review highlights specific breakthroughs in these areas but also concludes that the approach should be more widely adopted in the study of respiration per se as opposed to the more frequently studied respiration-related traits. While most respiration-related studies accessing natural variation focus on respiratory metabolites, novel high-throughput techniques to capture respiration rates will enable novel discoveries. As sucosystems . The exaosystems . Similaragnitude . Moreoveagnitude . The conagnitude . As suchagnitude . Whilst  m−2 s−1 . Finally m−2 s−1 . An extrspadices . Howeverspadices  and damaspadices . The aboactivity . It is iactivity , these lactivity , as descactivity . The vasArabidopsis thaliana) (Arabidopsis have largely focused on understanding the principles underlying metabolic regulation and the influence of metabolism on growth and development (Solanum lycopersicum), (Zea mays), (Oryza sativa)   and in ahaliana) . Studieselopment  whilst telopment , 2012b arsicum), ; starch,a mays),  and flav sativa) ). As for sativa) . The pri sativa) . MoleculQTL analysis makes use of the natural variation present within a species and has been successfully applied to various types of segregating populations . In planDespite the similarities between these two types of mapping populations, large differences exist in their genetic makeup and the resulting mapping approaches utilized. Recombination frequency is in general higher in RIL populations than in equally sized NIL populations, allowing analysis of fewer individuals. Each RIL contains several introgressed fragments and, on average, each genomic region is represented by an equal number of both parental genotypes in the population . TherefoOne disadvantage of the bi-parental approach is that it is limited by the allelic variance exhibited by the two parental lines. To circumvent this, the so-called multi-parental advanced generational inter-cross (MAGIC) populations  were developed. There are many variants on this including nested association mapping (NAM) populations  and the recently developed Complete-diallel design plus unbalanced breeding-like inter-cross (CUBIC) populations . HoweverComplement Factor H gene as being strongly associated with age-related macular degeneration. Over the last 16 years, it has proven powerful in dissecting the genetic basis for variation in a range of complex phenotypes including disease in humans and animals and physiological and agronomic traits in plants  . The aimn plants . That san plants , 2016b. n plants , howevern plants . Althougn plants . In addin plants . To offsn plants . Howevern plants  and has n plants , 2021b, trans-QTL. More directly associated with respiration, Triticum aestivum) (leucine-rich repeat receptor kinase 1 (LRK1) gene, as a major regulator of the rate of dark respiration  . The ricpiration , whilst piration . As statpiration , and thepiration , microtipiration  and micrpiration , it is lWhilst the number of studies directly assessing the rate of respiration is relatively rare those, which determine the levels of respiratory metabolites, are legion. This is probably largely due to the establishment of metabolomics techniques, which render the determination of metabolite levels to be accurately assessed across huge populations. We were able to list over 40 papers in which the levels of largely TCA cycle intermediates were determined . This liSolanum pennellii (LA0716) to the background of S. lycopersicum (cv. M82) by 2 assimilation rates and photosynthetic activity  was partially serendipitous due to their good coverage in GC-MS-based metabolomics. For this reason, a plethora of information is available across crops including tomato , sweet mactivity . Out of activity . After sBesides fruit quality, other physiology-related components such as plant growth and development, are strongly associated with the levels of respiratory metabolites and have also been dissected for QTL discovery. In this context, major emphasis is given to grain crops such as maize, for which the metabolic levels of an RIL population were analyzed at different developmental stages revealing mQTL harboring genes for 2-oxoglutarate dehydrogenase, malate dehydrogenase, aconitase, succinate dehydrogenase, phosphoenolpyruvate carboxylase, and thioredoxin H-type across tissues and a pairwise epistatic interaction for >25.9% . In addiA. thaliana was investigated in a plethora of studies profiling the levels of respiratory metabolites in various bi-parental populations , and common bean (Phaseolus vulgaris). Perhaps unsurprisingly, the first of these studies was focused on Arabidopsis—specifically on malate efflux in supporting aluminum (Al) tolerance. In these studies, Hoekenga and coworkers used RILs resulting from a cross between Landsberg erecta and Col-0 and examined malate exudation mediated Al tolerance. It is known that Al-activates the release of Al-binding organic acids from the root tip  and demonstrated co-localization of ACO3 with the master regulation of retrograde signaling Arabidopsis NAC domain-containing protein 17 leading to submergence induced metabolic priming in ACO3 overexpression lines.More recently, RILs of maize were screened for the ability to grow in phosphorus deficient soils since organic acid secretion represents an important strategy to sequester phosphate . In thisTo summarize, using natural variance as a means of dissecting the genetic architecture of respiration is beginning to complement transgenic and gene-editing-based work. That said, as we have illustrated, most of the studies to date look into traits associated with respiration rather than respiration per se. Considering both approaches, breeding populations which maximizes allelic diversity in a population allowing high resolution and GWAS having the potential to resolve many limitations such as population structure, gene–environment interactions, and missing heredity by gold standard genome sequences, will likely ultimately complementarily aid in defining the genetic determinants which influence respiratory related traits. Further, given the vast number of breeding populations as well as panels of accessions that can be used in GWASs alongside improvements of approaches to measure respiration in high-throughput with the recently established miniaturized methods described above which are adaptable to high-throughput studies, it is unlikely that this will remain the case for much longer. We anticipate that we will shortly be able to access the vast amount of data required to reveal the underlying genetic determinants of plant respiration. A further advantage that can be envisaged is the fact that such data could be integrated with the many other phenotypes that have been recorded for these populations, which will likely greatly enhance our knowledge of how the natural variation of respiration impacts other aspects of plant function (see Outstanding Questions).Recent innovations in high-throughput methods to determine respiration rates have reignited screening highly diverse natural populations in the field of ecophysiology.Over the last decades, a vast excess of rmQTL for a plethora of crops has been identified due to improvements in metabolomics techniques.Metabolic prediction models have emerged that outperform genomic predictions on crop performance with several respiratory metabolites being major predictors.Does natural diversity in respiration affect plant performance?If so, to what degree does it interconnect with other physiological aspects relevant to crop physiology?How did diversity in respiration emerge from an evolutionary perspective?The following materials are available in the online version of this article. List of natural variation studies assessing levels of respiratory metabolites in plants.kiac593_Supplementary_DataClick here for additional data file.


Accelerated biological vascular ageing is still a major driver of the increasing burden of cardiovascular disease and mortality. Exercise training delays this process, known as early vascular ageing, but often lacks effectiveness due to a lack of understanding of molecular and clinical adaptations to specific stimuli. This narrative review summarizes the current knowledge about the molecular and clinical vascular adaptations to acute and chronic exercise. It further addresses how training characteristics  may influence these processes. Finally, practical recommendations are given for exercise training to maintain and improve vascular health. Exercise increases shear stress on the vascular wall and stimulates the endothelial release of circulating growth factors and of exerkines from the skeletal muscle and other organs. As a result, remodeling within the vascular walls leads to a better vasodilator and -constrictor responsiveness, reduced arterial stiffness, arterio- and angiogenesis, higher antioxidative capacities, and reduced oxidative stress. Although current evidence about specific aspects of exercise training, such as F-I-T-T, is limited, and exact training recommendations cannot be given, some practical implications can be extracted. As such, repeated stimuli 5–7 days per week might be necessary to use the full potential of these favorable physiological alterations, and the cumulative volume of mechanical shear stress seems more important than peak shear stress. Because of distinct short- and long-term effects of resistance and aerobic exercise, including higher and moderate intensities, both types of exercise should be implemented in a comprehensive training regimen. As vascular adaptability towards exercise remains high at any age in both healthy individuals and patients with cardiovascular diseases, individualized exercise-based vascular health prevention should be implemented in any age group from children to centenarians. Accelerated biological vascular ageing (early vascular ageing) leads to early target organ damage and subsequently to diseases, such as atherosclerosis, chronic kidney disease, degenerative brain disease, and retinopathy . The preDuring exercise, the increased blood flow stresses the vasculature and increases luminal shear stress. In turn, shear stress causes the deformation of glycocalyx receptors on the lumen of endothelial cells, activating calcium channels. Calcium signaling leads to prostaglandin release and consequently induces cyclic adenosine monophosphate mediated smooth muscle relaxation. Luminal shear stress activates protein kinase B, inducing endothelial NO synthase phosphorylation and consequently NO release. NO interacts with guanylate cyclase, activating a cascade of molecular signaling which leads to reduced intracellular calcium and increased intracellular potassium, favoring cell membrane hyperpolarization and smooth muscle relaxation. In addition, when NO diffuses to the luminal side of the endothelial layer, it also exerts an antithrombotic action by inhibiting platelet adhesion and aggregation  Figure .Acute bouts of exercise also enhance proangiogenic stimuli, such as the vascular endothelial growth factor (VEGF), which in turn signals capillary development. Previous studies have shown VEGF increases in response to a single exercise bout . The levIt is well established that regular exercise training improves vascular function in both health and disease. Chronic training-related adaptations of the cardiovascular system improve tissue perfusion and nutrient exchange at rest and result in a greater capacity to increase them during exercise. In this context, both structural and functional adaptations of the blood vessels have been reported .Briefly, exercise stimulates angiogenesis, the formation of capillary networks, and arteriogenesis, the growth of preexistent collateral arterioles. Early reports showed a greater arteriolar and capillary density in trained individuals compared to untrained aged-matched controls . An incrStudies have also suggested that repeatedly elevated shear stress, as it may occur during exercise training, induces increases in the arterial luminal diameter . In detaFunctional vascular adaptations in response to exercise training are also evident in healthy individuals and in individuals with chronic diseases ,22. AlteCollectively, all these adaptations improve constriction and dilatation responses of the vascular smooth muscle cells to vasoactive factors, increase arterial compliance, and reduce the probability of flow-limiting stenosis when cardiovascular and/or metabolic disease are present. Exercise also increases the content of collagen and elastin of atherosclerotic plaques stabilizing plaque lesions and attenuating vascular stiffening/calcification.In addition to these macrovascular effects of exercise, exerkines  are released in response to acute and/or chronic exercise from the working skeletal muscle and the cardiometabolic, nervous, and immune systems and induce adaptations in the microvascular system . For exaAn increasing amount of evidence suggests a critical role of mitochondria in the exercise-induced benefits on the vascular smooth muscle cells. However, direct evidence is sparse and most of the available evidence is extrapolated from observation in cardiac and skeletal myocytes . MitochoExercise-induced adaptations involve improved mitochondrial biogenesis, signaling transduction, respiratory function, and reduced chronic oxidative stress . AdditioExercise promotes the degradation of damaged mitochondria via mitophagy ,31. MitoIn summary, chronic exercise improves mitochondrial content and dynamics, resulting in a better oxidative capacity. Although acute exercise bouts upregulate ROS generation, chronic regular exercise results in lower chronic oxidative stress and less inflammation.Regular exercise reduces the risk of cardiovascular morbidity and mortality by up to 44% , delays The extent and clinical relevance of vascular effects induced by single bouts of exercise and short-term interventions are idiosyncratic in a way. Although endothelial function appears to be modifiable within a few weeks of regular exercise , arteriaCardiovascular effects of chronic regular exercise are independent of sex and age ,40 and aSimilar observations regarding clinical vascular effects of exercise have been made for both healthy individuals and patients with comorbidities, such as metabolic syndrome , arteriaIt is an appealing thought that cardiorespiratory fitness or previous training level influence the vascular adaptability to an exercise stimulus. It seems only logical that a highly trained organism does not have much room for further optimizations. Studies about endothelial adaptations to exercise in highly trained athletes support this in part, as some of them report better endothelial function than in untrained individuals ,61,62, wThe World Health Organization recommends at least 75 min per week of vigorous physical activity or 150 min of moderate intensity . The relLongitudinal shear stress is a major stimulus for adaptive endothelial responses to exercise. Therefore, the total load of shear stimulus rather than the peak itself seems to be the critical determinant . An animAerobic exercise training: A meta-analysis of randomized controlled exercise interventions in humans found no association between the frequency of sessions and improvement of endothelial function with aerobic exercise training . FrequenResistance exercise training: A positive association between the frequency of resistance training sessions and improvement of endothelial function has been shown . As withThere are only a few studies, that compared intensity-dependent vascular functional and structural effects of the same exercise modality.Aerobic exercise training: One study conducted a 12-week aerobic, ergometer-based training intervention at mild, moderate, and high exercise intensity . InteresResistance exercise training: For resistance training, little evidence exists about the relationship between intensity and vascular adaptations, and it does not suggest a dose–response relationship between resistance exercise intensity and improvements in vascular function .Aerobic exercise training: The relationship of aerobic exercise with functional and structural vascular adaptations has been described in a dose–response pattern, with higher volumes of at least moderate-intensity exercise inducing higher functional vascular improvements . HoweverResistance training: Very limited data exist on the relationship of resistance exercise duration with functional and structural vascular adaptations. Therefore, no conclusions can be drawn to date.Continuous versus interval aerobic exercise training: High-intensity interval training (HIIT) is a frequently used method of improving fitness. A meta-analysis examining the effects of HIIT relative to moderate-intensity continuous training (MICT) on vascular function reported that HIIT was more effective at improving macrovascular  function than MICT. However, the authors reported that the variability in secondary outcome measures and the small sample sizes in the studies included limits this finding. Nevertheless, that review suggested that four intervals of 4 min (4 × 4 HIIT) at 85–95% of maximum or peak heart rate (HRmax/peak) interspersed with 3 min of active recovery at 60–70% HRmax/peak three times per week for 12–16 weeks is a type of exercise to enhance vascular function . AnotherAerobic, resistance (dynamic/isometric), and combined exercise training: Both aerobic and resistance exercise seem to be associated with idiosyncratic patterns of blood flow and shear stress, which lead to distinct effects on arterial function and remodeling . One stuIsometric exercise training has also been suggested as an effective intervention for inducing favorable vascular adaptations. In detail, a recent cross-over study showed that 4 weeks of isometric training  reduced arterial stiffness  and total peripheral resistance . In contAll exercise modalities  have been reported to induce improvements in vascular function depending on the characteristics of the exercise stimulus . BecauseDespite considerable scientific efforts, the mechanisms by which protective effects of exercise contribute to the maintenance and improvement of vascular health are still not fully understood. In consequence, evidence is lacking when it comes to the choice of optimal training programs for the individual ,92. FurtFurthermore, sex differences in the training adaptations of the vessels have been reported ,99. SpecExercise-induced hemodynamic changes lead to mechanical stress of the vascular wall, the release of circulating growth factors from the endothelium, and the release of exerkines from the exercising skeletal muscle and other organs. These three main adaptive stimuli lead to an increased activity of several molecular pathways within the vascular endothelial and smooth muscle cells, culminating in a better vasodilator and -constrictor responsiveness, reduced arterial stiffness, arterio- and angiogenesis, higher antioxidative capacities, and reduced oxidative stress. Recent research revealed a potential role of enhanced mitochondrial biogenesis and mitophagy, substrate metabolism, and insulin sensitivity in the vascular smooth muscle cells for exercise-induced vascular adaptations.Acute bouts of exercise induce different vascular responses than regular training. Also, vascular adaptability towards exercise is high at any age in both healthy individuals and patients with cardiovascular diseases. This emphasizes the usefulness of exercise-based vascular health prevention from children to centenarians. Although athletes’ arteries seem to have higher functional capacities and less pathological structural remodeling than those of nonathletes, clinical biomarkers often fail to demonstrate significant differences, at least at a younger age. This puts the discussion on the table whether an already healthy vascular organ can be improved by exercise to a superhealthy level or not.Current evidence about specific aspects of exercise training, such as F-I-T-T, is limited, and exact training recommendations cannot be given. However, some practical implications can be extracted:Some vascular adaptations, such as a favorable balance of angiogenesis and angiostasis as well as of vasodilator and vasoconstrictor responsiveness, require regular exercise, ideally throughout the entire life span. Therefore, individualization of exercise according to objective and subjective factors should be sought to achieve the best possible long-term training adherence.Repeated stimuli, at least every other day at initial stages and progressively increasing to 5–7 days per week, might be necessary to use the full potential of favorable physiological alterations, such as elevated blood pressure and improved glycemic control, which last for about 24 h post exercise.The cumulative volume of elevated shear stress seems more important than peak shear stress in terms of stimulating vascular remodeling. Thus, prolonged moderate-intensity workouts may be favored over shorter sessions with very high intensities, especially if injury prevention and long-term training adherence are important.High-intensity interval training may have additional benefits in the long-term, such as increased antioxidative and metabolic capacities, and thus should also be part of vascular exercise training.Resistance and aerobic exercise induce distinct macro- and microvascular adaptations; thus, both types of exercise should be implemented in comprehensive training for optimal vascular health.


Developmental Physiology can be broadly defined as the field of science aiming to understand the physiological processes shaping a fertilized egg of a species into a well-structured and functional multi-cellular organism. Animal studies are a major part of such investigations, during which animal embryos and newly born or newly hatched animals are examined to understand complex developmental processes. At the organ level, these examinations include morphological assessments for structural analysis, and physiological assessments for functional analysis of developing organs/systems, whereas at cell/tissue level, relevant analyses are carried out with molecular biology and biochemistry assays. Precise measurement of physiological parameters is required for understanding developmental processes of specific organs and organ systems in such examinations. Even though, there is a growing interest from the Developmental Biology community for such experimental techniques, most of these applications have been developed for specialized research labs and are not readily available for other interested researchers. This Research Topic aimed to present novel experimental techniques on developing animals for adaptation of useful techniques by other researchers, advancing the field of Developmental Physiology.Danio rerio, has been a popular animal model in the field, particularly with the advantage of transparency at early stages enabling real time visualization of internal organs. As such, the Research Topic includes three zebrafish papers presenting useful experimental techniques for different applications. Messerschmidt et al. presents an elegant technique for DNA plasmid delivery to Zebrafish endocardium via poly (lactic-co-glycolic acid) (PLGA) nanoparticles injection. This nanomedicine approach was found to be non-toxic as well on zebrafish. Interfering with gene expression via plasmid delivery has been applied for the first time on zebrafish and is expected to be adapted in similar future studies with zebrafish. This study successfully demonstrated PLGA nanoparticle-mediated target delivery to upregulate Notch related genes would be a potential cardiac therapeutic approach with minimum toxic effects. The other two zebrafish papers in the Research Topic are relevant to assessment of cardiac function. Transparency of zebrafish embryos enable monitoring red blood cells (RBCs) for measuring blood flow velocities and calculation of wall shear stress acting on vessel walls. Real-time and continuous tracking of RBCs for this purpose is a significant challenge especially if multiple vessels are to be tracked simultaneously. Maung Ye et al. have established a semi-automated high-throughput fluorescent imaging system to capture the flow of RBCs in an entire zebrafish between 2- and 6-day post-fertilization (dpf) and successfully imaged as many as 50 embryos simultaneously. Similar to blood vessels, the zebrafish embryonic heart is accessible during embryonic stages for imaging and interference. This unique future enables studying whether the embryonic heart is capable of acute adaptation of electrical and mechanical activity in response to changes in mechanical load via feedback processes known as “mechano-electric coupling” and “mechano-mechanical coupling”. These processes are well defined for adult heart but are not well studied for developing hearts. Baillie et al. presents a novel approach for the in vivo study of mechano-electric and mechano-mechanical coupling in the developing zebrafish heart, where acute in vivo atrial dilation  in larval zebrafish is achieved by a controlled injection into the venous circulation, combined with optical measurement of the acute electrical (change in heart rate) and mechanical (change in stroke area) response.Traditionally, mammalian models such as mice and rats have been the most commonly used and dominant animal models in developmental biological research, for obvious reasons. Yet, non-mammalian species also provide unique advantages in such investigations on developmental processes such as ease of culture, experimentation, and access to the embryos. In recent years, we have witnessed an increased interest and new application areas for a variety of non-mammalian developmental animal models. The Zebrafish, Alser et al. introduced a new surgical approach called right atrial ligation (RAL) for inducing hemodynamic alterations in the right side of the heart and for examining its consequences. The authors concluded that RAL does not induce severe flow disturbance and ventricular abnormalities consistent with clinical findings, allowing a better understanding of the hemodynamics-driven CHD development. The avian digestive system has remarkable similarities with humans, making the chicken embryo model appropriate for such studies. Shikaya et al. present an LED light-stimulating apparatus for optogenetic control of gut movements in the chicken embryo. Gut peristalsis, recognized as a wave-like progression along the anterior-posterior gut axis, plays a pivotal role in the transportation, digestion, and absorption of ingested materials. The embryonic gut, which has not experienced ingested materials, undergoes peristalsis, offering a powerful model for studying the intrinsic mechanisms underlying gut motility. Induced artificial peristaltic waves enabled the authors to examine critical processes for gut peristalsis to explore therapeutic methodologies for peristaltic disorders.The embryonic chicken is another popular animal model for developmental studies due to close resemblance of organ systems of the species with that of human, both morphologically and physiologically. One particular such system is the cardiovascular system. The avian heart develops very similar to human heart with a four chamber four valve configuration. Throughout the years, many surgical techniques has been developed on this model enabling interference with heart development to better understand the origins of congenital heart defects (CHDs) in human. Left atrial ligation, vitelline vessel clipping, and conotruncal banding are among the most popular techniques. In the Research Topic, Gan et al. used pigs (35 days) as a model to characterize tsRNAs by sequencing in normal and IUGR porcine skeletal muscle, uncovering the role of tsRNAs in IUGR porcine skeletal muscle development, thus providing insights into the prevention and treatment of IUGR in mammals. Jiang et al. developed a new device to test the hypothesis of mutual attraction behavior between male and female crabs with mature gonads by releasing the sexual pheromone so they could be examined. A novel polygon shape device, looking like a maze, comprised a discriminating area, a transparent cover plate located at the top of the area, and an external mechanical aerating device. Using the device, authors successfully isolated Chinese mitten crabs with mature gonads hence successfully showed that, ovarian development in the experimental group was higher than in the control group and was nearly fully mature, confirming the initial hypothesis. Yan et al. developed an in vitro approach for investigating spermatophore development and its effect on metabolite support for sperm storage in honey bees, Apis cerana. Here, the authors compared the developmental processes and metabolites of seminal vesicles of drones from different parentages (0–24 days) in honeybee colonies, including mated queens, virgin queens, and worker bees. Notably, the metabolomics of the seminal vesicles in drones from mated queens showed different metabolites in each stage. Particularly, squalene identified among them was validated as a protective effect on sperm vitality for in vitro experiments.In addition to studies on mammalian and non-mammalian established animal models, there is also a large number of developmental physiological studies on non-model wild, exotic, or farm animals. Monitoring physiological processes in such species is challenging and requires applying specialized tools and techniques. The Research Topic includes three articles in that category. Intrauterine growth restriction (IUGR) in humans often manifests as poor growth and delayed intellectual development, whereas in domestic animals, it increases mortality. As a novel epigenetic regulatory molecule, tRNA-derived small RNAs (tsRNAs) are reportedly involved in many biological processes. Presenting unique experimental applications to study developmental physiological processes in developing animals, we believe this Research Topic will provide valuable insights for researchers using the animal models presented here.