Crtc1 knockout mouse model of depression. The putative role of CRTC1 in the alteration of brain energy homeostasis observed in depression is also discussed. Finally, we highlight rodent and human studies supporting the critical involvement of CRTC1 in depression-associated obesity.Depression and obesity are major public health concerns, and there is mounting evidence that they share etiopathophysiological mechanisms. The neurobiological pathways involved in both mood and energy balance regulation are complex, multifactorial and still incompletely understood. As a coactivator of the pleiotropic transcription factor cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 1 (CRTC1) has recently emerged as a novel regulator of neuronal plasticity and brain functions, while CRTC1 dysfunction has been associated with neurodegenerative and psychiatric diseases. This review focuses on recent evidence emphasizing the critical role of CRTC1 in the neurobiology of depression and comorbid obesity. We discuss the role of CRTC1 downregulation in mediating chronic stress-induced depressive-like behaviors, and antidepressant response in the light of the previously characterized  N-methyl-D-aspartate (NMDA) receptor blocker ketamine  obesity, which is the main risk factor for metabolic syndrome . ClinicaBDNF) are critically involved in the concept of altered neuroplasticity in MDD   that would be corrected by antidepressants. However, current antidepressants require weeks of treatment to produce a clinical response, which suggests that their effects do not only rely on enhanced monoamines transmission, but rather to long-term changes in monoamines signaling and neuronal circuitry. Therefore, research efforts have been focusing on the long-term molecular changes that underlie depression and antidepressant treatments, and led to the neurotrophic and network hypotheses of depression, which proposed that impaired mechanisms of neuroplasticity are a core pathophysiological feature of MDD. Neuroplasticity is a fundamental mechanism of neuronal adaptation involving several forms of plasticity, such as adult hippocampal neurogenesis, neuronal survival and maturation, synaptogenesis, and structural plasticity . Decreased neuroplasticity in the hippocampus and prefrontal cortex, and the resulting problems in information processing within relevant neural networks might thus underlie mood disorders . Indeed,y in MDD . Moreovey in MDD . BDNF an (CRTC1) . Recent  (CRTC1) . This reThe CRTC family includes three members in mammals, with CRTC2 and CRTC3 expressed in most tissues, and CRTC1 mainly found in the brain . SeveralDe facto, the N-terminal domain of CRTCs interacts with the dimerization and DNA-binding bZIP domain of CREB in a phosphorylation-independent manner. Once recruited to gene promoters, CRTCs strongly activate CREB-mediated transcription through their C-terminal transactivation domain. CREB is nonetheless not constitutively activated by CRTCs, as their phosphorylation state regulates their cytoplasmic versus nuclear localization (2+-dependent protein phosphatase 2B (PP2B)/calcineurin leading to their dissociation from 14–3–3 proteins and subsequent nuclear translocation. Coincidently, increased cAMP levels stimulate calcium-mediated dephosphorylation by inhibiting salt-inducible kinases (SIKs) that phosphorylate CRTCs  and in the repeated open-space forced swim test (OSFST), social withdrawal, decreased sexual motivation, psychomotor retardation, and increased emotional response to stressful events , which suggests that CRTC1 is required for conventional antidepressant therapy  inhibitor suberoylanilide hydroxamic acid  partially rescues the depressive-like behavior of –/–Crtc1 mice and restores Bdnf expression in the prefrontal cortex -mediated overexpression of SIK2 in the hippocampus of non-stressed mice induces depressive-like behaviors in the FST, tail suspension test, sucrose preference test, and social interaction test, thus mimicking the effects of chronic stress. Hippocampal SIK2 overexpression lowers nuclear and total CRTC1 levels, downregulates BDNF and its signaling cascade, and decreases adult hippocampal neurogenesis. Conversely, AAV-short hairpin RNA (shRNA)-mediated knockdown of hippocampal SIK2 or genetic knockout of Sik2 protect mice against both chronic stress models of depression with antidepressant-like effects that require the downstream CRTC1-CREB-BDNF pathway. Finally, fluoxetine, venlafaxine and mirtazapine, belonging to three different antidepressant classes, all reverse the effects of CUMS and CSDS on hippocampal SIK2 and CRTC1, and their antidepressant actions are fully abolished by hippocampal CRTC1 silencing. Two follow-up studies from the same laboratory then showed that the antidepressant effects of imipramine depend on CRTC1 in the medial prefrontal cortex -induced depressive-like behaviors . Systemi–/–Crtc1 mice  in the FST paradigm  in psychiatric cohorts and in individuals with MDD  with obesity markers in the general population. To our knowledge, this association was first studied by CRTC1 SNP rs6510997  with BMI, weight or waist circumference in the general population. Similarly, CRTC1 locus did not reach genome-wide significance for BMI in the study of CRTC1 SNP rs757318 was found, for the first time, to be associated with Body Fat percentage (BF%) and BMI in a genome-wide association study (GWAS) aiming at establishing a link between adiposity and cardiometabolic disease risk  complicate the interpretation of these GWAS studies. Moreover, due to the lack of knowledge about the biological effect of the tested SNPs on CRTC1’s function in humans (enhancement or decrease of CRTC1 activity in the brain), it is difficult to know whether the sex difference in energy balance regulation observed in –/–Crtc1 mice is a specific feature of rodents.Several human studies evaluated the association of ase risk . This stpression . Taken t–/–Crtc1 mice exhibited hyperphagia and body weight gain from early adult age with consequent development of obesity. The obese state of these mutant mice was also accompanied by reduced locomotor activity, lower energy expenditure and impaired sensitivity to leptin and insulin. However, it should be emphasized that there are gender differences regarding the vulnerability to develop obesity in this mouse model. Indeed, we showed that –/–Crtc1 females are not hyperphagic and are less prone to gain weight as compared to mutant males, whose hyperphagia appears to be related to altered circadian locomotor activity  mouse models should greatly help to decipher the specific role of CRTC1 in various brain regions and cell types. To date, there has been only one article reporting the use of a Crtc1 cKO mouse model  is of particular importance for the suppression of food consumption, as it mediates leptin activity in the hypothalamus. In line with these molecular interactions, obese leptin-deficient ob/ob mice have a lower expression of Cart in the hypothalamus, and peripheral leptin injection normalizes hypothalamic CART peptide levels in these obese mice  mRNA expression and lower Cart transcription in the arcuate nucleus of obese –/–Crtc1 mice. Conversely, younger hyperphagic but not obese –/–Crtc1 mice that are still leptin-sensitive, show comparable number of phospho-STAT3 positive cells in the arcuate nucleus after leptin infusion and similar leptin receptor (LepRb) and Cart mRNA levels as compared to lean wild-type mice , whereas BDNF depletion in the VTA affects the reward function of the mesolimbic dopamine system and leads to excessive intake of palatable HFF, but not of standard chow, and to increased body weight under HFF conditions  that prevents the regular activity of the receptor was identified in patients exhibiting overweight and severe obesity , which impedes the correct secretion and signaling of BDNF, was correlated with obesity predisposition in children and adolescents . This gene controls food intake in the arcuate nucleus by integrating leptin and glucocorticoid signaling  from inappropriate phase shifting caused not only by exposure to sudden changes in light intensity during the night, but also by abnormal Zeitgeber stimuli  that are all known to affect its resetting. Because the SCN master clock controls the other clocks located in other brain regions and in peripheral organs, an abrupt shift of the SCN clock would severely compromise normal physiological functions of the organism [see discussion in Drosophila showed that CRTC mutation affects the circadian oscillation of clock genes expression producing a phase delay especially in PERIOD and TIMLESS proteins. This work highlights that the interaction between CRTC homologs and the circadian clock machinery has likely an ancestral origin and selectively evolved among different species  in humans severely increases the risk for developing both psychiatric and metabolic diseases . Accordi obesity . Many en obesity . It is lCN cells . This hy the SCN . In line the SCN . More re the SCN . This ef the SCN . Besides the SCN . Moreove the SCN . In the  species .in vivo and the consequent effect on the circadian energy homeostasis are not completely understood, the behavioral observation of –/–Crtc1 mice suggested that the obesity of mutant males is due to overeating during the resting phase of the light cycle and to circadian alteration of spontaneous locomotor activity  in psychiatric cohorts and in the general population (This review highlighted the increasing evidence of the pivotal role of the transcription coactivator CRTC1 in MDD and comorbid obesity. Mice lacking CRTC1 exhibit depressive-like endophenotypes ,b and anpulation . HoweverRecent reports highlighted the instrumental role of ventral hippocampal CRTC1 in mediating chronic stress- and LPS-induced depressive-like behaviors, and antidepressant response in mice . Jiang BCR, AC, LG, and J-RC drafted and edited the manuscript. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Schizosaccharomyces pombe, revealing how chromosomes, cytoskeleton, and cell cycle progression are organized and particularly how these are differentiated in mitosis and meiosis. These studies illuminate that meiosis is strategically designed to fulfill two missions: faithful segregation of genetic materials and production of genetic diversity in descendants through elaboration by meiosis-specific factors in collaboration with general factors.Meiosis is a specialized style of cell division conserved in eukaryotes, particularly designed for the production of gametes. A huge number of studies to date have demonstrated how chromosomes behave and how meiotic events are controlled. Yeast substantially contributed to the understanding of the molecular mechanisms of meiosis in the past decades. Recently, evidence began to accumulate to draw a perspective landscape showing that chromosomes and microtubules are mutually influenced: microtubules regulate chromosomes, whereas chromosomes also regulate microtubule behaviors. Here we focus on lessons from recent advancement in genetical and cytological studies of the fission yeast  Eukaryotic cells undergo two styles of cell division. Mitosis is a type of cell division for somatic cells and for the asexual reproduction of unicellular eukaryotic cells. Meiosis is the type of cell division for the production of gametes in sexual reproduction. How mitosis and meiosis are differentially designed and conducted is a long-standing key question in the field of cell biology. Yeast cells undergo both types of divisions that can be switched according to environmental conditions, and therefore yeast cells have been studied to reveal underlying molecular mechanisms. In the last few decades, a considerable number of studies revealed that cells exploit meiosis-specific factors to shift the division style from the standard mitotic one to the specialized meiotic one. We, in this review, focus on how such meiosis-specific factors dramatically modulate the way of divisions, featuring fission yeast as an example.SMC1 and Psm3SMC3, kleisin/Rad21, and HEAT repeat Psc3SCC3.As one of the most evident and essential differences in mitosis and meiosis is configuration of chromosomes, we briefly give an overview on how chromosomes differ in those divisions. In both divisions, chromosomes are duplicated in the S phase of the cell cycle, resulting in forming a pair of the replicated chromosomes defined as sister chromatids . During The molecular basis constituting meiosis-specific chromosome configuration is largely attributed to meiotic cohesin, in which kleisin subunit Rad21 is replaced by Rec8 . Rec8 isThe kinetochore is assembled at the centromere of a chromosome, which serves as a dock site for spindle microtubule emanated from the spindle pole . In mitoIn mitosis, sister kinetochores built on core centromeres of sister chromatids are oppositely oriented in a back-to-back manner  cells lose Rec8 at centromeres as a result. Thus, meiotic kinetochore protein Meikin constitutes the mono-orientation of sister kinetochores as well as protects meiotic cohesin at centromeres through the recruitment of shugoshin. Shugoshin recruits PP2A to counteract the phosphorylation of the kleisin subunit of the cohesin complex to prevent cleavage (In the absence of Moa1 (or Meikin), localization of the Shugoshin protein (Sgo1 in fission yeast meiosis and SGO2 or SGOL2 in mouse meiosis) diminished . As shugcleavage .via Polo kinase. Polo kinase is one of the mitotic kinases which mainly localize to spindle poles  , and it brings all the telomeres toward SPBs by sliding along the nuclear envelope using the cytoplasmic microtubules tethered at SPBs. The LINC complex in  (Ssm4)] .Saccharomyces cerevisiae) or microtubule  plays functions in the reorganization of chromosome states into the telomere-led bouquet arrangement , SPBs are fragmented, which results in defective spindles such as monopolar and multipolar ones  tend to lose CENP-A (the centromere-specific variant of histone H3) and Swi6 [the heterochromatin protein 1 (HP1) ortholog] at centromeres, indicating that the telomere bouquet is required for the maintenance of heterochromatin during meiosis  at SPBs at the later stage of meiotic prophase . BouquetFurther investigation to address the biological meaning of telomere bouquet, except for pairing of homologous chromosomes, will clarify how the conserved chromosomes’ behavior functions for the production of gametes.Another essential phenomenon seen during the initial stage of meiotic events is reorganization of kinetochore and SPB components.In fission yeast, most of the kinetochore components, including both inner and outer factors, stably constitute kinetochores throughout the mitotic cell cycle. There are only few exceptions: the Dam1 complex is a mitosis-specific kinetochore component, while the Mis18 complex disappears in mitosis . Componevia the mating pheromone–MAPK pathway in the early stage of meiosis is responsible for the disappearance of the kinetochore components. A reason for making slim kinetochores is for the detachment of centromeres from SPBs  are located close to SPBs in the interphase of the mitotic cell cycle . This alThe SPBs, duplicated in interphase, are separated from each other on the surface of the nucleus, as microtubules emanated from each of the SPBs start to overlap and interdigitate upon mitotic entry . FinallyOn the contrary, in cells entering meiosis I, positioning of chromosomes is completely upside-down as a result of centromere dissociation and telomere clustering. In addition, chromosomes are duplicated as sister chromatids, and homologous chromosomes are paired with chiasmata as a result of meiotic recombination during the horse-tail nuclear movement, as illustrated in When cells enter meiosis I, the horse-tail nuclear movement ceases, and microtubules are nucleated from SPBs toward inside the nucleus as observed at mitotic entry. In contrast to mitotic entry, meiotic cells, at this stage, start to nucleate an extensive radial array of microtubules from SPBs .The extended microtubules then capture kinetochores scattered in the nucleus and then shrink to retrieve the attached kinetochores toward SPBs . The retWhen homologous kinetochores are captured and pulled by microtubules, the mode of attachment may be mostly monopolar, the state in which both kinetochores are pulled by microtubules emanated from the same spindle pole. This may be resolved by Aurora B kinase, as budding yeast meiotic kinetochores retrieved in a monopolar manner are converted to bipolar attachment through phosphorylation by the Aurora B kinase Ipl1 . The kinDuring retrieval of kinetochores by pivoting monopolar microtubules, formation of the bipolar spindle (separation of two SPBs) should be repressed, although the system that surveys the completion of the scattered kinetochores does not appear very strict, as occasionally bipolar spindle starts to assemble even before the completion of kinetochore retrieval . At leasRegarding regulation of SPB separation, a meiosis-specific telomere-associated protein, Ndj1, is known to localize to SPBs together with Mps3 (a SUN-domain protein) in budding yeast meiosis to suppress the premature separation of SPBs , 2017. PIn summary, the extensive microtubules are assembled to relocate chromosomes to the original position as seen in mitotic entry, thereby minimizing the potential risk of segregation errors in meiosis I.S. pombe ortholog of the microtubule-associated protein transforming acidic coiled-coil protein (TACC) for this purpose. Alp7 primarily localizes to SPBs and microtubules. Alp7 also localizes to mitotic kinetochores once captured by spindle microtubules, which means that Alp7 is delivered to kinetochores by microtubules and stabilizes kinetochore–microtubule attachment in mitosis , the  mitosis . Althoug mitosis . Alp7 pr mitosis .Thus, cells employ two machineries—extension of radial microtubules and precious localization of Alp7 to kinetochores— to synergistically promote relocation of chromosomes. Do these machineries operate also during mitosis or only during meiosis? The radial array of microtubules is not evident in cells at mitotic onset, in which kinetochores are constantly located in the vicinity of SPBs. When kinetochores are artificially detached from SPBs upon entry into mitosis, for example, by the use of transient exposure to microtubule poisons, similar long microtubules are assembled after drug washout to capture and collect the scattered kinetochores. Thus, the machinery utilizing extending microtubules may also operate during mitosis as a backup system to respond to the unexpected risk, although it has not been clarified if the molecular mechanisms for microtubule extension are identical in mitosis and in meiosis. Alternatively, either SPB separation or maturation in meiosis I could be repressed by slim SPBs during meiotic prophase to efficiently form a radial microtubule array.In meiosis, however, extension of microtubules is observed in cells at the stage without exception, and the microtubules complete kinetochore retrieval mostly by the time SPBs start to separate , suggestAs mentioned above, Plo1 localizes to pre-attached kinetochores using Moa1 (Meikin) as a platform; therefore, Alp7 localization to the kinetochores is also a meiosis-specific event. Taken together, we consider that Moa1–Plo1 plays the third function in meiosis—at the onset of meiosis I, kinetochores are highlighted as center for microtubule control: Moa1 (Meikin) recruits Plo1 (Polo kinase), which deposits Alp7 (TACC) to stably capture microtubules emanated radially from spindle poles.Moa1–Plo1 has an additional role: Plo1 at meiotic kinetochores also phosphorylates Spc7 (KNL1) of the outer kinetochore components. This affects the localization of Bub1 kinase which is known as a checkpoint kinase and phosphorylates histone H2A to recruit shugoshin at centromeres . In mitoThus, Moa1–Plo1 plays a central role to dictate a number of meiosis-specific events regarding the interaction of kinetochores and microtubules, thereby differentiating meiosis from mitosis.The progression of kinetochore–microtubule association is monitored by the spindle assembly checkpoint (SAC) machinery in mitosis and meiosis. Briefly, kinetochores unattached to microtubules are recognized by the Mad1–Mad2 complex, the main components of SAC. When chromosomes are repositioned at the onset of meiosis I, the unattached kinetochores are not recognized by Mad1–Mad2. This is probably due to a lack of sufficient CDK activity, which is a prerequisite for the localization of Mad1–Mad2 to unattached kinetochores .For an entire resolution of the bouquet arrangement, telomeres that have been clustered around SPBs during meiotic prophase are detached from SPBs upon entry , althougIt has been recently shown that difference in chromosome configuration in mitosis and meiosis affects bipolar spindle organization using their kinetic properties.The assembly of bipolar spindle is based on the elongation of microtubules and their mutual and physical interaction. Spindle microtubules are emanated from both of the two SPBs, and they interact with each other to separate the SPBs outward, which is the major driving force for bipolar spindle formation.As illustrated in On the contrary, members belonging to another subfamily kinesin-14 (Pkl1 and Klp2) are minus-end-directed and generate inward forces for SPBs . Pkl1 prcut7Δ) is lethal with an adjacent pair of SPBs, which extend the monopolar spindle therefrom. The lethality of cut7Δ and cut7-ts (temperature sensitive) mutants is suppressed by a simultaneous knock-out of pkl1 , which is known to connect a pair of interdigitating microtubules as an anti-parallel bundle . This in mitosis , and mic mitosis . Similar mitosis .cut7Δ pkl1Δ mitosis . Moreover, when the sister kinetochores are unfastened by reduction of centromeric cohesion using deletion of Swi6 (HP1)  , the outi6 (HP1) . These rcut7Δ pkl1Δ cells are not able to separate SPBs in meiosis I (cut7Δ pkl1Δ moa1Δ cells), SPBs are separated  or CENP-L, is depleted, separation of centrosomes is delayed albeit partially, and this is due to defects in the formation of kinetochore microtubules (kinetochore fibers or k-fibers) .There are two major pathways for centrosome separation in HeLa mitosis: the aurora A-dependent pathway, which is presumably for centrosomal microtubule-mediated separation, and the kinetochore-dependent pathway . The kinWhen the nuclear envelope breakdown precedes centrosome separation in prometaphase, lateral attachment and kinetochores to microtubules and their lateral transport are promoted to form a ring-like alignment of chromosomes, called prometaphase rosette . The proDuring acentrosomal meiosis I of mouse oocytes, the Ndc80 complex of outer kinetochores accumulate the microtubule crosslinker Prc1 (yeast Ase1) to kinetochores, which becomes a center for microtubule bundling to assemble the functional bipolar spindle even without positional cues at spindle poles . Thus, tAs mentioned above, the SAC machinery monitors the state of kinetochore–microtubule interaction, and in the case of problems, SAC arrests cell cycle progression in metaphase. SAC detects two types of erroneous interactions: an improper attachment and a lack of tension between kinetochores . The oveskp1-ts), the anaphase spindle becomes abnormally bent in the nucleus, both in mitotic and meiotic anaphase  complex. SCF constitutes a conserved ubiquitin ligase family and contributes a number of cellular phenomena, and the fission yeast orthologs of the components are Skp1, Cul1, and at least 18 F-box proteins [reviewed in anaphase .The bend spindle in anaphase I is due to unresolved meiotic recombination intermediates that remained until anaphase as evidenced by the prolonged foci of Rad51 (the RecA homolog) indicating sites of meiotic recombination . When meIn conclusion, Skp1 and the F-box helicase Fbh1 are required for the resolution of meiotic recombination intermediates, although it remains to be elucidated which protein is targeted by SCF-Skp1–Fbh1 for degradation for the resolution .Arabidopsis ask1 mutant (Ask1 is the Skp1 ortholog) has the spindle which displays an overall normal structure but somewhat longer than that of WT cells during meiosis I  and meiosis II (MII) without replicating DNAs, which is a clear contrast to the single M phase per cell cycle in mitotically growing cells. The interval between MI and MII is called the interkinesis period.cdc2/tws1 mutant cannot enter meiosis II, and terminates meiosis with the formation of the spore wall    containsl spores .mes1 mutant has been isolated as a mes (meiosis second) mutant defective in meiosis II, although the mes1 mutant does not display the spore wall unlike cdc2/tws1  (The dc2/tws1 . The mes (APC/C) , the meg (APC/C) .The APC/C is, in general, activated by the coactivator Cdc20 (Slp1 in fission yeast) both in mitosis and meiosis, but in meiosis, Fzr1  also assists the activation of APC/C . In WT mmes1Δ), APC/C is prematurely activated by Fzr1 in anaphase I, which terminates meiosis early, right after anaphase I, without initiating meiosis II  functions twice, namely, at meiosis I and II. The activity of SAC during two sequential divisions may be regulated in a continuous manner. When the first division is delayed by SAC, the anaphase onset of meiosis II is advanced, which means that the SAC effect was reduced at meiosis II to compensate the previous delay that occurred in meiosis I .In conclusion, the number of meiotic divisions is exclusively determined as two, neither one nor three. This biological rule strictly conserved and complied among eukaryotes is defined by the repetitive battles of the “CDK–APC/C derby”, which is reinforced by meiosis-specific factors Mes1 and Fzr1.S. pombe Mes1 are OSD1 in plants and Erp1/Emi2 in vertebrates  is also an APC/C inhibitor, which ensures initiation of meiosis II together with TAM , and the tam osd1 double mutant cannot initiate meiosis II (Arabidopsis TDM1/MS5 (THREE DIVISION MUTANT 1/MALE STERILE 5) is the functional homolog of Fzr1 and is required for exit from meiosis. The tdm1/ms5 mutant exhibits the aberrant third meiosis similar to the S. pombe fzr1Δ mutant . Both karyotes , but in karyotes . In anapkaryotes .spo gene mutants, which are involved in the assembly of the forespore membrane. When the nuclear envelope expands in anaphase II, the lipid components constituting the nuclear envelope may be in a shortage because the components may need to be preferentially used for the assembly of the forespore membrane. This idea is based on the fact that vNEBD does not occur when the vesicle transport pathway that conveys membrane components from Golgi to endoplasmic reticulum is inhibited by a drug  is expected to localize constantly to the cytoplasm to govern the Ran GTPase-dependent nucleocytoplasmic transport. The aberrant nuclear entry of RanGAP indicates that the nucleocytoplasmic transport is invalidated during meiosis II. Even when the nuclear envelope seemingly persists as in closed meiosis II, the nuclear conditions can be temporarily neutralized as is seen in open mitosis of higher eukaryotes.Interestingly, vNEBD accompanies nuclear entry of the cytoplasmic RanGAP protein , 2011. RThe biological roles of vNEBD had been undefined, but recently it was shown to promote the maturation of spores through redistribution of the nuclear proteasome subunit Rpn11 to the cytoplasm . This meFurther studies will illuminate the molecular mechanisms to trigger vNEBD as well as the biological significance of the phenomenon. As the interplay between the nuclear envelope and the genome contributes to the determination of cell fate [reviewed in Another unexpected aspect of sporulation events is the effect of the forespore membrane on the spindle of meiosis II.In general, the spindle comprises three types of microtubules: kinetochore microtubules  as mentioned earlier see , interpospo15 mutant lacking meiosis II-specific SPB modification as well as in the meu14Δ spn6Δ double mutant, showing the disorganized forespore membrane by depletion of both LEP and septin structures  are exposed to microtubule poisons. It is also possible that a constant increase of the nuclear membrane components, which are supposed to be used for nuclear elongation in anaphase, caused an abundance in surplus in the absence of spindle elongation, resulting in aberrant nuclear fission  might have evolved from other topoisomerase genes as a copy specific for homolog pairing in meiosis, and this could be a key incident to acquire meiotic recombination and the following reductional division in meiosis I.The evolutionary origin of meiosis has been discussed from the viewpoint of the phenomena for a long period, and one of the most reasonable ideas must be that meiosis was evolved from mitosis . AlthougThe meiotic cohesin Rec8 could likewise be originated from a duplicated copy of the mitotic cohesin Rad21. Fzr1, a meiosis-specific activator of APC/C, might have evolved from the mitotic one Slp1 (Cdc20). Those key factors might have defined the outline of meiosis as a newly acquired division system. In addition to those copied genes, meiosis-specific genes whose ancestors are currently unknown are also created to fine-tune meiotic events to the current state.per se is common among eukaryotes. The molecular mechanisms are thought to be fine-tuned in each organism depending on internal and external reasons such as the lifestyle and surrounding environment. Considering similarities and differences among species and in between two types of divisions, we will be able to converge the divergent mechanisms to explore the ultimate origin in the future.On the other hand, we also know that molecules or detailed molecular mechanisms in meiosis have been differentiated depending on species, although the whole system of meiosis MS conceived the framework of the entire manuscript. MS, YK, and MT wrote the manuscript. MS prepared the figures. All the authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Globally, most young women have an unmet need for sexual and reproductive health (SRH), which remains a public health concern. Identifying the predictors can help reduce this challenge.This scoping review maps evidence on predictors of adverse sexual and reproductive health outcomes among young women in South Africa.Askey and O’Malley’s framework guided this review. We searched five databases from January 2000 to December 2020 using relevant keywords, Boolean terms and medical subject heading terms. All relevant extracted data were organised into the study themes, and summary of all the findings were reported in a narrative format.Nine studies met the inclusion criteria out of 1219 studies identified. Four out of the nine studies were national-based studies, while the remaining five studies were conducted in Western Cape (two), Eastern Cape (two) and KwaZulu-Natal (one). Out of the nine studies included, three reported predictors of unintended pregnancy, while six reported predictors of sexually transmitted infections and HIV among young women in South Africa. The most prevailing predictors of adverse sexual and reproductive health outcomes were gender-based violence and alcohol use, while other predictors were lower socio-economic status, place of residence, multiple sexual partnerships, low education and being between the ages of 20–24 years.We conclude that gender-based violence and alcohol abuse are the most prevailing predictors of adverse sexual and reproductive health outcomes among young women in South Africa. The results from this review will give an account of the prevailing factors predicting adverse sexual and reproductive health outcomes in terms of unintended pregnancy and STIs/HIV among young women in South Africa. Additionally, the result could also shape the direction of the national policymakers in developing targeted interventions that will address the adverse sexual and reproductive health outcomes among young women in South Africa, as no study in South Africa has been able to underscore this.36 in designing this study, and we followed the checklist of Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews (PRISMA-ScR) to report this study’s findings.31We adopted the Arksey and O’Malley guidelines methodological frameworksThis study research question was: ‘What the predictors of adverse sexual and reproductive health outcomes, including unintended pregnancy, STIs/HIV among young women aged 15–24 in South Africa are?’30.The eligibility criteria for potential articles to address the research question were determined using the population concept context (PCC) framework, as depicted in Table 1We searched for publications on predictors of adverse sexual and reproductive health outcomes in terms of unintended pregnancy and STIs/HIV among young women in South Africa between January 2000 and December 2020. A preliminary search was performed on PubMed using the keywords ‘predictors’ AND ‘sexual and reproductive health’ AND ‘young women’ AND ‘South Africa’ to ensure a comprehensive search. The returned index terms on the search were then used to develop comprehensive terms using the peer review of electronic search strategies 2015 guideline checklist to assess, evaluate and revise our comprehensive vocabulary before performing our main search. We then searched using all identified Medical Subject Headings (MeSH) terms to ensure that all relevant studies were included. The following databases were searched African journals online, web of science, Scopus, PubMed and CINAHL.To identify grey literature, WHO, United Nations Population Fund (UNFPA) and Guttmacher web pages were searched, while Google Scholar was searched for published theses. Finally, we searched the reference list of all review studies found in the search to determine more eligible studies. Eligible studies were exported to the Endnote version X9’s library for abstract and full article screening after the keyword search and title screening. Articles published between January 2000 and December 2020 were included.The following inclusion criteria were applied: (1) studies on unintended pregnancy predictors among young women in South Africa; (2) studies on STI predictors among young women in South Africa; (3) studies on HIV predictors among young women in South Africa; (4) grey literature  on unintended pregnancy, and STIs/HIV predictors among young women in South Africa; (5) studies conducted among young women and men who reported the studies’ outcomes separately; (6) articles published between 2000 and 2020 and (7) article published in English. Exclusion criteria comprised: (1) studies that do not focus on unintended pregnancy and STIs/HIV predictors among young women in South Africa; (2) grey literature or articles published prior to 2000 and after 2020; (3) studies available in languages other than English; (4) studies with the target population of young women below 15 years and above 24 years and (5) studies with a focus on young men.After the retrieved articles were exported to EndNote X9’s library, the study selection was in three phases. An independent reviewer conducted the title screening and duplicates removal. Another reviewer conducted the abstract and full article screening. Two independent reviewers were involved in this process by following the study inclusion and exclusion criteria. The research question derived from the eligibility criteria was used to develop a screening form used throughout the screening process. In cases of unresolved disagreement, another member of the research team (T.B.) provided the third opinion through a thorough discussion on why an article should be included or excluded.n), study population, age group, predictors of unintended pregnancy, predictors of STIs and HIV (key and significant findings)A data charting form was developed to help determine the suitable variables to be extracted to answer the study research question. Data from included studies were extracted using the following domain author and publication year, study aim, study province or country, study design, research method, sample size , average quality (51% – 75%) and low quality (≤ 50%). Irrespective of the score, all assessed studies were included.A mixed-method assessment tool (MMAT), version 2018, was adopted and piloted by the two independent reviewers to assess the consistency of the selected studies.This study was approved by the Humanities and Social Science Research Ethics Committee of the University of KwaZulu-Natal on the 21st of February 2021, with protocol reference number HSSREC/00002192/2020.36) shows the process of article screening, inclusion and exclusion. The initial search yielded 1224 results, from which we excluded 1096 because of duplicates and title unconformity. A total of 25 studies were assessed for full-text eligibility, which led to further exclusion of 16 that did not meet our inclusion criteria, leaving us with nine studies to be included in our analysis.The PRISMA flow diagram depicted 36 shows 40 while the remaining five (66%) studies were conducted in different provinces; Western Cape42 and Eastern Cape43 had two studies each and one study was conducted in KwaZulu-Natal.26 Six (67%) were cross-sectional study design,40, two (22%) studies followed longitudinal design43 and one (11%) was a randomised control trial.42 All the included studies were quantitative. The sample size of the included studies ranged from 8841 to 11 90440 respondents. The respondents were aged 15–24.Four (44%) out of nine studies included were national-based studies,43 One of these was conducted among young women in Eastern Cape, South Africa, and reported that young women between 17 years and 24 years, young women who have ever had a life experience of sexual abuse and young women who ever drank alcohol were more likely to report unintended pregnancies.2743The second was a longitudinal cohort study conducted among adolescent girls aged 15–18 years. The study showed that adolescent girls who had lifetime physical abuse, those within the lower socio-economic status and the assertion that teenage girls and her boyfriend were main mutual partners were predictors of unintended pregnancies.37The other was a nationwide representative cross-sectional study conducted among young women between the age of 15 years and 24 years in South Africa. The study concluded that young women with higher education, those not living together with a spouse, young women residing in the KwaZulu-Natal province and those having regular partners were more likely to report unintended pregnancies.42 as shown in 41Six studies reported predictors of HIV and AIDS among young women in South Africa,26 The randomised control trial of 388 young women between the ages of 16 years and 24 years conducted in the Western Cape showed that young women involved in alcohol use and those who reported having a sexual partner with STIs were more likely to report having concurrent HPV/STIs.42One was a cross-sectional study conducted among young women aged 15–24 years in KwaZulu-Natal, South Africa, with the aim of investigating the acceptability and feasibility of home-based sampling of STIs and Bacterial Vaginosis (BV) and to measure prevalence and factors associated with STIs/BV. The study concluded that young women in school or those working were less likely to experience STIs/BV. However, young women who had ever drunk alcohol, those involved in genital touching and young women with HSV-2 were more likely to have STIs/BV.38The national cross-sectional survey of 3092 adolescent girls and young women (AGYW) in South Africa reported that young women between 20 years and 24 years and AGYW who reported condom use at last sexual intercourse were more likely to report HIV infection. Adolescent girls and young women with sexual partners within five years of age, with tertiary level education, having low risk of alcohol use and having one sexual partner were less likely to report HIV infection.40 It concluded that young women with higher odds of reporting HIV infection had a history of unusual vaginal discharge in the past 12 months, were of the black race, resided in the urban area and were aged 20–24 years. Besides, they were young women with educational levels below high school, young women who have been sexually active for more than 12 months, with an additional sexual life partner, and young women involved in condomless sex at most recent sex. Similarly, another nationally representative study of HIV infection among 1708 young women aged 15–24 years reporting one lifetime partner concluded that young women who had not completed high school and young women between the age of 20 years and 24 years were more likely to be infected with HIV.39Another was a wide range of national studies conducted by Pettifor and Rees.Our scoping review was conducted to map existing literature on the predictors of adverse sexual and reproductive health outcomes among young women in South Africa.43 Sexual abuse, use of alcohol,27 physical abuse,43 an assertion on the main mutual partnership, lower socio-economic status,43 higher educational attainment, living arrangement, provincial residence and having a regular partner37 were the identified predictors.Three (33%) of the nine included studies reported predictors of unintended pregnancy among young women in South Africa.43 and Ibisomi and Odimegwu,37 signifying a key predictor of unintended pregnancy among young women in South Africa. This is similar to a study conducted among Bangladeshi women who concluded that unintended pregnancy is higher among women who had ever experienced physical violence,44 and the same conclusion was reported in a similar study conducted in Peru among pregnant women.45Physical abuse as a predictor of unintended pregnancy was reported twice in the study by Christofides and Jewkes27 This is in concordance with a study conducted in Nepal by Acharya and Paudel46 who concluded that young women who had ever experienced sexual violence had a higher likelihood (2.3%) of reporting unintended pregnancy. Similarly, a study conducted by Ahinkorah and Seidu47 in 22 SSA countries also linked sexual violence to unintended pregnancy. In the same vein, a self-reported periconceptional substance use study conducted among women reported that women who use alcohol were more likely to report unintended pregnancy.48Sexual abuse and alcohol use were identified as predictors of unintended pregnancy among young women in South Africa.37 These predictors are similar to the conclusion of a study conducted on individual and contextual factors associated with unintended pregnancy among 6791 AGYW (aged 15–24 years) in 10 SSA countries.We found that higher educational attainment, not living together with a spouse, residing in the KwaZulu-Natal province and having a regular partner were predictors of unintended pregnancy among young women in South Africa.49 Women’s level of education has always been a critical factor in decision-making, and the impact of educational attainment on sexual and reproductive health, particularly unintended pregnancy, has been discussed in the past.50 This study result aligns with a study conducted in Ghana by Ameyaw51 and a study conducted in Ethiopia by Habte and Teklu.52 As young women with a higher level of education are often employed, it could be that the young women often miss their family planning service appointment or find it difficult to plan their reproductive health needs because of work pressure.53We found higher education attainment and variation in type place of residence as predictors of unintended pregnancy among young women in South Africa.43 This finding is in line with a study conducted by Iseyemi, Zhao54 that women with lower socio-economic status tend to report unintended pregnancy compared to their counterparts with higher socio-economic status. This finding might be because young women with lower socio-economic status could not make independent financial decisions or could not afford suitable contraception methods.55Lower socio-economic status was also a predictor of unintended pregnancy identified in this study.42 The study findings show that being HIV-positive was reported as a predictor to HR-HPV among young women in South Africa.41 Alcohol use, touching of the genital area, being HSV-2 positive were predictors of having STIs/BV26 and having a sexual partner with STIs was reported as a predictor of having concurrent HPV/STIs.42 Similarly, a study conducted by Seth and Wingood56 among young African American women also identified alcohol use as a strong predictor of having STIs. In the same vein, being exposed to any form of STIs, including HIV and HS-2, has been reported to be a predictor of having any other form of STIs in the later life of young women.57The remaining six studies included in this study reported predictors of STIs/HIV among young women in South Africa.38 young South African women whose population group were black, those who have been reporting unusual vaginal discharge in the past 12 months, those residing in the urban area, those with lower educational attainment, being sexually active, having multiple sexual partners, those involved in condomless sexual intercourse40 and young women between the age of 20–24 years were more likely to report having HIV.39Furthermore, our study reported that the use of condoms during sexual intercourse in the last 5-year was reported as a predictor of HIV,58 which concluded that having multiple sexual partners remains one of the strong predictors of having STIs, including HIV. Similarly, another study conducted in Ethiopia supported these findings.59 We also identified involving in condomless sexual intercourse as a predictor of reporting being HIV-positive among young women in South Africa; however, a study conducted in Malawi opposed this finding as the study reported that there is no significant relationship between condom use during sex and being HIV-positive,60 while another study conducted in Uganda supported our findings that condom use during sexual intercourse reduces the likelihood of being HIV-positive.61 However, our study also reported that condom use during sexual intercourse in the last 5-year could be a risk factor for HIV.38 This may be that the practice of condom use started after the young women had contracted the virus as such condomising during sexual activities could halt the transmission of the virus to their sexual partners.62This study’s results are in corroboration with a study conducted in Uganda by Nankinga and Misinde,61 and Nutor and Duah,63 respectively, concluded that young women who reside in the urban area, those less educated and those between the age of 20–24 years have higher odds of reporting being HIV-positive compared to their counterparts who reside in a rural area, more educated and those between the of age 15–19 years.Finally, our findings indicated that young women in South Africa between the age of 20–24 years, those with less education and those residing in urban areas were more likely to report being infected with HIV. These findings are in line with mapping studies conducted in Uganda and Malawi by Chimoyi and MusengeThis study’s findings are relevant to policy and public health. Predictors of adverse sexual and reproductive health outcomes among young women in South Africa identified in this study are important in developing required interventions and policies to halt its continuous increase. Among identified predictors of adverse sexual and reproductive health outcomes among young women in South Africa, gender-based violence was most prevailing to unintended pregnancy, while alcohol use was identified as the common predictor to both unintended pregnancy and STIs/HIV, and this calls for the attention of policymakers, government agencies, non-governmental organisations and key stakeholders in policy formation and implementation to develop and implement behaviour and social policy that will be targeted at eliminating gender-based violence exposure and alcohol use abuse among young women in South Africa to reduce or eliminate adverse sexual and reproductive health outcomes.Regarding public health implications, this study’s findings also identified residences (area of residence or province of residence) and other health behavioural factors as predictors of adverse sexual and reproductive health outcomes. This will provide public health providers with the blueprint that will guide their programmes and interventions. Furthermore, it will help ensure optimal utilisation of scarce resources to reduce adverse sexual and reproductive health outcomes, including unintended pregnancy and STIs/HIV among young women in South Africa.These research findings identified gender-based violence exposure and alcohol use as the most prevailing predictors of adverse sexual and reproductive health outcomes among young women in South Africa. However, what is unknown is the degree to which these two predictors influence these adverse outcomes at household and community levels; as such future studies should consider conducting primary research that will help the policymakers and stakeholders in understanding the extent to which adverse sexual and reproductive health outcomes among young women in South Africa are being influenced by these predictors  at both household and community levels.This study has numerous strengths. Firstly, scoping review allows different study designs to be included in a study, and this allowed the authors to systematically search and select relevant literature to describe and map the available evidence on adverse sexual and reproductive health outcomes among young women in South Africa. This study design also allowed us to further identify literature gaps useful to inform future research and policy implications. To the best of our knowledge, this study is the first scoping review focusing on adverse sexual and reproductive health outcomes among young women in South Africa in terms of unintended pregnancy and STIs/HIV covering 20 years range. However, there is no study without limitation. The study possibly failed to capture some other relevant articles because we searched fewer databases in the study. Also, we were not involved in the study design and data collection of any of the studies included in this study. Despite these limitations, this review provided evidence useful to guide future research in eliminating or reducing adverse sexual and reproductive health outcomes among young women in South Africa.This study has revealed evidence of existing literature on adverse sexual and reproductive health outcomes among young women in South Africa while identifying gaps for future research. We conclude that predictors of adverse sexual and reproductive health outcomes (i.e. unintended pregnancy and STIs/HIV among young women in South Africa) were lower socio-economic status, place of residence, multiple sexual partners, lower educational level and being between the ages of 20–24 years. However, the most prevailing predictors among all the identified predictors were gender-based violence  and alcohol use. This study findings call for the attention of key stakeholders towards policy formation and development of behaviour and social intervention, such as encouraging the young women to speak up after the incidents and constant community engagement by government or non-governmental organisations on the adverse impact of gender-based violence and alcohol use on sexual and reproductive health outcomes of young women in South Africa. The community engagement can be in the form of playlets and one-on-one discussions, while the victims who speak up should be given rewards to encourage other young women to speak up. Particular interest should be channelled towards the marginalised communities in the urban areas and hard-reach areas in rural South Africa.


Disruptions to developmental cell signaling pathways and transcriptional cascades have been implicated in tumor initiation, maintenance and progression. Resurgence of aberrant neurodevelopmental programs in the context of brain tumors highlights the numerous parallels that exist between developmental and oncologic mechanisms. A deeper understanding of how dysregulated developmental factors contribute to brain tumor oncogenesis and disease progression will help to identify potential therapeutic targets for these malignancies. In this review, we summarize the current literature concerning developmental signaling cascades and neurodevelopmentally-regulated transcriptional programs. We also examine their respective contributions towards tumor initiation, maintenance, and progression in both pediatric and adult brain tumors and highlight relevant differentiation therapies and putative candidates for prospective treatments. Despite extraordinary technological, pharmacological and immunotherapeutic advances in other cancer fields, overall survival for malignant central nervous system (CNS) tumors remains at a dismal 36% with the most aggressive subtypes conferring a survival rate of merely 5% . CNS tumDevastating survival rates for the more lethal brain tumor variants are in large part due to poorly defined tumor margins caused by rampant proliferation and unchecked promigratory pathways. These diffuse tumor boundaries have proven impossible to eradicate using current therapeutic techniques  and thusin utero development and tumorigenesis  has been implicated as a prognostic marker for a number of neurological tumor subsets and is believed to play an important role in the resistance of neurological tumors to therapeutic alkylating agents such as temozolomide (TMZ) and nitrosourea derivatives -activated, wingless-type MMTV integration site family (WNT)-activated, group 3, and group 4 , more rein utero development. Remarkably, the capacity for self-renewal through cell division can give rise to cancer phenotypes when altered or aberrantly controlled.While the identification of a cell of origin for brain tumor subtypes has yet to be entirely defined, many researchers agree that maintenance and continued dissemination of brain tumor cells depends upon a self-renewing, stem cell-like population of neural progenitors. Stem cells represent a heterogeneous population of undifferentiated cells with the potential to develop into numerous cell types . These cLike normal stem cells, cancer stem cell (CSC) division is asymmetric, giving rise to two populations. One daughter cell retains the property of self-renewal like the parent, while the other daughter cell retains the ability to differentiate but not self-renew, giving rise to tumor cell populations . These CCancer stem cells of CNS origin have the ability to grow on non-adherent surfaces and give rise to spherical cell colonies known as neurospheres. CD133-positive cells isolated from neurospheres are capable of self-replication, giving rise to new neurospheres, which are then able to differentiate into principal cell types of the CNS including neurons, astrocytes, and oligodendrocytes . The CD1Cancer stem cells have also been isolated from gliomas in which they are thought to sit at the top of a cellular hierarchy within tumors , revieweEfforts to identify a definitive marker for GSCs have proven challenging. Initially, GSCs were isolated from CD133-positive cells and demonstrated a potent ability to reconstitute tumors in xenograft models, although CD133-negative cells have also been reported to possess stem-like properties that mechanistically support tumor growth . AdditioCells with stem-like properties have also been isolated from a wide range of adult and pediatric brain tumors such as ependymomas and neuroectodermal tumors . CD15-poCollectively, the robust body of literature examining the role of stem cells and CSCs in CNS tumors has demonstrated an increased appreciation for the developmental paradigms in cancer biology. The reliance of tumors on stem cell renewal and differentiation potential strongly parallels the cellular growth and differentiation pathways found in the developing CNS. In particular, the identification of CSCs endowed with properties of self-renewal and the ability to propagate tumor progression has emphasized the need for further investigation and understanding of the molecular mechanisms that drive CNS stem and progenitor cell proliferation and differentiation. Shifting emphasis away from defining common mechanisms amongst tumor categories and refocusing on defining parallels between developmental paradigms and tumorigenesis remains a promising avenue of pursuit for developing targeted therapeutic strategies for particular CNS cancer types brain tumor subtypes.The CNS is derived from the neural plate which folds to form a neural tube in a delicately timed embryonic process known as primary neurulation. This tubular structure will become the basis for the entirety of the brain and spinal cord. Following neurulation, neural crest cells that will give rise to the peripheral nervous system are disconnected from the neural tube, which serves as a primitive embryonic precursor of the CNS. The processes of neural induction, migration and differentiation within the developing nervous system are initiated and maintained by the presence of cell signaling molecules and growth factors secreted from specific embryonic loci. A select family of signaling molecules, known as morphogens, diffuse throughout tissue across varying concentration gradients to help direct the cell fate and differentiation processes of tissue patterning. SHH, bone morphogenetic proteins (BMPs), WNT ligands, NOTCH ligands, chordin (CHRD), Hippo signaling members, and retinoic acid (RA) are each morphogen signaling families that significantly contribute to these neurogenic and gliogenic events. These organizational signals first function to pattern the developing neural tube. As neurodevelopment continues, a series of concatenated or stochastic genetic and epigenetic signatures produce iterations of cellular differentiation and proliferation that culminates in highly diverse populations of CNS cells with a variety of mature CNS functions. The expression patterns generated during the first stages of embryogenesis establish expression domains that lead to the establishment of progenitor regions. These regions are further refined spatially and are maintained by the expression of specific sets of TFs. The combinatorial expression and interaction of the transcriptional factors within the progenitor domains specify cell fate and help to establish cell identity . Both spAn abundance of research over the past half century has demonstrated recurrent and essential roles for many of these early embryonic signaling pathways in the context of CNS tumors. In the following sections, we will summarize the literature pertaining to the most well-studied of these pathways and will highlight seminal work in the fields of developmental and cancer biology that has helped shape the developmental lens through which we can view brain tumors.Sonic hedgehog (SHH) is a morphogen secreted from the notochord in the developing embryo and is responsible for patterning of the limbs , midlineLongstanding evidence has implicated SHH pathway activation in the regulation of renewable adult stem cell populations , suggestActivity of the tumor suppressor PTEN has been shown to influence phosphatidylinositol 3-kinase (PI3K) signaling, which then works in conjunction with SHH signaling to promote tumor growth and viability . PTEN plIn medulloblastoma, some evidence suggests that tumors may originate from the external granule layer of the cerebellum . The extBone morphogenetic proteins (BMPs) represent a large group of cytokines with the potent ability to initiate ectopic bone formation . Since tBone morphogenetic proteins also regulate mesoderm and cartilage formation and help direct postnatal development of bone . During In particular, BMP signaling is involved in regulating the transcription of genes involved in cell specification including intracellular interactions used during cellular morphogenesis, apoptosis, proliferation, and differentiation . During ex vivo delivery of BMP4 was shown to potently inhibit the ability of human-derived GBM cells to successfully initiate tumor formation following intracerebral transplantation, while in vivo delivery of BMP4 effectively blocked tumor growth and reduced associated mortality following intracerebral grafting  formation, and other key functions in a wide variety of cells . InductiDysregulation of TGFβ signaling or its downstream pathways have been associated with the pathogenesis of multiple CNS tumors, including adult gliomas such as GBM , pediatrIn the search for better therapeutic treatments for malignant glioma, an important consideration is the unintended activation of wound responses and subsequent induction of TGFβ signaling following chemotherapy, radiation or surgical resection of tumors. To this end, activation of TGFβ signaling has been observed in patient-derived GBM cell lines that have been treated with TMZ or radiation and results in enhanced migration and infiltration . Owing tWithin the developing CNS, wingless-type MMTV integration site family (WNT) proteins work to regulate cell proliferation and its expression is active both during early phases of development as well as during later stages of organ and tissue growth. WNT signaling can occur through the WNT/β-catenin-dependent canonical pathway or through the WNT/β-catenin independent pathway. In the WNT/β-catenin canonical pathway WNT binding to its target receptors leads to intracellular accumulation and nuclear translocation of β-catenin, a coactivator of TFs encoded by the CTNNB1 gene that regulates expression of pro-survival and cell proliferation genes . Non-canWingless-type proteins are amongst some of the most well-studied in the context of brain tumors, and have been shown to bidirectionally support tumor progression and oncogenesis in a context-dependent manner. WNT signaling in the context of brain tumors has been most extensively studied in medulloblastoma, GBM and other astrocytoma subtypes . In meduIn glioma, experimentation with SFRP1 as an inhibitor of the WNT pathway led to the discovery of its role as a direct target of miR-32, which is highly upregulated in invasive glioma cells . In GBM,Like its SHH and WNT counterparts, notch receptor (NOTCH) signaling is an essential contributor to early neurodevelopment with an important role in the maintenance of NSC populations . NOTCH sNOTCH signaling in cancer mirrors its functions in neurodevelopment, impacting cell fate and maintenance of CSCs . Activatin vitro and in vivo  and NOTCH pathway proteins may function to promote proliferation of cancer cells. EGFR is involved in a number of cell processes including proliferation, migration, and cell survival . Studiestrans-RA, more commonly referred to as RA. As an essential component of early embryonic development, RA is widely recognized for its teratogenicity most frequently encountered with sustained use of retinoid pharmaceuticals during pregnancy , including the metabolite all-regnancy . RA is aregnancy . In embrregnancy . RA can regnancy . Additioregnancy . Retinoicis-RA has been used for the treatment of recurrent GBM although significant systemic toxicity has been noted with its use  genes constitute a family of nine developmental genes encoding nuclear TFs with critical roles in the formation of organs and tissues . All ninAlthough structurally similar, each PAX gene imparts unique downstream effects and varies in its regulatory contributions to organogenesis. PAX1, for example regulates epithelial differentiation within and development of the thymus , whereasWithin the field of glioma biology, PAX3 has been established as a regulator of GSCs through its modulation of glial fibrillary acidic protein (GFAP) expression . PAX3 inThe sex determining region Y (SRY) box family of transcription factors (SOXs) is composed of 20 members containing a related high motility group (HMG) DNA binding domain. They are further categorized into 8 subgroups based on sequence similarity of the HMG group, which tend to share biochemical properties and often demonstrate overlapping expression patterns and functional redundancy. The SOX group in its entirety serve as developmental regulators with functions in many organs including CNS tissues. In particular, they are important for stem cell maintenance and have been attributed roles in tissue regeneration and tumorigenesis . Importain vivo -induced glioma in mice  genes are transcription factors with CCAAT box binding domains present within their consensus sequence. NFI family members include NFIA, NFIB, NIFC, and NFIX and have distinct roles in normal development. Mutations in these genes are associated with various developmental aberrations owing to disturbances in cellular proliferation and differentiation pathways that are mediated primarily through transcriptional control of downstream NFI target genes . NFIA anRoles for NFIA and NFIB as tumor suppressors in glioma have been documented, and expression of these two factors is inversely correlated with tumor grade such that higher grade tumors are associated with lower expression of NFIA or NFIB . IncreasNuclear factor IA is lost as part of chromosome 1p31 and low expression of NFIA is associated with oligodendrogliomas . StrikinProneural basic helix-loop-helix (bHLH) transcription factors are essential regulators of neural cell fate in the developing CNS and in regions of the adult NSC niches. As suggested by their namesake, bHLH factors contain a helix-loop-helix domain that is utilized for dimerization and binding to the enhancer box motif consensus sequence CANNTG. Some of the most well-studied of these TFs in development and brain tumors are OLIG2, atonal bHLH transcription factor 1 (ATOH1) and Achaete-Scute family bHLH transcription factor 1 (ASCL1). Although mutations in proneural bHLH factors are not commonplace in brain tumors, dysregulated expression levels of these TFs in some tumor subtypes may direct disease course through respective downstream changes to gene expression.As a key TF controlling glial cell fate in the developing CNS, OLIG2 shows a diverse repertoire of functions in neurodevelopment. It is required for the generation of motor neuron populations in the spinal cord and likewise is necessary for successful generation of OPCs and their subsequent maturation in the spinal cord and cortex . In the Another important regulator of the developing brain and spinal cord cell populations is ATOH1, which is a TF expressed in progenitor populations throughout several regions of the brain and the dorsal spinal cord ([reviewed in Achaete-Scute family bHLH transcription factor 1 (ASCL1) is also required for the specification of interneuron populations in the developing spinal cord and for the generation of several subsets of neuronal populations in the brain . In addiIn vitro experiments using cultured glioma cells have revealed ASCL1 is necessary for cellular proliferation via activation of WNT signaling (With respect to brain tumors, ASCL1 is expressed in GBM, astrocytoma, and oligodendrogliomas . In vitrignaling . In addiignaling . Notablyignaling . In miceignaling . In thesignaling .The convergence of neurodevelopmental pathways with other signal transduction cascades in both development and disease has long been established reviewed in The most robust of these relationships is demonstrated by ATOH1-mediated transcriptional control of development and medulloblastoma progression. ATOH1 is required for development of the cerebellum where it works in a SHH-dependent manner to regulate cerebellar GCPs . ATOH1 aIn developing glial cells, HES1 represses ASCL1 expression while ASCL1 inversely activates HES5 . A similPost-translational modifications to OLIG2 mediate migration and proliferation of both OPCs and GSCs in development and glioma, respectively . WhereasDuring neurogenesis PAX6 is critical for the generation of discrete progenitor domains that occur in response to a ventral SHH signaling gradient, which leads to the production of motor neurons and ventral interneurons . In bothSimilarly, the SOX family of genes can interact with SHH, TGFβ and WNT signaling pathways in both the contexts of development and tumorigenesis (reviewed in cis-RA have been used for other cancers, including the predominantly PNS cancer of neuroblastoma, a multitude of developmental targets remain unexplored as potentially exploitable therapeutic modulators of brain tumors. In particular, TFs have been historically regarded as “untargetable” owing to the complex nature of protein-DNA and protein-protein interactions. However, recent strategies employing TF DNA binding inhibition or blockage of cofactor interactions have emerged and have begun to challenge this perspective.Despite the growing body of literature describing roles for developmental programs and transcriptional networks in tumor initiation and progression, methods for practically targeting these pathways have remained elusive. While differentiating therapies such as 13-More recent approaches utilizing proteasomal degradation of TFs have shown some promise . In addiIt is important to note that in addition to the early embryonic signaling pathways and TFs highlighted in this review, a number of developmentally-driven epigenetic aberrations have been identified in both adult and pediatric brain tumors, although these alterations seem to be more relevant to the initiation of brain tumors in the pediatric population. While the genetic mutational landscape of pediatric brain tumors appears to be sparser than adult gliomas, mutations in histone modifiers including HIST1H3B/C, HIST2H3C, and H3F3A lead to changes in methylation and acetylation profiles of histone 3. The consequences of these histone mutations result in global dysregulation, particularly overexpression of entire chromosomal regions including the expression of essential developmental regulators of cell proliferation, migration and differentiation . As suchTo date, the majority of oncologic research and treatment has viewed cancer through an anthropomorphizing lens that has characterized cancer cells as malevolent and corrupt entities. Commonly used descriptors such as “aggressive” and “invasive” coupled with phrases like “hijacked” and “infiltrating” have imparted a sense of volitional evil onto these non-sentient illnesses. This context of mal-intent in which the problem of cancer has been placed has had profound effects on the ways in which we have attempted to combat these diseases. Researchers and clinicians alike have been prompted to develop anticancer treatments and therapeutics designed to “kill” and “eradicate” their targets. These hard-hitting counterattacks often employ perilous and toxic mechanisms of action, frequently leading to irreparable and fatal side effects in an attempt to contain and eliminate the disease. As a means of minimizing toxicity and damage to the patient, the fields of precision medicine and immunotherapy have attempted to trade in their weapons of mass destruction in exchange for patient-specific armamentariums of therapeutics specifically designed to target tumor cells while leaving non-diseased tissue unharmed. But these approaches maintain and perpetuate the notion of cancer as “bad” or “malicious,” and thus continue to employ tactics of destruction as a means to an end.in utero and perinatal development. As opposed to alterations occurring in individual pathways, genes or proteins, entire developmental programs have been identified as dysregulated drivers of brain tumors. These programs include VEGF and FGF-mediated tumor derived angiogenesis (Recent genetic and epigenetic data have provided evidence that many cancers possess molecular fingerprints with tremendous similarities to developmental cells including stem cells and progenitors. Some oncologic diseases demonstrate such profound molecular likeness to known precursor cells that it has prompted many researchers to view cancer as a disease of development rather than a series of spontaneous and transformative events. The highly proliferative, migratory and self-renewing capacities of cells have not only become a hallmark of cancer, but additionally have been assigned as quintessential traits of the rapidly expanding cell populations characteristic of ogenesis , synapseogenesis , regulatogenesis , and gliogenesis . Given tin vivo to help them achieve their proper fate. These therapies aiming to direct the fate of tumor cells toward more differentiated and less malignant states– termed differentiation therapy- remains enigmatic in the case of solid neoplasms, including those occurring in the brain and CNS. For these therapies to become more feasible, continued investigations into the processes regulating cell lineage commitment and differentiation both during development and tumorigenesis must continue. While great progress in the field of brain tumor biology has been made over the last two decades, much remains to be defined before plausible treatment options for adult and pediatric brain tumors are attained and become commonplace in a clinical setting. Thus, integration of developmental biology into the current dogmas of oncogenesis, malignant transformation and tumor evolution can help to guide future research endeavors and elucidate novel therapeutic targets for these lethal malignancies of the CNS.If this theory of cancer as a developmentally misguided event holds true, a solution to this conundrum may be more easily reached through reeducation and redirection rather than annihilation and elimination. The task would now be to identify with which developmental progenitors these oncogenic cells most closely correlate, to determine the naturally-occurring molecular and physiological events that are responsible for regulating their developmental differentiation, and to expose cancer cells to these transformative signaling events RC and SG researched data for the article and contributed to the writing and editing of the manuscript. Both authors have read and approved the document.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


After heavy rainfall, submerged plants in flooded lands undergo transient hypoxia until water recedes and normoxia is recovered. The accumulated information on the physiological and molecular events occurring during the hypoxia phase contrasts with the limited knowledge on the reoxygenation process after hypoxia, which has often been overlooked in many studies in plants. Phenotypic alterations during recovery are due to potentiated oxidative stress generated by simultaneous reoxygenation and reillumination leading to cell damage. Besides processes such as N-degron proteolytic pathway-mediated O2 sensing, or mitochondria-driven metabolic alterations, other molecular events controlling gene expression have been recently proposed as key regulators of hypoxia and reoxygenation. RNA regulatory functions, chromatin remodeling, protein synthesis, and post-translational modifications must all be studied in depth in the coming years to improve our knowledge on hypoxia–reoxygenation transition in plants, a topic with relevance in agricultural biotechnology in the context of global climate change.Plants are very plastic in adapting growth and development to changing adverse environmental conditions. This feature will be essential for plants to survive climate changes characterized by extreme temperatures and rainfall. Although plants require molecular oxygen (O Plant responses to hypoxia and subsequent reoxygenation occur through a network of processes involving oxygen sensing, RNA function, chromatin remodeling, gene expression, and protein synthesis, which together allow plants to either escape or tolerate the stress. An effective strategy for risk reduction in agriculture must be grounded on a better knowledge of plant adaptation to climate change and the elucidation of key processes involved in plant stress responses. Adverse effects may be different depending on the flooding condition, affecting only the roots (waterlogging) or both roots and shoots  (2) depletion due to less availability in water compared with air restrains growth and causes cell damage. These effects increase with duration of the submergence period and with high temperatures as O2 consumption due to plant respiration increases  has estimated losses of around US$19 billion in developing world agriculture (2005–2015) due to floods  and cell damage . Among five ERFVIIs in Arabidopsis, three of them, related to AP2 RAP2.2, 2.3, and 2.12, are constitutively expressed  relies on the activities of protein disulfide isomerase (PDI) and thiol oxidase, which transfers electrons from PDI to molecular O2  have all been reported to regulate responses to hypoxia H, or ATP, is the molecule that provides the most energy to animals and plants and is crucial for sustaining large complex life forms , other plant hormones such as ethylene and abscisic acid (ABA) play crucial roles in the genetically controlled survival of plants to hypoxia  under wanditions .2 availability  and VERNALIZATION 2 (VRN2) to hypoxia  and indirectly also of protein S-nitrosylation -triggered signaling as well as proteins with O2On the other hand, although plants and animals are quite different in triggering responses to hypoxia and subsequent reoxygenation, plant researchers should take advantage of the extensive knowledge accumulated in the hypoxia–reoxygenation transition in animal models. Comparative analyses will allow us to find new components involved in key processes such as O-sensing domains will be crucial to understand the hypoxia–reoxygenation transition in plants. Other membrane-related processes such as endomembrane protein trafficking or autophagy and the corresponding components involved should also be extensively studied in plants, with emphasis on the analysis of post-translational modifications that are likely to represent a relevant level of regulation in hypoxia and post-hypoxia. This information will not only be of interest for basic science but will also have a tremendous impact on potential biotechnological applications for future agriculture in an environmental frame of acute climate change.


Procolobus gordonorum) and the yellow baboon . These species have contrasting diets and lifestyles, but live sympatrically in both human-impacted and pristine forests in the Udzungwa Mountains of Tanzania. Using non-invasive faecal pellets, helminths were identified using standard microscopy while bacteria and fungi were characterized by sequencing the V1–V3 variable region of the 16S rRNA gene for bacteria and the ITS1–ITS2 fragment for fungi. Our results show that both diversity and composition of bacteria and fungi are associated with variation in helminth presence. Although interactions differed by habitat type, in both primates we found that Strongyloides was negatively associated and Trichuris was positively associated with bacterial and fungal richness. To our knowledge, this is one of the few studies demonstrating an interaction between helminth and gut microbiota communities in wild non-human primates.The mammalian gastrointestinal tract harbours a highly complex ecosystem composed of a variety of micro-  and macro-organisms (helminths). Although most microbiota research focuses on the variation of single gut components, the crosstalk between components is still poorly characterized, especially in hosts living under natural conditions. We investigated the gut micro-biodiversity  of 158 individuals of two wild non-human primates, the Udzungwa red colobus ( As the bacterial community exceeds all other components within the gut in terms of number and species diversity3, our knowledge of the microbiota is shaped by a disproportionate focus on this gut component. A plethora of evidence suggests that a rich and diverse gut bacterial community is beneficial to host health6 by maintaining important metabolic and immune functions9, and contributing to colonization resistance against enteric pathogens12. However, other relevant (but mostly neglected) gut components are also potentially beneficial or neutral depending on species and context. For example, although they have been mainly studied for their pathogenic characteristics13, gut helminths secrete an array of molecules that can directly affect host immune response14, or may do so indirectly by interacting with the gut microbiota by modifying bacterial richness and diversity19.Healthy mammalian gastrointestinal tracts harbour a complex ecosystem where micro- (i.e. bacteria and fungi) and macrobiota (i.e. protists and helminths) co-exist and have co-evolved in association with their mutual hosts20. The majority of studies focussing on this topic derive from laboratory animal experiments23, but few observations in humans25 and wild non-human animals26 have revealed associations between gut bacterial communities and helminth infection (but see28). Due to the potential beneficial consequences of such interactions for the overall health and well-being of the hosts , investigating the gut communities of animal species closely related to humans (i.e. non-human primates) living under natural conditions is of particular relevance. Studies of these associations will provide a critical foundation to understanding the potential mechanisms that underpin the interplay between helminths, microbiota and hosts, and will deepen our awareness of animal health with possible conservation implications.Although the field is developing quickly, little information is available on the details of micro-/macrobiota interactions in the gut, and interactions of this microdiversity with the host30. However, they are facing escalating loss and fragmentation of optimal habitat, making this mammalian group one of the most threatened on Earth31. Recent research we conducted on primates living sympatrically in human-modified and pristine habitats has highlighted the impact of habitat changes on gut bacterial and fungal diversity33, as well as on helminth infections35. Although a few recent studies have evaluated the diversity and composition of the gut bacterial communities of non-human primates naturally infected by helminths39, here we compare both the bacterial and fungal components in helminth-positive and helminth-negative individuals to investigate: (i) whether bacterial and fungal richness and/or composition vary in primates with different ecological adaptations residing in either pristine or human-impacted forests; (ii) which bacterial and fungal taxa are responsible for such variation; and (iii) which of the detected helminths interplay with bacterial and fungal richness.Non-human primates represent a crucial element of tropical ecosystems, contributing to forest regeneration and ecosystem health35, of 158 faecal samples collected from 89 red colobus and 69 yellow baboons 76.6%  were positive for eggs of at least one of the five helminth types identified, two of which (nematodes) could be classified to genus , while another three to higher taxonomic levels . No metazoan larvae or adults were detected with the gauze-washing method. Instead32, showed that the most prevalent bacterial phyla in both red colobus and baboons were Firmicutes, Bacteroidetes, Proteobacteria and Spirochetes, accounting for 75.3% and 84.6% of the total bacterial amplicons, respectively; the four prevalent and classified phyla of fungi were Ascomycota, Basidiomycota and Zygomycota for both host species.This paper investigated the interactions between helminth presence and gut microbiota components (bacteria and fungi) in two primate species (red colobus monkeys and yellow baboons) living in two forest types (intact and fragmented). As reported inStrongyloides, strongylid nematodes, and Trichuris. The same three taxa were also the most prevalent helminth types, both in yellow baboons  and Udzungwa red colobus . Specifically, yellow baboons helminth-positive for strongylid nematodes had lower bacterial richness than helminth-negative individuals living in the Magombera fragmented forest (hereafter FF: fragmented forest) , two to the Bacteroidales and the remaining four were unclassified  and the presence or absence of helminths  in two species of wild non-human primates living in the same intact and human-modified tropical forest blocks. We found that changes in gut microbiota richness and diversity in both primate species were associated with the presence of certain helminth types, but that this variation was also affected by habitat. Given the known effects of low gut microbiota diversity in human health and laboratory animals, the loss of natural levels of micro-biodiversity could have wide-ranging and devastating effects on the survival of wild animal species, but the drivers and rate of loss in free-living populations is virtually unknown. Our study provides a novel addition to the rare studiesTo the best of our knowledge this is the first study that uses ITS1-2 Illumina MiSeq technology to characterize gut fungal communities and associate them with helminth presence.Trichuris sp. and Strongyloides sp. since these taxa are present in most social groups of both primate species , and more thoroughly discussed in the literature than the broader taxonomic helminth groups that could be identified here. Helminths of both genera parasitize a wide variety of different mammalian hosts41, although they have different life cycles. Embryonated eggs of Trichuris spp. are shed in the faeces; larvae develop inside the eggs in a moist environment and are ingested by new hosts with food, water, and soil. Once in the small intestine, Trichuris eggs are stimulated by the cecal microbiota to hatch and first-stage larvae embed themselves into the mucosa of the large intestine; after mating, female whipworms produce eggs to complete the cycle42. Instead, Strongyloides leave the host either as first stage larvae or embryonated eggs shed into the environment, but go through several free-living stages before being ingested, and inhabiting the mucosa of the small intestine43. Previous studies of bacterial microbiota and the soil-transmitted Trichuris and Strongyloides helminths have reported various results, from no association  to alteration of the gut microbiota, by reducing45 or increasing47 bacterial richness and diversity. We found robust patterns of associations between bacterial and fungal components of the microbiota and helminths across the two primate species. Bacterial and fungal richness increased, and fungal composition changed when individual primates were infected by Trichuris, while bacterial richness declined in individuals infected with Strongyloides. This was generally true for both the leaf-eating, arboreal red colobus monkey and the omnivorous, terrestrial yellow baboon, although habitat also had some effect. Presence of strongylid nematodes, Strongyloides or Trichuris all increased fungal richness in yellow baboons in FF, while nematode presence  was associated with lower bacterial richness in this species in the same habitat. Nematode presence  was also associated with lower bacterial richness in red colobus, but in PF. Although studies of the interactions between helminths and microbiota in wild animal populations are still relatively new, we speculate that the discrepancy found here may derive from a temporary instability in microbiota composition as a result of helminth infections which may recover over time, as already found in humans under controlled settings17. Further longitudinal studies on the same wild populations could help to fulfil this gap and reveal the actual influence of each gut component over time.To better understand the biological meaning of the observed associations, we restricted our discussion here to the two soil-transmitted helminths, namely 48. Moreover, Trichuris infection is known to ameliorate inflammatory bowel disorders in humans49. As shown in studies conducted on humans46 and in a pioneer study on non-human primates18, Trichuris infections were also beneficial to restoring bacterial diversity. Indeed, after being therapeutically infected with Trichuris gut bacterial communities were reversed in juvenile rhesus macaques (Macaca mulatta) with colitis as bacterial richness was restored to levels comparable to those of healthy macaques18. Interestingly, our findings in wild primates agree with these results, showing a positive association between Trichuris presence and bacterial richness. The positive interaction between Trichuris and bacterial richness we found in Udzungwa red colobus inhabiting FF are particularly intriguing, since these same populations have been shown to suffer loss of bacterial diversity due to the poorer diet (i.e. lower tree diversity compared to intact forests) in this degraded habitat33. Similarly, the same association found in yellow baboons was restricted to individuals living in the pristine forest, that have a lower bacterial richness compared to animals living in the human-modified forest, where they supplement their diet by raiding crops and feeding on human organic waste. Thus, positive associations between Trichuris presence and bacterial richness in our wild primate models may reflect an ecological strategy to ameliorate low gut microbiota.However, it has been suggested previously that a high level of bacterial richness and diversity is considered a desirable traitTrichuris, both Udzungwa red colobus (in PF) and yellow baboons (in both PF and FF) positive for Strongyloides had lower bacterial richness compared to Strongyloides negative ones. This apparently contradicts the studies conducted in human and non-human primates which found a positive association47 or no association44 between Strongyloides and bacterial richness. However, an experimental study conducted on mice infected with S. venezuelensis revealed a reduction in bacterial richness at peak of infection45, reflecting temporary bacterial alteration potentially due to gut immune responses. Therefore, we cannot exclude the possibility that the lower bacterial richness in Strongyloides-individuals observed here also reflect a transitory effect characteristic of this helminth in any habitat.In contrast to the results for Strongyloides secrete a variety of proteins in the host gut, which have antimicrobial activities leading to alteration in bacterial diversity and composition as also recently observed in laboratory mice50. In fact, while we observed reduction of gut bacterial diversity in association with Strongyloides infection, the concurrent change in beta diversity  shows that primate species respond differently to helminth presence. Changes in bacterial composition for the Udzungwa red colobus in PF appears to have been driven by Lachnospiraceae and Ruminococcaceae bacterial families. Both families are associated with degradation of complex plant material like cellulose and lignin52, which may well reflect their folivorous diet, as also found in most of the leaf-eating primates and ruminants54. However, although both families are associated with energy metabolic advantages, their high abundance has been related to metabolic disorders56. Moreover, the genus Pseudoflavonifractor, a biomarker of obesity and diabetes, was also overrepresented in individuals infected by Strongyloides, implying that, besides being associated with an overall reduction of bacterial richness, Strongyloides may contribute to the emergence of less beneficial bacterial taxa and thus, to the disruption of the metabolic balance within a healthy gut57.Blastocystis58, such as Saccharomyces boulardii59, as well as Candida albicans and C. glabrata60. Thus, our findings are pioneering this field. We found, for example, that similarly to bacterial microbiota, both Trichuris and Strongyloides helminths were positively associated with fungal richness in both yellow baboons and Udzungwa red colobus living in FF. However, since no data are available for comparison with our results, and the mechanism behind these associations is difficult to disentangle, we can only conclude that fungal richness, similarly to that of bacteria, is probably highly relevant for gut function61. However, the notion that either a competitive or a beneficial association between gut components exists cannot be verified at this time.No studies in either experimental and natural settings are available on the interaction between gut fungal communities and the helminths taxa we identified here, although some human models have shown that fungal taxa may be positively associated with parasitic colonization by Although causal relationships must be further investigated, the current study underlines the importance of considering the associations between gut components in investigations of wild animal health and conservation status, especially in endangered species threatened by increasing human pressure. Our findings revealed that environmental factors may play an important role in shaping such associations. Thus, to clarify to what extent biological and environmental variables are interconnected, their transmission potential and the direct consequences on animal status, future studies would benefit from better classification of each gut component and determination of their metabolic functions, as well as broadening the investigations to include additional host gut components (e.g. viruses), and the microbiota of their surrounding ecosystem .Procolobus gordonorum) and yellow baboon  following32 in the Udzungwa Mountains of Tanzania , which affect the conservation status of the primate populations living within them65. Remaining forests are threatened by intensive agriculture66, and primates outside the Udzungwa Mountains National Park  are particularly vulnerable to hunting and other human disturbance67.We sampled faecal pellets of the Udzungwa red colobus  and 69 yellow baboons  we examined 2 ml of faecal suspension using optical microscopy at 400× magnification . Based on morphological characteristics, eggs were identified for each helminth taxon. Lastly, using what was left of the faecal sample, adult and larval helminths were collected using the ‘gauze-washing’ method71 and observed via stereo microscopy  at 8–40× magnification.Each faecal sample was divided in two parts: the subsamples used to identify helminths were preserved in 10 ml of 10% neutral buffered formalin and stored at ambient temperature (20–25 °C) until transport to the Fondazione Edmund Mach (FEM), Italy where they were stored at 4 °C before shipment to the University of Veterinary Sciences in Brno, Czech Republic, for parasitological analysis. Helminth identification was carried out using both modified Sheather’s flotation and faecal sedimentation techniques32). Briefly, from each faecal sample, we extracted and amplified the whole DNA using the same protocols73, and later sequenced the V1-V3 regions of the 16S ribosomal RNA gene for bacteria and the ITS1-ITS2 region for fungi using Illumina MiSeq technology. The software MICCA74 was used to identify amplicon sequence variants (SVs).The faecal subsamples used for microbiota analysis were preserved in 96% ethanol and kept at 4 °C before transporting them to FEM, stored at − 80 °C and shipped to the University of Illinois, USA for analysis  for both bacteria and fungi were estimated and used them as dependent variables in regression models testing the relationship between gut microbiota  richness and helminth presence separately for each primate species in each forest type (PF and FF). To identify statistically significant effects of infection by helminths on bacterial and fungal richness we performed a post-hoc analysis on marginal means estimated using a Generalized Linear Model (GLM) that guarantees robust results for unbalanced study groups. Specifically, species richness (Chao1) and diversity (Shannon) of bacteria and fungi were used as dependent variables in a GLM with Poisson error distribution, with helminth presence (‘Positive’) or absence (‘Negative’) for dicrocoeliid trematodes, spirurid and strongylid nematodes, Strongyloides, and Trichuris as independent variables. The model used was:Species indicates the primate species, Parasite indicates the helminth type, and Forest indicates PF or FF, and Chao1/Shannon indicate either Chao1 or Shannon entropy. Contrasts between marginal means for ‘Positive’ and ‘Negative’ groups for each primate species, parasite and forest and significant test were computed using the package emmeans 1.5.3 on the fitted model76. The effect of helminth presence on beta diversity of bacteria and fungi was assessed by PERMANOVA using the function adonis2 from the vegan 2.5-7 package. Homogeneity of dispersions was controlled by ANOVA of the multivariate dispersions of the groups obtained using the function betadisper from the vegan 2.5-7 package. DESeq2 was used to identify which bacterial and fungal taxa explained the differences observed in their overall relative abundance between helminth infected and non-infected individuals.All statistical analyses were conducted using the The authors confirm they did not interact with or disrupt any of the primate species surveyed in any way. Faecal sample collection was non-invasive, without direct contact or interaction with the animals. Highly trained fieldworkers strictly adhered to the ‘Code of Best Practices for Field Primatology’ published by the International Primatological Society (IPS) as well as the ‘Principles for the Ethical Treatment of Primates’ of the American Society of Primatologists (ASP). Data collection complied with legal requirements and laws governing wildlife research in Tanzania. Research permits (2016-267-ER-2009-49) were obtained through the Tanzania Commission for Science and Technology (COSTECH), Tanzania Wildlife Research Institute (TAWIRI) and Tanzania National Parks (TANAPA).Supplementary Information 1.Supplementary Tables.