Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. The considerable human, social, and economic impacts of COVID-19 have demonstrated a global lack of health system resilience, highlighting gaps in health system capacities due to fragmented approaches to health system financing, planning, and implementation. One of the key actions for ensuring equitable essential health services in all countries in normal situations as well as emergencies is through strengthening the primary healthcare (PHC) system. In the context of the unfolding pandemic, the Iranian Ministry of Health and Medical Education (MoHME) undertook a variety of strategic actions to ensure the sustainability of health services during the current health emergency and to promote health system resilience against future shocks. Right after the Alma-Ata declaration in 1978, MoHME pursued the PHC philosophy incorporating the principles within the WHO health system framework and its six building blocks. In response to the evolving pandemic, MoHME put in place several interventions to ensure the maintenance of essential health services in addition to the provision of response. Some interventions were new, informed by global experience with COVID-19, while others leveraged existing strengths within the existing health system. Those were taking a whole-of-government approach; leveraging the PHC capacity; supporting the workforce; strengthening preparedness and response; improving access to medicines, vaccines, and health products; and leveraging the health information system into the pandemic response. Health system strengthening that promotes resilience is imperative for governments as health systems are fundamental to sustainable socioeconomic development. In recognition of this, the WHO Eastern Mediterranean Regional Office (EMRO) has recently outlined regional priorities for advancing universal health coverage (UHC) and ensuring health security. Iran's approach both prior to and during the pandemic is strongly aligned with those regional priorities, which are “primary health care-oriented models; enhancing health workforce; promoting equity; enabling environment for research; improving access to countermeasures; and fostering health system resilience.”This article is part of the Research Topic ‘ The considerable human, social, and economic impacts of COVID-19 have demonstrated a global lack of health system resilience, highlighting gaps in health system capacities due to fragmented approaches to health system investment, planning, and implementation. Widespread and prolonged disruptions to essential health services were seen in virtually all countries, regardless of their income status or their level of development . There iIn the context of the unfolding pandemic, the Ministry of Health and Medical Education (MoHME) undertook a variety of strategic actions to respond to the pandemic, to ensure the sustainability of health services during the current health emergency, and to promote health system resilience against future shocks.Iran is the seventeenth largest country in the world with an area of 1.648 million square kilometers  of whichThe health system falls under the mandates of the MoHME in Iran which is responsible for the provision of health services as well as medical education, research, and health policy . Iran haThere are more than 5 million non-Iranian nationals  currently living in Iran. This is an enormous challenge for the country's health system and one, which Iran has taken seriously and systematically. The country has an established refugee health extension program through which refugee-specific CHCs (Behdasht-Sara) are constructed within refugee camps. Peer physicians and community health workers (Behbakhsh) from the refugee population, who have received training in Iran, are recruited to provide services in the camps. The United Nations High Commissioner for Refugees (UNHCR) supports the construction of specific CHCs and the recruitment of those according to the health extension program. Each refugee-specific CHC is affiliated with the nearest CHC. In addition, if a refugee attends any urban or rural CHC, they are entitled to receive the same level of public health services at no cost as Iranian residents. Peer health workers selected from the migrant population are recruited in health houses in refugee/migrant camps and serve as assistants of health staff in the PHC system. Some of these health houses are established and recruited through UNHCR support as an international partner; however, given the expanding refugee population, demand is greater than the current capacity.As of 2017, there were 981 hospitals with 129,604 ordinary beds and 8,264 adult Intensive Care Unit (ICU) beds in the country. The hospital bed-population ratio was lower compared with developed countries, and their distribution varied by geographical area.While there are two sectors for the delivery of clinical services within Iran, i.e., public and private, all public health services such as immunization, children and maternal health, mental health, etc., are provided free of charge. In the public sector, 70% of treatment service fees are covered by the national health insurance system. The MoHME operates public hospitals, both general and special ones, throughout Iran. Public hospitals are typically under the direct management of universities, while private hospitals are regulated and supervised by MoHME.The national electronic health record (EHR) system has been operating since 2007 following the Open-EHR reference model. For each patient or family who comes to CHCs, health posts and houses in urban and rural areas an EHRThe Iranian integrated disease surveillance and response system (IDSR) was established in 2016. Although called a “syndromic surveillance system” (Triple S or SSS) with its original early warning (EWAR) component based on a syndromic approach, Triple S is a broad-based four-module system including modules on early warning, case-based epidemiological surveillance, lab-based surveillance, and automated reports . It was Iran was one of the first countries to experience the rapid progression of the COVID-19 pandemic. The first peak occurred at the end of March 2020, with around 3,200 daily cases, which created a very challenging situation for the people and officials .Iran faced constraints in relation to personal protective equipment as well as hospital and laboratory equipment as a result of the global supply shortage due to the rapid and high demand exacerbated by delayed delivery timeframes at the beginning of the pandemic. Restrictions on the international transfer of payments from Iran's banking system to international banks added to this challenge.In response to the evolving pandemic, Iran put in place several interventions to ensure the maintenance of essential health services in addition to the provision of response. Some interventions were new, informed by global experience with COVID-19 while others leveraged existing strengths within the existing health system.In response to the pandemic, the government established several mechanisms to support a whole-of-government, whole-of-society approach including the National Steering Committee (NSC) of COVID-19. This committee is led by the President and as of late summer 2022, this committee continues to meet, each Saturday, with different cabinet ministers and high-ranking national authorities .Box 1Another whole-of-government mechanism called the National Committee for COVID-19 management has been established by the Ministry of Interior, which is in charge of the implementation of policies set by the NSC. All the executive officials of the counterpart ministries of the NSC are members of this committee.As of late summer 2022, when the seventh wave of the pandemic had just ended, provincial health authorities were continuing to hold weekly virtual meetings with health authorities at the national level to review the pandemic situation, discuss the challenges, exchange lessons learned, and address any issues identified  from other clinical disciplines received short-course training and were redeployed during the pandemic to provide assistance to infectious disease specialists, pulmonologists, internists, pediatricians, and ICU specialists who were on the frontline of providing care to patients with COVID-19. During the peak of the pandemic, a national database of nurses was established to enable the recruitment and redeployment of nurses across provinces.Regarding surge capacity, the workforce has been strengthened by hiring through 90-day contracts and by extending the time of the contract. In addition to this, one of the measures taken by MoHME has been the periodic assessment of health system capacity in each province, especially during the peak of pandemic waves to support the redeployment of staff. For example, when the delta wave hit the country from July till the end of September 2021, the clinical sector of some provinces was overwhelmed, using the periodic assessment to identify workforce capacity. The Ministry was able to mobilize reserve physicians and nurses to the hospitals of severely affected provinces (surge capacity) to maintain clinical services for hospitalized patients.Recognizing the serious risk of burnout among frontline healthcare workers (HCWs), Iran has followed a variety of actions to support and empower HCWs in the clinical sector including the development of a program for improving their psychosocial wellbeing, to address mental health issues and prevent burnout during COVID-19.Looking to ensure future capacity, capacity-building for online teaching was addressed in schools of Medicine and Nursing since 2020, by equipping these with the necessary infrastructure, planning, and conducting training of trainers (TOTs) courses for faculty staff. Thus, it was possible to hold online classes for the students. In addition, many webinars were held during the pandemic to support the training of the healthcare workforce and exchange experiences and learning.In late June 2022, we conducted a multisectorial multidisciplinary workshop in Tabriz city, Iran, attended by 175 stakeholders of all relevant MoHME departments, ministries, and organizations to reach a consensus and consolidate an integrated Pandemic Influenza, COVID-19, preparedness, response, and recovery plan (IPICPRP), which has also integrated acute respiratory infections with epidemic potential. The attendance rate was high (just two invitees were absent). The three back-to-back multidisciplinary workshops helped gather perspectives and feedback on the draft plan, which followed WHO recommendations , 15.The updated pandemic plan was developed in light of the COVID-19 response. In the plan, strategic actions are categorized according to four phases , and respective activities for each action with timelines, responsible agency, partners, and budget are included with the aid of extensive multidisciplinary and multisectoral deliberations.via bilateral contracts and domestic production.New strategies taken by the Global Fund and Gavi to improve service coverage and address inequities in Iran demonstrate how the partnership of international agencies can improve some building blocks of the health system and secure health system functions including better access to health commodities and integrated communicable disease surveillance. Recent reclassification as a lower-middle income country (LMIC) by the World Bank will enable Iran to benefit from Gavi support as a beneficiary of COVID-19 and other vaccines. Gavi supports Advance Market Commitment (AMC) countries, which are mostly LMIC ones. This is important to combat pandemics and epidemics and can empower the health system of many countries against health emergencies. Iran received more than 10 million doses of COVID-19 vaccines from Gavi through the COVAX mechanism as a non-AMC country. However, as of 18 December 2022, the total vaccine shots received by the Iranian population reached approximately 155 million doses,During the pandemic, the Global Fund supported the COVID-19 response by providing personal protective equipments (PPEs), RT-PCR machines, and cold-chain equipment in support of COVID-19 vaccine deployment. After the pandemic, such equipment can continue to be leveraged to support health system infrastructures and improve service delivery, especially surveillance and response functions. Therefore, these partnerships are important in achieving a more resilient health system . Also, tCOVID-19 medications and vaccines were distributed all over the country based on population size and provincial needs. The MoHME leveraged the already existing supply chain of the PHC system as shown in As sufficient vaccines became available in the summer of 2021, vaccination was expanded to include all people regardless of nationality, religion, or ethnicity. Leveraging the existing countrywide PHC including its vaccine-distribution capacity, the Iranian MoHME established roughly 1,200 mass vaccination centers in stadiums, museums, schools, and so forth as an adjunct to PHC. This enabled Iran to achieve a COVID-19 primary vaccination coverage rate of around 75% up until January 2022.In addition, Iran has developed a local production capacity for seven domestic COVID-19 vaccines, which can be regarded as one of the key lessons from the pandemic and has established the country's capacity for the production of medical countermeasures for epidemic-prone diseases. These include vaccines across different technology platforms such as protein-based, inactivated, and adenoviral vector vaccines. Local production of an mRNA-based vaccine is currently under investigation (December 2022). Efforts are ongoing to receive the WHO emergency use listing (EUL) of the locally produced vaccines with the support of Iran's Food and Drug Administration (FDA). Many clinical trials were designed and implemented in different phases on locally produced vaccinesThe current capacity can be leveraged to produce other vaccines, improve response capacities for other communicable diseases, and achieve a more resilient health system against the next health emergency. However, more support from WHO and WHO/EMRO is needed for technology transfer and assisting local producers in receiving WHO/EULs and prequalification in order to leverage currently existing capacities.Some medications for treating COVID-19 were also produced locally, and Iran produced PPE locally to overcome the shortages, which were apparent at the beginning of the pandemic.The Electronic Health Record (EHR), which was in place several years before the pandemic, was adapted to register suspected cases of COVID-19 and their contacts and to record delivered services including testing and treatments. Leveraging the existing EHR capacity, an electronic registry was added to support the national vaccination campaign against COVID-19.The syndromic surveillance system (SSS) platform was adapted by adding COVID-19 under respiratory syndromes, i.e., ILI (influenza-like illness), SARI (Severe Acute Respiratory infection), and ARI (acute respiratory infection) in addition to the differentials of acute respiratory illness previously included such as Influenza types and subtypes.Health system strengthening that promotes resilience is imperative for governments as resilient health systems are fundamental to improving, achieving, and maintaining equity in populations' health and wellbeing; responding to public health emergencies, and enabling sustainable socioeconomic development. In recognition of this, the 69th regional committee of WHO/EMRO published a technical article in September 2022 outlining regional priorities for advancing UHC and ensuring health security  by building health system resilience. These priorities include:Establishing primary healthcare-oriented models of care.Enhancing fit-for-purpose, fit-to-practice health workforce.Promoting equity and enhancing financial protection.Enabling an environment for research, innovation, and learning.Improving access to medicines, vaccines, and health products.Fostering an integrated approach in policy, planning, and investments for long-term health system resilience.Iran's approach both prior to and during the pandemic is strongly aligned with these regional priorities. For example, the IPICPRP promotes an integrated approach in preparedness, response, and recovery planning for long-term resilience while strengthening health and emergency and disaster risk management by creating platforms to tackle multi-hazards. The multisectoral national committees established to support the COVID-19 response represent a whole-of-government approach to health that strengthens emergency management. Such structures can be maintained within the recovery phase to provide a holistic government approach to health, not just during emergencies. This multisectoralism was also apparent in the development of local capacities for the delivery of PPE, medicines, and vaccines and is aligned with improving access to medicines and technologies and securing supply chains in support of emergency preparedness and response. The multiple innovative approaches applied to ensure workforce capacities including redeployment and additional training are aligned with a fit-for-practice workforce.By leveraging existing PHC capacities and infrastructure, Iran has been able to achieve, as of November 2022, a first-dose vaccination coverage of 73.8%. This rivals the figures for many developed countries such as Germany, France, and the USA with vaccination coverage of 77.74%, 80.51%, and 80.43%, respectively . With thThe MoHME is currently planning to further build on this in support of health systems resilience by applying the approach to vulnerable populations pursued with COVID-19 vaccination to routine immunization. This will involve integrating routine immunization of refugee populations to fill the gaps in TB detection rate and COVID-19 vaccination.Existing capacities in PHC and HIS were also leveraged to support the maintenance of services and to promote high uptake of COVID-19 vaccination. Disruptions to essential services were seen globally according to the 3rd report of pulse surveys, with an average decrease of 36% and 49% in communicable disease services and immunization coverage worldwide, respectively .During the COVID-19 peak, a guideline issued by the MoHME states that in case of a regular bed occupancy rate beyond 50% and ICU bed occupancy beyond 60%, the admission of patients for elective operations could be canceled by the chancellor board of the university. In the recovery phase of the pandemic, those beds have returned to routine healthcare services, e.g., devotion to elective procedures and operations .According to World Bank data, Iran's GDP per capita stood at 2,756.7 in 2020 far below that recorded for Germany, France, and the USA which reached 50,801.8, 43,518.5, and 69,287.5 respectively . When plIn spite of efforts made to integrate between different health information systems such as different EHR systems and surveillance platforms, e.g., SSS, the COVID-19 pandemic demonstrated that further work is needed in the area of integrated and interoperable health information systems to address the issue of data fragmentation.Regarding technology transfer and local vaccine production, this is a cumbersome area that needs much more support from WHO and investment from global partners. Challenges in the electronic wiring between Iranian and international banking systems to supply medical countermeasures and support technology transfer is another constraint, which negatively affects health system resilience, and those need to be addressed before the hit of the next health emergency or pandemic.The immense variety of strategic actions and activities taken by Iran in responding to the COVID-19 pandemic means that the picture we have drawn here is, inevitably, incomplete. Some of the omissions concern major initiatives, for instance, the establishment of a laboratory network of more than 500 labs with molecular diagnostics and/or viral sequencing capacities. The authors' own involvement in certain aspects of the COVID-19 response and not others is also likely to have biased the representation. Nonetheless, the article prioritized and synthesized a vast amount of evidence and experience of policy and decision-makers and academics from Iran's MoHME and leading Iranian universities and institutes. It can suggest ideas and lessons for other countries in responding to and recovering from future public health emergencies, particularly in demonstrating PHC-oriented models of care, mass vaccination centers, and building capacity in domestic vaccine production.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Primary liver cancer is the seventh-most-common cancer worldwide and the fourth-leading cause of cancer mortality. In the current era of precision medicine, the diagnosis and management of liver cancer are full of challenges and prospects. Mesoporous nanoparticles are often designed as specific carriers of drugs and imaging agents because of their special morphology and physical and chemical properties. In recent years, the design of the elemental composition and morphology of mesoporous nanoparticles have greatly improved their drug-loading efficiency, biocompatibility and biodegradability. Especially in the field of primary liver cancer, mesoporous nanoparticles have been modified as highly tumor-specific imaging contrast agents and targeting therapeutic medicine. Various generations of complexes and structures have been determined for the complicated clinical management requirements. In this review, we summarize these advanced mesoporous designs in the different diagnostic and therapeutic fields of liver cancer and discuss the relevant advantages and disadvantages of transforming applications. By comparing the material properties, drug-delivery characteristics and application methods of different kinds of mesoporous materials in liver cancer, we try to help determine the most suitable drug carriers and information media for future clinical trials. We hope to improve the fabrication of biomedical mesoporous nanoparticles and provide direct evidence for specific cancer management. Liver cancer is the sixth-most-common primary cancer and the fourth-leading cause of cancer-related mortality worldwide ,2. HepatMesoporous materials have been gradually developed as controlled drug-delivery carriers, since the discovery of their biological characteristics ,19,20,21In order to summarize the recent research on the delivery of drugs by mesoporous nanoparticles for liver cancer, we reviewed the literature on this topic and systematically summarized their points for further discussion. This systematic review mainly analyzes the properties of different mesoporous nanoparticles and the advantages and disadvantages of drug delivery from the perspective of different nanocomposites . CurrentNanoparticles that are composed of silicon oxide or other silicon derivatives as mesoporous carriers have been the most widely used drug or molecular carriers in the field of nano-therapy for liver cancer ,36,37,38Compared with other mesoporous particles, the pore size of ordered mesoporous carbon (OMC) is more uniform, and the distribution and arrangement of mesoporous carbon are more regular ,44,45,46Mesoporous bioactive glass is widely used in drug release in response to tumor microenvironment stimulation, due to its unique biodegradation properties ,49,50,51Different from the elemental composition of the above-mentioned mesoporous materials, the iron elements of iron oxide enable it to have the potential of contrast agent imaging, except for drug loading ,54,55. MMesoporous polydopamine is often used as the surface coating of nanoparticles or self-assembled into separate nanoparticles for the delivery of tumor-inhibition drugs and the transmission of biological information ,61,62. SThe traditional diagnosis of liver cancer relies on the detection of serum alpha-fetoprotein (AFP) and imaging methods such as ultrasound and magnetic resonance ,65. HoweIn addition, the accurate diagnosis of liver cancer depends on the judgment of magnetic resonance imaging ,70. In oIn addition to the development of traditional imaging and serum diagnosis methods, mesoporous materials are more important in expanding new accurate diagnosis methods for liver cancer, in the context of the development of precision medicine . CirculaThe main methods for the local treatment of liver cancer using nanomaterials include local injection or paint of nanomaterials, photothermal ablation, photodynamic therapy and transhepatic arterial chemoembolization (TACE) ,76,77. SPhotothermal therapy is considered to be a very promising method for local tumor treatment because of its effective energy conversion and local temperature increasement ,79,80,81Compared with photothermal energy conversion, Shanyou et al. used TLS11a DNA aptamer as a photocatalyst to combine with BPQDs/Pt hybrid organosilicon for photodynamic therapy of liver cancer  Figure . This stIf the location of liver cancer is not suitable for local resection and ablation, TACE is an effective treatment to inhibit the growth of liver cancer. Li et al. used periodic mesoporous organosilicon and magnetic ferric oxide nanoparticles loaded with doxorubicin as arterial embolization agents  Figure . Using CIn contrast to the local strategy, systemic therapy involves administering drugs intravenously or orally into the bloodstream ,90,91. TCompared with the improvement of gene-editing efficiency, the delivery and sustained release of chemotherapy drugs is another important development direction of mesoporous materials in the treatment of liver cancer. Xiaoqin used large-pore mesoporous silicon to achieve targeted delivery of arsenide Trioxide (ATO), which is a recognized solid tumor-treatment drug . This stImmunotherapy through systemic circulatory system has not been effectively developed in the design of mesoporous materials for liver cancer ,104,105.In recent years, with the deep understanding of the microenvironment of chronic liver inflammation, chronic liver fibrosis with multiple cell participation, inflammatory factor mediated and liver stromal cell gene mutation is one of the main etiological causes of primary liver cancer ,107,108.In addition to the above biomedical approaches, the herbal extract costunolide (COS) has also been found to be effective in inhibiting liver fibrosis. Xia et al. used pH-responsive MSNs to attach to COS, the main design concept of which was the unstable release of methacrylic acid copolymer in acidic solution . This stAyman et al. found that MSNs have significant hepatorenal toxicity, which may itself cause liver function and histological changes . The levAs a kind of superior biomaterials, mesoporous nanoparticles have been widely used in the diagnosis and treatment of liver cancer in recent years ,117,118.Although the development of mesoporous nanoparticles is very rapid, there are still some limitations and deficiencies in biological applications. The disadvantages are mainly reflected as follows: (1) Some monomer mesoporous nanoparticles such as MSNs have liver and kidney toxicity, so they cannot be directly applied to the treatment of liver cancer and other tumors. Methods must be used to reduce or neutralize the toxicity of the material. In addition, because the source and mechanism of toxicity of materials are not clear, researchers need to further think about and discover the causes of organ dysfunction. In addition, as a large number of nanoparticles accumulate in the liver, the primary site of HCC, in order for them to play a role, it is necessary to pay attention to the elemental toxicity of these mesoporous nanoparticles and the systemic toxicity caused by their aggregation. (2) Many researchers have ignored the comprehensive characterization of the properties of mesoporous materials in order to pursue comprehensive strategies of drug delivery and combination therapy. This is mainly reflected in the insufficiency of electron microscope observation, the lack of solution stability and agglomeration experiment, the lack of property verification after drug release and the limitation of in vitro verification of biological reactive oxygen species. (3) Due to the particularity of the tumor microenvironment of liver cancer, its blood supply characteristics are inconsistent with those of other malignant tumors, so the immune cells and inflammation are also different. Therefore, it is necessary for more researchers to conduct experiments on tumor models in situ of the liver, in order to draw meaningful conclusions. In fact, due to the strong nanoparticle adsorption and drug removal effect of the liver itself, many nanocarriers are often unable to accurately reach the tumor site delivery. This is also one of the main reasons for the low efficacy and drug tolerance of some new drugs in clinical development. (4) Last but not least, a large number of studies on mesoporous materials only focus on the loading and release of drugs and do not pay attention to the different physical and chemical properties and biological properties of different mesoporous materials when they are used as carriers to target tumors. This needs to be further improved in future studies.In the era of precision medicine guiding scientific research and clinical practice, the research and development of mesoporous nanoparticles is becoming more and more targeted and individually adaptable. As the context of systematic treatment tends to be microscopic and diversified, it is believed that mesoporous materials can contribute more strategies to the diagnosis and treatment of liver cancer in tissue engineering, tumor precision therapy, immunology and other fields. At the same time, in the field of real-time tumor monitoring and early screening of diseases, mesoporous nanomaterials also shoulder a great mission, so the advantages of these tasks are due to mesoporous nanomaterials’ strong ability of multi-molecule integration. In the future, the main development directions of mesoporous nanomaterials in the field of liver cancer and even cancer diagnosis and treatment may be as follows: (1) more biomimetic and biocompatible mesoporous particles as nano-drug carriers; (2) more efficient energy and image transformation to facilitate the identification of tumor regions and metastases; and (3) more precise and targeted development of new antigens and related chemical groups. In the future comprehensive diagnosis and treatment of liver cancer, it is believed that more and more mesoporous nanomaterials will be applied to clinical trials and precision medicine.


Human infertility, of both male and female origin, is often caused by the deficient response of the testis and the ovary to hormonal stimuli that govern sperm and oocyte development and fertilization. The effects of hormones and other extracellular ligands involved in these events are often mediated by G-protein-coupled receptors that employ cyclic adenosine monophosphate (cAMP) as the principal second messenger transducing the receptor-generated signal to downstream elements. This opinion article summarizes the actions of cAMP in sperm and oocyte development and fertilization, leading to therapeutic actions targeting cAMP metabolism to alleviate human male and female infertility. Despite the application of new diagnostic and therapeutic methods to deal with human infertility, there has still been a continuous increase in infertility cases over the last 10 years [After its discovery by Dr. Earl W. Sutherland in 1958, there has been accumulating evidence showing that this small hydrophilic molecule is involved in many physiological processes in a variety of cells and tissues . PrincipG-proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli from outside a cell to its interior. G-protein-coupled receptors (GPCR) constitute the largest class of cell surface receptors; GPCR genes account for 5% of the human genome .Binding of cAMP to the regulatory subunit of PKA leads to dissociation of its catalytic subunit which, in turn, phosphorylates specific serine and threonine residues on numerous target proteins, including cAMP response element (CRE) which subsequently migrates to the cell nucleus and interacts with cAMP-response element binding protein (CREB), a transcription factor involved in various intracellular processes, including proliferation, differentiation and survival. The action of CREB is regulated by cAMP-response element modulator (CREM) . The fieThe cAMP subcellular nanodomains, identified in various cell types, include those located in the plasma membrane, A-kinase anchoring proteins (AKAPs) 5, 7, 9 and 12, ezrin, mitochondria , Ras-related protein 32, peripheral-type benzodiazepine receptor–associated protein, Wiskott–Aldrich syndrome protein verprolin homologous-1, sphingosine kinase-interacting protein, mitochondrial matrix, mitocondrial-exchange protein directly activated by cAMP, mitochondrial phosphodiesterases, Golgi apparatus and centrosome  . In spitSpermatogenesis is governed by the two pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), acting on the Leydig cells and the Sertoli cells, respectively; the former is engaged in the synthesis of testosterone (T) and the latter acts in synergy with T, responsible for the production of regulatory molecules and nutrients needed for the maintenance of spermatogenesis . The facAn in-vitro study performed with samples of testicular tissue, obtained by biopsies in men with obstructive azoospermia and normal spermatogenesis, showed that the two essential effects of FSH, stimulation of germ cell differentiation and inhibition of apoptosis, can be mimicked by increasing the intracellular concentration of cAMP with the use of the cAMP phosphodiesterase inhibitor pentoxifylline .The essential role of CRE in cAMP signaling in the testes was confirmed in several experimental animal studies, showing that, in response to an increase in the intracellular concentration of cAMP, CREM regulates cAMP-responsive element (CRE)-mediated transcription through binding to CRE  and thatLike spermatogenesis, cAMP is also a central, though not the only, player in mammalian oogenesis from the time point at which ovarian follicles develop an antral cavity, become responsive to the pituitary gonadotropins FSH and LH and initiate the process of oocyte maturation . Oocyte Hence, meiotic maturation must be held back until the completion of the cytoplasmic maturation in order to allow the formation of a fully developmentally competent oocyte, and this condition is even more important in species with late MZT, such as humans, bovine animals and pigs, compared with the species with early MZT, such as rodents. cAMP signaling is intimately involved in this developmental control event. Antral follicle growth and oocyte maturation are controlled by FSH and LH, which act through the FSH receptor (FSHR) and LH receptor (LHR), respectively. As to FSHR, it displays various chemical isoforms due to both structural variations and differences in charge and functional activity . PreviouAs mentioned in The resumption of meiotic maturation is possible due to the active maturation promoting factor (MPF), a heterodimer consisting of two subunits: the regulatory cyclin B and the catalytic cyclin-dependent kinase (CDK) ,29. As tThe role of cAMP in fertilization is mainly related to changes in sperm movement and acrosome reaction, both of them closely preceding sperm entry into the oocyte. The main changes occurring in spermatozoa after ejaculation include hyperactivation, a change in sperm movement pattern required for sperm penetration of the oocyte, followed by the acrosome reaction induced by molecules present in the cumulus oophorus and the zona pellucida. cAMP is intimately involved and is indispensable for both of these key events . cAMP acTreatments targeting cAMP to assist fertilization have been used in cases of both male and female infertility.In spermatozoa, the level of cAMP is tightly and dynamically regulated by two major enzymes, the adenylyl cyclases (ACs) and the phosphodiesterases (PDEs), which catalyze, respectively, the synthesis and degradation of cAMP . Since tIn addition to the data about in vitro use of PTX, there are data suggesting that in vivo oral intake of PTX can improve human sperm motility ,45.Since the early 2000s, PTX has been used as an adjuvant treatment for women with thin endometria during their implantation window, in IVF attempts with both the patients’ own and donated ,47,48 ooIt is well known that cAMP has functions in many tissues. The ways of manipulating the level of cAMP in patients at the level of its production are currently unknown. Consequently, the only clues for therapeutic action aimed at increasing the intracellular level of cAMP are related to the control of its biodegradation. In this article, covering the roles of cAMP in the processes of spermatogenesis, oogenesis and fertilization, the current experience with the use of PTX, the inhibitor of intracellular cAMP biodegradation, is put together. New perspectives, pointing to the development of PTX analogs with more specific actions on particular cAMP targets in germ cells, are also mentioned.


Archaea have expanded the FtsZ/tubulin protein family with sequences closely related to eukaryotic tubulins. In addition, we report novel CetZ-like groups in Halobacterota and Asgardarchaeota. Investigating the C-termini of prokaryotic paralogs basal to eukaryotic tubulins, we show that archaeal CetZ, as well as the plasmidic TubZ from Firmicutes, most likely originated from archaeal FtsZ. Finally, prokaryotic tubulins are restricted to Odinarchaeaota and Prosthecobacter species, and they seem to belong to different molecular systems. However, their phylogenies suggest that they are closely related to α/β-tubulins pointing to a potential ancestrality of these eukaryotic paralogs of tubulins.The origin of the FtsZ/tubulin protein family was extremely relevant for life since these proteins are present in nearly all organisms, carrying out essential functions such as cell division or forming a major part of the cytoskeleton in eukaryotes. Therefore, investigating the early evolution of the FtsZ/tubulin protein family could reveal crucial aspects of the diversification of the three domains of life. In this study, we revisited the phylogenies of the FtsZ/tubulin protein family in an extensive prokaryotic diversity, focusing on the main evolutionary events that occurred during its evolution. We found evidence of its early origin in the last universal common ancestor since FtsZ was present in the last common ancestor of Bacteria and Archaea. In bacteria,  Members of the FtsZ/tubulin protein family are small GTPases that orchestrate essential cellular processes such as cell division in prokaryotes and eukaryotes or establishing the cytoskeleton in eukaryotes . These pdcw gene cluster; In prokaryotes, FtsZ polymerizes to form a ring in the septal region of dividing cells, recruiting and cooperating with other proteins to carry out the process of division . In BactTo provide a global overview of the evolution of the FtsZ/tubulin protein family, we reconstructed a phylogeny of representative sequences representing the diversity of subfamilies, their relationships, and their domain architecture . The FtsThe domain architecture of these proteins shows a conserved N-terminus, while the C-termini have diverged between the subfamilies: FtsZ sequences have the FtsZ_C domain, and tubulins have tubulin_C domain . Remarkably, the archaeal paralogs basal to tubulins, including CetZ, did not present any recognizable Pfam domain. These observations on the C-terminus domains suggest a dynamic evolutionary region whose evolution could clarify the relationships between the members of these protein families. This is important because the evolutionary relationships between some of these prokaryotic proteins and eukaryotic tubulins are still debated.Nitrosoarcheaum genus led to the suggestion of the archaeal origin of tubulins  since it is in nearly all Bacteria and Archaea , both fotubulins . Howevertubulins . Therefotubulins  will helIn this study, we revisit the evolutionary history of the FtsZ/tubulin protein family, focusing on the main events in its evolution: (i) the early evolution of FtsZ in Bacteria and Archaea, (ii) the origins of archaeal paralogs found basal to tubulins based on their C-termini, and (iii) the relationships between eukaryotic tubulins and prokaryotic tubulins. Addressing these conundrums, we provide evidence for the early origin and evolution of this protein family and clarify some relationships of archaeal paralogs, showing that the C-termini of CetZ and TubZ relate their origin with archaeal FtsZ.Two datasets were built, one including bacterial and archaeal FtsZs (BA reconstruction) and the other including only the bacterial sequences (B reconstruction). After removing redundancy by taxonomic classes and spurious sequences, the final multiple sequence alignments (MSAs) were treated with three different trimming methods, referred to as Manual-, BMGE-, and trimAl-gt70-trimming . Subsequently, we performed phylogenetic reconstructions using empirical models automatically selected by Modelfinder  and compIn the resulting reconstructions, most bacterial phyla show a monophyletic pattern, although the topology was sensitive to different parameters, such as taxonomic sampling, sequence redundancy threshold, and phylogenetic methods . Basal nTaking the Manual + UFBoot2 + MF reconstruction as a reference, the phylogeny was better resolved in the B reconstruction than in the BA reconstruction since the basal nodes better resolved the relationships between bacterial phyla , indicating possible subfunctionalization due to gene duplication.We then inspected the genomic association of all these prokaryotic FtsZs . The mos or MraY , which fftsZ, coding for FtsZ1 and FtsZ2, with the exception of Crenarchaeota archaea that mostly retained FtsZ2, or present divergent FtsZs branching outside of the canonical archaeal FtsZ groups  with the other CetZ-like proteins  but also weaker similarities  with FtsZ, in particular with the archaeal sequences , providing consistent support for the evolutionary relationship observed in the phylogenetic reconstructions , another one by Halobacterota , and the third one by artubulins . The intNitrososphaera korensis is associated with a potential Snf7 protein upstream, as previously observed . The latter suggests that the expression of the archaea FtsZ gene (mainly FtsZ1) is concurrent with an increase in protein biosynthesis, perhaps necessary for preparing the cell division. In contrast, peptidoglycan biosynthesis genes are nearly absent in archaea, except for a few Euryarchaeota, such as Methylobacteriales and Methylopyrales, that are able to produce peptidoglycan-like cell walls made up of pseudomurein, and whose biosynthesis has a common origin with the bacterial murein, but not necessarily reflecting an LGT from bacteria , suggesting that the duplication of FtsZ and acquisition of pseudomurein in these Euryarchaeaota orders were independent. In fact, although intradomain LGT of FtsZ can not be discarded, it is important to note that we did not detect any case of FtsZ LGT between bacteria and archaea. Therefore, this scenario of different genome landscapes around ftsZ genes is possibly a reflection of the evolutionary pressures that happened during the divergence between Bacteria and Archaea, such as the loss or acquisition of peptidoglycan biosynthesis.In this study, we investigated the early origin and diversification of the main members of the FtsZ/tubulin protein family, which was already present in the LUCA. We inferred that FtsZ was present in the LBCA and LACA, although, in the latter, FtsZ was duplicated before the diversification of the Archaea domain. The differences in the gene organization around the bacteria . NeverthOur analyses also demonstrate that the C-termini of these proteins contain enough evolutionary signals to solve their relationships. In particular, we show that the archaeal CetZ (mainly found in the Euryarchaeota supergroup) and the plasmidic TubZ (found in Firmicutes), most likely originated from archaeal FtsZ. This last observation regarding TubZ could clarify previous claims regarding the affiliation of TubZ to prokaryotic FtsZ . In contProkaryotic tubulins, such as BtubA/B and OdinTubulin, seem to be closely related to α- and β-tubulins. This could be an indication of the origin and diversification of eukaryotic tubulins from α- and β-tubulin paralogs, and consequently, the basal position of the rest of the tubulins could be the result of strong divergence due to subfunctionalization. In fact, the monophyletic branching of BtubA/B in some of our reconstructions could reflect a reminiscence of the early diversification of tubulins by gene duplications, although further analyses are required to test this assumption. Nevertheless, while prokaryotic tubulins are probably involved in different cellular processes, there is no doubt that they are similar to the ancestral eukaryotic molecular systems or complexes. Altogether, our analyses revisit the evolution of the main members of the FtsZ/tubulin protein family, providing evidence of its early origin and diversification across the three domains of life.–3; To collect homologous sequences from the tubulin/FtsZ protein family, we performed HMMSEARCH (HMMER 3.1b2)  with MAFFT v7.310 , appliedFrom these reduced datasets, we built different datasets for specific purposes: that is, focused on prokaryotic FtsZ , all tubFor the phylogenies of bacterial FtsZs , we randFor the phylogeny including FtsZ, tubulins, and others , 5, the For the phylogeny of tubulins and CetZ(–like) sequences , we manuPhylogenies were inferred using maximum-likelihood methods with IQ-TREE . We obtaTo analyze the genome contexts of the tubulin/FtsZ protein family, the DNA sequence corresponding to 10 Kb surrounding (5 kb up/downstream) each of the respective coding genes was extracted. In that fragment, genes were predicted using Prodigal , with deTo build the protein models  of the C-termini of the different proteins of interest , the sequences were aligned individually, and soft gap trimming was applied with trimAl (–gt 0.1). Then, the C-termini fragments were extracted starting from the end of the Tubulin Pfam domain (N-terminus domain). Protein models were made using HMMBUILD  and wereThe original contributions presented in this study are included in the article/DD: funding acquisition and supervision. CS-M and DS-N: investigation and formal analysis. All authors contributed to the article and approved the submitted version.


Traditional aerial manipulation systems were usually composed of rigid-link manipulators attached to an aerial platform, arising several rigidity-related issues such as difficulties of reach, compliant motion, adaptability to object’s shape and pose uncertainties, and safety of human-manipulator interactions, especially in unstructured and confined environments. To address these issues, partially compliant manipulators, composed of rigid links and compliant/flexible joints, were proposed; however, they still suffer from insufficient dexterity and maneuverability. In this article, a new set of compliant aerial manipulators is suggested. For this purpose, the concept of aerial continuum manipulation system (ACMS) is introduced, several conceptual configurations are proposed, and the functionalities of ACMSs for different applications are discussed. Then, the performances of proposed aerial manipulators are compared with conventional aerial manipulators by implementing available benchmarks in the literature. To enhance the comparison, new features with related benchmarks are presented and used for evaluation purposes. In this study, the advantages of ACMSs over their rigid-link counterparts are illustrated and the potential applications of ACMSs are suggested. The open problems such as those related to dynamic coupling and control of ACMSs are also highlighted. Owing to the advantages of UAVs, there has been a recent shift of focus to expanding their use from passively “seeing” the environment to physical (active) interactions with their surroundings, leading to the introduction of aerial manipulation systems (AMSs) . Aerial As degrees of freedoms (DOFs) of aerial manipulators are desired to increase, more rigid arms and actuators were implemented, leading to increasing the weight of conventional manipulators. To resolve this issue, several solutions were considered in the literature. Conventionally, more powerful aerial platforms like helicopters were used . HoweverAs discussed above, trade-off between DOFs and weight of conventional manipulators restricts their dexterity and maneuverability.With rigid-link arms, uncertainties related to the shape and pose (position and orientation) of the objects would readily lead to the failure of grasp and aerial manipulation tasks. Reaching challenging and hardly accessible sites also requires significant dexterity that cannot be readily achieved with traditional rigid-link arms as they may require intricate fabrication, integration, and instrumentation . Hence, To overcome the aforementioned limitations, we have proposed the new paradigm of aerial continuum manipulation in which compliant continuum robots (CRs) are integrated into aerial vehicles. CRs usually involve a continuous backbone (with infinite DOFs) enabling them to adapt their shapes readily to the shapes of the objects during grasp, and maneuver easily in crowded environments. This property also makes them a safer choice to interact with humans for collaborative tasks. Additionally, CRs come with the potential advantage of high dexterity/weight ratio, higher output force/weight ratio, and stiffness modulation . The afoIn summary, despite the desired characteristics of conventional aerial manipulators, they are still premature and accommodating nature-inspired mechanisms/designs could advance the functionality of aerial manipulators. Soft continuum robots offer all necessary features of an anticipated aerial robot for many day-to-day applications.gripper and/or manipulator level.The literature on aerial continuum manipulation has focused on implementing continuum arms in the At the gripper level, At the manipulator level, several works  have impconcentric-tube CRs as the core element of aerial continuum manipulation systems (ACMSs). Next, various configuration designs for ACMSs are given. The advantages of the proposed ACMSs over their rigid-link counterparts are provided and possible challenges are discussed. The article is dedicated to concept explanation and hence, modeling and control aspects of ACMSs are left to our future research. Finally, benchmarks are provided to compare ACMSs with their counterparts .In this article, being inspired by elephant trunks or octopus arms, we envision introducing a novel concept of continuously flexible or continuum robots for aerial manipulation. We propose tendon-driven The envisaged continuum manipulator for aerial missions should be light, fully flexible, and with the possibility of simultaneous bending and elongation for reaching hard-to-access spaces in cluttered environments. Furthermore, the manipulator is expected to perform manipulation tasks ranging from simple grasping to complicated missions. Hence, it needs to modulate its payload capacity and stiffness, on-demand, in response to the surrounding.CRs present flexible and light manipulators with a higher payload-to-weight ratio than rigid robots. The actuation type is the main parameter of determining the CRs’ payload capacity. Concerning the actuation type, continuum arms can be classified into five groups: tendon-driven, concentric tube, pneumatic, hydraulic, and magnetically actuated CRs. Tendon-driven CRs are slender continuum arms that have a reasonable payload to weight ratio. They present a compact robot structure and provide position accuracy and operation precision in constrained space. Conventional concentric-tube CRs work with pre-curved tubes and generally have a small payload capacity. The main feature of these robots is their modular design, maintaining the compactness and miniaturization of the robot. To combine the compactness of concentric tube CRs with higher payload capacities, tendon-bent concentric tube CRs have been proposed . Pneumattendon-driven concentric tube CRs are suggested for aerial manipulation. A schematic configuration of the proposed manipulator has been shown in In this study aerial continuum manipulation, the flexibility of the arm in ACMS also leads to its increased ability for recovering from anomaly conditions such as possible collisions with the environment. The continuum manipulator could easily shrink underneath the UAV when it is not in operation which increases the maneuverability of the flying platform. Furthermore, the continuum manipulators can be used as contact/force sensors during operation which is a great advantage in conducting compliant motions/precise missions where extra force sensor attachment is not feasible. These advantages are almost impossible with rigid-link aerial manipulators. Regarding cooperative arrangement, it also enables implementation of different arms’ types, according to the specified mission, offering great flexibility in design.Regarding In the following, the general framework for mathematical modeling of an ACMS consists of a tendon-driven concentric tube manipulator attached to the quadrotor has been presented.Due to the advantages such as lightweight, high mobility, and versatility, quadrotors have usually been purposed for AMSs. Accordingly, the equations of motions for the quadrotor can be describe as follows :Y˙i=gi along the backbone can accurately approximate the backbone with continuous channels. Regarding concentric-tube robots, they theoretically consist of Concerning the tendon-driven actuation, elastic backbones with In this design, as the exposed portion of each tube should be uniformly covered by the spacer disks, the number of disks and the exposed length of each section should be predetermined in the design phase. This will produce a length limitation for the whole robot. For example, for the concentric tube robot consisting of 3 tubes shown in Based on the above hypothetical design, considering the small stiffness of the springs, neglecting the friction force and looseness between the tubes , the equs and t, respectively. Also, The variables platform  to tendoplatform , robot wRegarding the length change of the tubes, as the insertion speed and acceleration occur at much smaller frequencies than the natural frequencies of the continuum robot, it is practically reasonable to assume that the insertion speed and acceleration of the tubes are relatively small, making it possible to quasi-statically model the insertion of the tube with the extension rate qins . ConcernTo sum up, the modeling method considers the insertion of the tubes as well as their bending. For this purpose, the length of the tubes will be updated based on the given quasi-static insertion rate and then the tendon tensions will bend the whole robot based on L is the total length of the CR, we would have:Aside from the equations of motion, the Boundary Conditions (BCs) have to be determined. Besides, there are other consistency conditions, maintaining the connection of quadrotor-manipulator, that needs to be satisfied during the solution. Regarding the boundary conditions, the tendon tensions produce concentrated loads and moments When it comes to the consistency conditions, the following relations need to be maintained at the proximal end of the CR, where the robot attached to the quadrotor at point A:In the following, we tailored the introduced novel concepts of ACMS for several applications. The proposed aerial platforms are expected to either simplify the mission or improve the manipulation performance.A cooperative manipulation can be achieved by 1) multiple drones each using its own CR  or 2) onThis ACMS configuration  will proCompared to a separate container, a self-container CR has reduced effects on the center-of-gravity (CoG) of the AMS, leading to a smaller form factor for aerial manipulation to maintain dynamic stability and handling. These advantages will accompany intrinsic characteristics of CRs, e.g., forming flexible postures during sampling which makes the sampling procedure easier. The benefits of this feature will be more highlighted when the self-container arm is used in a cooperative aerial manipulation arrangement, converting the ACMS to a flying lab for aerial rapid tests.Object transportation is one of the well-known applications of aerial manipulators. In this context, both robotic manipulators and single grippers have been used. With robotic manipulators of several DOFs, the stabilization of the orientation for the whole system becomes problematic. Regarding single grippers, an offset between the CoG of the aerial robot and the object is expectable which also leads to flight instability. The bigger the object is, the worse this issue persists. Another challenge will appear when the AMS is expected to grasp large objects, bigger than the gripper. For this purpose,  proposedTo address this shortcoming, a whole-body continuum aerial manipulation is proposed  in whichPractical benchmarks are crucial for evaluating the performance of any AMS including ACMSs. The introduced benchmark is an extension of the previous work  to highlGenerally, the aerial robotic manipulators need to be as light and low inertia as possible because of severe dynamic coupling with the floating base. One of the main challenges of AMSs is the CoG variation of the aerial platform due to the attachment of the aerial manipulator and, more severely, by the dynamics of the manipulator in the air. In addition to their lower weight and inertia, continuum robots, because of their flexibility, have the advantage of taking the optimal form to have minimal effects on the CoG of the flying base. They can also jam, just underneath the aerial platform, when there is no need to manipulate. It will benefit the dynamics and stability of the flying platform, at least during hovering and approach.Regarding agility, it is defined as the system’s ability to perform quick direction changes, as well as fast stops and starts . In confEnergy performance is another feature that greatly contributes to the performance and functionality of AMSs. It directly depends on the energy consumption of the AMS. The lower the energy consumption is, the higher becomes the energy performance. Lower energy consumption means longer achievable mission time/distance. Two factors highly affect the energy performance: the AMS weight and its agility. Reducing the payload will increase the energy performance. Regarding the latter factor, higher agility leads to lower energy consumption over the mission as agile manipulators will spend less time performing the given task.• Trajectory accuracy. We cannot compare robots’ structures based on this feature as it highly depends on other factors than the structure of the robot.• Positioning accuracy and repeatability. More details and information is necessary. However, more control effort is usually needed to maintain the position accuracy and repeatability of CRs .• Payload capacity. Rigid-link manipulators have a larger payload capacity than continuum manipulators. However, CRs usually provide higher payload/weight ratio than rigid-link manipulators .• Force/load estimation and control. Rigid-link manipulators would benefit from producing higher force amplitudes. However, ease of shape-based force-estimation along with lower rise time and overshoot of CRs will provide considerable advantages over their rigid-link counterparts .• Collision detection and reaction. This advantage of CRs has been clearly demonstrated in the literature .• Agility. In general, due to their links’ rigidity, conventional rigid-link robots provide superior agility, supporting rapid manipulation tasks.• Object grasping. The shape adaptability of CRs will earn a better success rate . Further• Contact force control. Compliance of CRs will reduce the contact impact on position of the aerial platform, yielding better performance with CRs .• Multirotor position control. For the same reason as above, a better performance with CRs is expected. The built-in compliance will also reduce • Jammability. The CoG deviation of CRs could be much lower than rigid-link manipulators as they can easily pack and bring up the CoG of the manipulator just beneath the aerial platform. CRs could also optimize their form to adopt minimum overall CoG deviation during manipulation. Therefore, this will translate into lower negative impacts on dynamics and stability of AMSs.• Energy performance: While continuum robots possess lower weights , rigid robots offer better agility (with less time spent for manipulation tasks), both impacting the consumed energy positively.Regarding the above features and metrics, we can compare the ACMSs with conventional rigid-link manipulators  as folloIn this article, we introduced the concept of ACMSs with variety of assemblies and applications. The focus was placed on the functionality of manipulation and the contributions of CRs into the context of aerial manipulation. Additionally, benchmarks for evaluating the performance of ACMSs were presented and the advantages of ACMSs over their conventional rigid-link counterparts were given. The introduced concept can considerably improve the aerial manipulation performance, particularly in the missions involving manipulation in confined and unstructured environments and/or interactions with humans.The presented work has opened several challenging subjects that need to be addressed in future works. Continuum nature of arms present notable challenges in coupled kinematic/dynamic modeling of the whole system. Nonlinear and coupled nature of the system dynamics along with modeling uncertainties introduce significant difficulties into free and compliant motion control design for ACMSs. Additionally, robustness to disturbances such as wind gusts are more pronounced in control and planner designs for ACMSs which are equipped with flexible and light arms. Finally, the proposed platforms might face different challenges and constraints enforced through their implementation and will also require further studies pertaining to their usability in a variety of missions.


Background: Dissociative disorders encompass loss of integration in essential functions such as memory, consciousness, perception, motor control, and identity. Nevertheless, neuroimaging studies, albeit scarce, have suggested the existence of particular brain activation patterns in patients belonging to this diagnostic category. The aim of this review is to identify the main functional neuroimaging correlates of dissociative disorders. Methods: we searched the PubMed database to identify functional neuroimaging studies conducted on subjects with a diagnosis of a dissociative disorder, following the PRISMA guidelines. In the end, we included 13 studies in this systematic review, conducted on 51 patients with dissociative identity disorder (DID), 28 subjects affected by depersonalization disorder, 24 with dissociative amnesia, and 6 with other or not specified dissociative disorders. Results: Prefrontal cortex dysfunction seems prominent. In addition, changes in the functional neural network of the caudate are related to alterations of identity state and maintenance of an altered mental status in DID. Another role in DID seems to be played by a dysfunction of the anterior cingulate gyrus. Other regions, including parietal, temporal, and insular cortices, and subcortical areas were reported to be dysfunctional in dissociative disorders. Conclusions: Prefrontal dysfunction is frequently reported in dissociative disorders. Functional changes in other cortical and subcortical areas can be correlated with these diagnoses. Further studies are needed to clarify the neurofunctional correlations of each dissociative disorder in affected patients, in order to identify better tailored treatments. Dissociation encompasses loss of integration in essential functions such as memory, consciousness, perception, motor control, and identity . AlthougIn the last four decades, neuroimaging studies have focused on dissociative disorders, suggesting the existence of particular brain activation patterns in patients belonging to this diagnostic category. These studies have shown regional cerebral blood flow (rCBF) or glucose metabolism (CMRglu) changes in the temporal, parietal (implicated in dissociative and conversion phenomena), and orbitofrontal (likely involved in the integration of the self) cortices, in the hippocampus , in the basal ganglia, and in other areas. However, they have reached different, and at times conflicting, conclusions, finding out hyperactivation of brain areas in some cases ,13,14, aEstablished models have linked dissociation with increased recruitment in regions involved in executive control ,17, suchWe hypothesized that there could be common functional changes in patients with a DSM diagnosis of dissociative disorders across different brain regions during task execution and/or during resting state, and that these alterations would match impaired performance of neurocognitive tasks. Considering the low prevalence of dissociative disorders, the low number of functional neuroimaging studies and their mostly inconsistent results, we aimed to clarify the main neural functional pattern associated with these diagnoses. This review aimed to identify alterations in functional neuroimaging techniques reports, and to correlate them with impaired neurocognitive performance and psychopathology of patients with DDs.http://www.pubmed.gov; accessed on 2 August 2022) to identify functional neuroimaging studies conducted on subjects with a diagnosis of dissociative disorder . We followed the methods of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement) [A search was conducted using the international scientific database PubMed (atement) . First, We included articles on functional neuroimaging studies in samples of patients diagnosed with dissociative disorders  according to the DSM criteria, regardless of the presence of healthy controls in the study. We excluded case reports, case studies, pharmacological trials, reviews, studies on children, studies employing techniques other than functional neuroimaging, and studies involving patients with other psychiatric diagnoses. Three reviewers screened each record and each report reviewed, and collected reported data, working independently from each other, and subsequently verifying together the appropriateness of the procedure, and proofreading the included data and results. Two reviewers independently assessed the risk of bias in each included study, considering the sample number, the inclusion/exclusion criteria of participants, the consistency of the sample, and the methods employed, and used the Scottish Intercollegiate Guidelines Network (SIGN) quality assessment tool . We did Based on these criteria, we analyzed 61 studies, from which we excluded 48 studies, of which 26 were unrelated to the subject, 6 were case reports/case studies ,25,26,27The main study outcomes for which data were sought were changes in neural cortical and subcortical activation patterns and changes in neural metabolism correlated with the diagnosis of a dissociative disorder and/or with symptom severity in patients with a dissociative disorder.The potential methodological quality of the study and risk of bias were examined through the SIGN quality assessment tool . All stuWe summarized the search procedure in The most prominent functional changes have been found across the limbic system of subjects, mostly when they performed particular tasks whose execution may be affected by the disease.Different functional neuroimaging studies were based on the Theory of Structural Dissociation of the Personality in DID, according to which patients retain traumatic memories fixed in the emotional part (EP), while some personality parts are apparently normal (ANP), in order to mentally avoid traumatic memories . The EP DPD patients have also shown anomalies in the neural function of some parts of the paralimbic system. The right anterior cingulate cortex (ACC) hyperactivates during face processing (self vs. stranger), which has been interpreted as a correlate of conflict between the conscious and unconscious aspects of self-processing in DPD . It has Changes in frontal and prefrontal cortices are an important finding of the review, and they particularly correlate with specific tasks or states of identity explained below.DID patients showed hyperactivation of the prefrontal cortex during resting state, particularly in the dorsomedial area, and other areas of the default mode network (DMN), in comparison with healthy controls (actors) . This suA PET study has shown reduced resting state metabolism of the right inferolateral prefrontal cortex in patients with autobiographical memory loss due to dissociative amnesia, compared with healthy controls . This reDuring an identity traumatic state in patients affected by DID, a reduced activation of the ventromedial prefrontal cortex and left frontal pole has been observed at fMRI during an n-back working memory task . In addiOther prefrontal areas  have been found to hyperactivate during verbal working memory tasks in patients with DID or not specified dissociative disorder, when compared to healthy controls, and the same seems to happen in the left parietal lobe . The samVarious studies have also confirmed the presence of neurofunctional changes in the prefrontal cortex of DPD patients. In fact, during face processing (self vs. stranger faces), these patients had hyperactivation of the bilateral medial prefrontal cortices (PFCs) and left middle frontal gyrus (MFG), as well as the right anterior cingulate cortex ,49. SeveIn addition to what has already been underlined above, other scattered cortical areas seem to undergo changes in dissociative disorders.The left occipito-temporal junction was hyperactivated in the EP parts of DID patients, compared to the EP of controls, correlating with the role of this part of the cortex in face-sensitivity . In addiChanges in subcortical activation patterns have been found in dissociative disorder cases, mostly in the thalamic regions.Compared to the EP part of controls , those of DID patients, when showed neutral human faces, had a hyperactivation in the brainstem area, in correlation with clinical aspects of DID, for example hyperarousal .The ANP of DID patients, compared to the EP, showed bilateral thalamus hyperactivation during resting state, and the same happens in healthy controls simulating ANP compared to when they simulate EP . This fiThe main limitation of this systematic review are related to the small number of functional neuroimaging studies in dissociative disorders. Because of this we have focused on the entire spectrum of dissociative disorders, and for this reason the eligibility criteria were heterogeneous. Another limitation is the use of only one database (PubMed), although we performed a further search by examining the bibliographies of relevant articles. The results of our systematic review should be taken with caution, since most of the included studies had samples with less than 45 patients, which may involve a significant risk of bias ; furtherIn conclusion, few functional neuroimaging studies currently concentrate on dissociative disorders. Nevertheless, it is possible to underline some consistent evidence on the cerebral functioning correlates of these diseases. Prefrontal cortex dysfunction seems prominent and can correlate with both traumatic identity states and neutral identity states in DID, and with the phenomena of depersonalization in DPD. In addition, changes in the functional neural network of the caudate were related to alterations of identity state and maintenance of an altered mental status in DID patients. Another role in DID seems to be played by a dysfunction of the anterior cingulate gyrus. Other areas involved in proprioception, interoception, self-awareness, and theory of mind, including parietal, temporal, and insular cortices, were reported to be dysfunctional in dissociative disorders. Further studies are needed to clarify the neurofunctional correlates of single dissociative disorders in affected patients, in order to identify better tailored treatments.