Tyrosine kinases relay signals from diverse leukocyte antigen receptors, innate immune receptors, and cytokine receptors, and therefore mediate the recruitment and activation of various leukocyte populations. Non-receptor tyrosine kinases of the Jak, Src, Syk, and Btk families play major roles in various immune-mediated disorders, and small-molecule tyrosine kinase inhibitors are emerging novel therapeutics in a number of those diseases. Autoimmune and inflammatory skin diseases represent a broad spectrum of immune-mediated diseases. Genetic and pharmacological studies in humans and mice support the role of tyrosine kinases in several inflammatory skin diseases. Atopic dermatitis and psoriasis are characterized by an inflammatory microenvironment which activates cytokine receptors coupled to the Jak-Stat signaling pathway. Jak kinases are also implicated in alopecia areata and vitiligo, skin disorders mediated by cytotoxic T lymphocytes. Genetic studies indicate a critical role for Src-family kinases and Syk in animal models of autoantibody-mediated blistering skin diseases. Here, we review the various tyrosine kinase signaling pathways and their role in various autoimmune and inflammatory skin diseases. Special emphasis will be placed on identification of potential therapeutic targets, as well as on ongoing preclinical and clinical studies for the treatment of inflammatory skin diseases by small-molecule tyrosine kinase inhibitors. Tyrosine kinases are intracellular enzymes mediating tyrosine phosphorylation of downstream molecules. They play a critical role in signal transduction by various cell surface receptors including, among others, growth factor receptors, adhesion receptors, immunoreceptors, and cytokine receptors. Given their role in multiple signaling processes and disease pathogenesis, tyrosine kinases have emerged as excellent therapeutic targets for the targeted therapy of various diseases. Indeed, small molecule tyrosine kinase inhibitors became important contributors to the pharmacological control of a diverse array of diseases including various malignant processes and immune-mediated diseases such as autoimmune and inflammatory conditions .Inflammatory joint diseases such as rheumatoid arthritis have been in the focus of the development of tyrosine kinase inhibitors for therapeutic purposes within the area of immune mediated diseases . This haIn this review article, we summarize our current knowledge and understanding of the role of tyrosine kinases in autoimmune and inflammatory skin diseases. We first provide an overview of the various receptor and non-receptor tyrosine kinases and their role in immunological and inflammatory processes. We then summarize the role of the various tyrosine kinases in specific autoimmune or inflammatory skin diseases. Special emphasis is placed on genetic studies in mice and humans indicating a role for tyrosine kinase pathways in inflammatory skin diseases, as well as the preclinical and clinical development of tyrosine kinases inhibitors for the targeted pharmacological therapy of those diseases.Non-receptor tyrosine kinases are intracellular tyrosine kinases without a direct role in sensing extracellular cues. Nevertheless, these tyrosine kinases are often coupled to various cell surface receptors and are intimately involved in the transmission of extracellular signals to downstream intracellular signaling pathways and cellular effector functions.There are a total of 10 different non-receptor tyrosine kinase families. Of those, we will discuss Janus kinases , Src-family kinases, and the Syk tyrosine kinase, as well as members of the Btk kinase family.The Janus kinase family consists of four members: Jak1, Jak2, Jak3, and Tyk2. While Jak1, Jak2, and Tyk2 are ubiquitously expressed, the expression of Jak3 is limited to the hematopoietic compartment.These kinases are primarily involved in the signal transduction of various cytokine receptors which are grouped into type I  and type II  cytokine receptors. Since Jak-coupled cytokine receptors act as dimers, Jak family kinase activity is also mediated by involving two Jak-family kinases. In most cases, the two cooperating kinases are different , although Jak2 can also cooperate with another Jak2 molecule (“homodimer”). Upon ligand binding, the conformational changes of the receptor and/or ligand-induced dimerization promotes Jak activation, which leads to autophosphorylation of tyrosine residues of the kinase itself, further augmenting its kinase activity. Jaks then phosphorylate the receptor chains, allowing the recruitment of various signal transducer and activator of transcription (Stat) transcription factors. Stat molecules are then also phosphorylated by Jak kinases, leading to dimerization and translocation to the nucleus where they activate or repress gene expression and influence epigenetic alterations . These bJak3−/− mice further confirmed the critical role of Jak3 in lymphoid development , as well as through receptors that utilize the common γ-chain (γc) or the shared gp130 subunit. Jak1 deficiency in mice leads to defective lymphoid development and neurological defects resulting in perinatal lethality without disturbing other hemopoietic lineages . Signalielopment , 10. Tykelopment , 12. Tyk in vivo .Given their central role in cytokine signaling it is not surprising that Jaks have a role in several immune mediated diseases involving autoimmunity, transplant rejection, and malignancies. Therefore, pharmacological targeting of Jaks was plausible and Jak inhibitors have been extensively studied in several clinical studies. A critical aspect of Jak inhibitors is their selectivity profile for the different Jak family kinases which determines the spectrum of their biological effects. The most studied Jak inhibitor is tofacitinib, which ameliorated autoimmune arthritides in various animal models –20 and pThe Src kinase family includes nine members  which are involved in many signaling pathways in immune cells including immunoreceptor as well as integrin signaling. Src-family kinase activity is regulated by tyrosine phosphorylation and Src homology 2 and 3 (SH2 and SH3) mediated protein-protein interactions with partner proteins containing phosphotyrosine or proline-rich motifs, respectively. Src-family kinases are ubiquitously expressed, although different cells express different family members. Within the immune system, T cells express Lck and Fyn, B cells express Fyn, Lyn, and Blk, and myeloid cells express Hck, Fgr, and Lyn . Spleen Immunoreceptors such as B cell receptors (BCR), T cell receptors (TCR), and various activating Fc receptors of innate immune cells are physically associated with transmembrane adapter proteins carrying immunoreceptor tyrosine-based activation motifs (ITAMs). Ligand-receptor interaction results in the enzymatic activation of Src-family kinases phosphorylating the ITAM motifs in the receptor subunits . Dually 1 and β2 integrins. A prominent feature of Src-family kinases is a significant functional overlap between individual family members. Therefore, in contrast to Jak kinases, individual Src-family kinases are not essential for a given response and complete inhibition of a signaling pathway often requires combinational deletion of multiple kinases in myeloid cells. FcγR mediated phagocytosis is slowed in macrophages lacking Hck, Fgr, and Lyn  is involved in the development and activation of B cells through BCR and Toll-like receptor (TLR) signaling . PatientReceptor tyrosine kinases represent a large family of receptors recognizing various hormones, cytokines, and growth factors . They foEGFR and its related receptors, PDGFRs, VEGF receptors and their intact signaling are essential for normal embryonic development and adult tissue homeostasis including cell survival, proliferation, adhesion and migration. Their deregulation has been associated with many human diseases, including immune-mediated disorders and cancer. Targeted therapy by receptor tyrosine kinase inhibitors revolutionized cancer therapy . VEGF reH2 dominated immune response is essential in the pathogenesis causing eczematous dermatitis with intense pruritus accompanied by elevated serum concentrations of IgE. AD is commonly associated with other TH2 mediated allergic diseases called the “atopic-allergic march” (Atopic dermatitis (AD) is the most common inflammatory skin disease. A Tc march” .H2 response and allergen-induced sensitization  in vitro. This suggests that IL-4 receptor signaling in keratinocytes can further contribute to barrier impairment and inflammation in AD  then act as effectors inducing keratinocyte proliferation and hyperkeratosis. They also enhance the production of inflammatory cytokines and chemokines  by keratinocytes, leading to recruitment of other effector cells like neutrophils, further contributing to tissue damage and establishing the inflammatory milieu  have been approved for the treatment of psoriasis in the last few years . IL-23 r lesions . Sano et lesions . Epiderm lesions .Pharmacological inhibition of the Jak-Stat pathway showed promising results in murine models of psoriasis reducing disease pathology, keratinocyte-activation, and proinflammatory cytokine levels , 98, 114Topical treatment provides an excellent opportunity to overcome possible systemic adverse effects. Tofacitinib ointment also showed greater efficacy compared to vehicle at week 8, but failed to be superior to placebo at week 12 in a phase IIb study . TopicalOral treatment of novel, more selective inhibitors also improved symptoms and were well-tolerated in patients with psoriasis in phase II trials –127, 129H17 cells  is the main cause of non-scarring hair loss most commonly occurring in the scalp. The upregulation of several Jak-Stat pathway components downstream of γ-chain containing cytokines  was detected in AA skin both from humans and mice. In a mouse model of AA, systemic administration of Jak inhibitors successfully prevented the development of disease. Moreover, both systemic and topical administration was able to reverse established disease and even promoted hair regrowth . Gene exIn case of vitiligo cytotoxic T cell-mediated melanocyte destruction causes depigmentation leading to the occurrence of white spots throughout the body surface of patients. IFNγ produced by activated melanocyte-specific cytotoxic T lymphocytes is strongly implicated in the disease pathogenesis by promoting further T cell accumulation in the skin through IFNγ-dependent chemokines like CXCL10 . In addiGiven the multiple role of IFNγ in vitiligo, inhibition of the Jak-Stat pathway may represent a promising therapeutic strategy. Beside some case reports and retrospective studies showing benefits of Jak inhibitors treating vitiligo patients , 153, soAn additional important aspect of AA and vitiligo is that these diseases mostly cause cosmetic concern with emotional problems. Therefore, analyzing the safety and benefit profile of potential treatments is extremely important and Jak inhibitors should be very carefully tested in this regard.Pemphigus vulgaris and foliaceus are severe autoimmune blistering skin diseases with autoantibodies that are directed against the desmosomal cadherins, mainly desmoglein 3 (Dsg3) and Dsg1. These are required for the proper intercellular adhesion of keratinocytes and autoantibody deposition results in flaccid blister formation within the epidermis affecting mucous membranes and skin. Pemphigus vulgaris (PV) can be life threatening causing significant loss of the physical barrier. Application of artificial barriers like ointments can improve barrier function but there is an unmet need for definitive treatment.Given the central role of Btk and Syk in B cell development and activation, these kinases may promote pathogenic antibody production in pemphigus. An inhibitor of Btk is under current evaluation in an open-label phase II clinical trial in pemphigus (NCT02704429) moreover, a randomized, double-blind placebo-controlled phase III study is already recruiting patients (NCT03762265).H2 cytokines like IL-4, IL-9, and IL-21, that utilize Jak-family kinases are known to contribute to the induction and regulation of autoantibody production in pemphigus  is the most prevalent autoimmune bullous disease. Antibody formation directed against key hemidesmosomal components BP180 , and/or BP230 results in subepidermal blistering phenotype. Urticarial plaques and pruritus are also present in most of the cases which is a unique symptom among the pemphigoid group. Epidermolysis bullosa acquisita (EBA) is a very rare disease characterized by autoantibodies directed against type VII collagen (C7), the key anchoring fibril in the upper dermis, also causing subepidermal blister formation .Antibody deposition to the basement membrane is the key feature in the pathogenesis, demonstrated by the fact that passive transfer of either anti-BP180 or anti-C7 antibodies isolated either from human patients or generated against human or murine antigens result in a severe blistering phenotype in mice –176. Thein vitro using human cryosections and in in vivo mouse models  without affecting their intrinsic migratory capacity. Src and Syk kinases are also responsible for the amplification of the inflammation process through the release of mediators that recruit neutrophils and/or directly damage dermal-epidermal junction in experimental pemphigoid models like proteases and superoxide. Therefore, these non-receptor tyrosine kinases may be good candidates for therapeutic intervention in the future, even though the development of specific inhibitors has yet to be solved.Taken together, Fc receptors and βSeveral proinflammatory cytokine levels are elevated in blister fluid of BP patients such as IL-1β, IL-4, IL-6, IL-8, and TSLP , 203–205Almost all patients with systemic lupus erythematosus (SLE) develop lupus-specific cutaneous symptoms at some point in the disease course. There are also patients with cutaneous lupus that do not meet other diagnostic criteria for SLE. SLE is characterized by autoreactive B cells and autoantibody formation which proposes the role for Syk and Btk, non-receptor tyrosine kinases mediating BCR signaling, in disease development. The partially selective Syk inhibitor fostamatinib prevented the development of skin disease and significantly reduced established skin disease in lupus-prone mice . In addiNeutrophilic dermatoses represent a group of disorders characterized by massive neutrophil infiltration in the skin without evidence of infection. Signs of systemic inflammation often accompanies skin pathology and they are often associated with malignancies and autoimmune diseases like RA and inflammatory bowel diseases. Interestingly, autoinflammatory diseases share various common features with neutrophilic dermatoses suggesting some similarities in the pathogenesis . Since aAbnormalities in neutrophil function is obviously implicated in the pathogenesis. The SH2 domain-containing tyrosine phosphatase SHP-1 is essential for inhibiting proinflammatory signal transduction and loss-of-function mutation of SHP-1 in mice causes severe cutaneous inflammation resembling human neutrophilic dermatoses. Kanneganti and her group showed that IL-1α signaling through IL-1R and adaptor protein Myd88 drives inflammation in this model where tyrosine phosphorylation of Myd88 is counterregulated by SHP-1 and Syk . DysfuncCytokine dysregulation are considered as contributing factors to the development of the disease. Elevation of serum G-CSF was detected in patients with active disease of unknown origin , moreoveSafety information from long-term studies of Jak inhibitor treatment are limited due to the novelty of these drugs. Most data are available from RA patients , but theSafety profile is considered generally acceptable, infections and laboratory abnormalities can be observed as major adverse events . The incTaken together, Jak inhibitor treatment has not higher risk than biologics overall. However, skin diseases often present as less severe but chronic symptoms where risk/benefit ratio should be carefully considered upon choosing appropriate treatment. Nevertheless, the possibility of topical application represents an excellent opportunity which deserve further elaboration.The highly effective treatment of various malignancies by tyrosine kinase inhibitors and the regulatory approval of Jak inhibitors for the targeted therapy of rheumatoid arthritis has generated major interest in the therapeutic targeting of other diseases, including inflammatory skin diseases, by tyrosine kinase inhibitors. Besides the most extensively studied Jak inhibitors, compounds targeting other kinases such as Syk, Src-family kinases, or Btk are also expected to emerge as new therapeutics for inflammatory dermatitis. The more and more detailed understanding of individual kinase family members and the development of novel inhibitors with more specifically tailored specificities toward individual kinases are expected to lead to more refined therapies driving the field toward personalized targeted therapeutic approaches. Skin diseases also provide unique opportunities for the development of novel small molecule therapeutics, mostly through the opportunity of topical application without systemic side effects. On the other hand, the cosmetic aspects of skin diseases and the role of skin and mucous membranes as critical barriers between the internal and external environment also present substantial challenges during the development of novel therapeutics. Taken together, the scientific community may expect exciting major advances in the field of understanding and targeting tyrosine kinases in inflammatory skin diseases in the coming years.KS and AM wrote the manuscript. TN provided intellectual advice.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.


Oil palm expansion resulted in 2 million hectares (Mha) of forest loss globally in 2000–2010. Despite accounting for 24% (4.5 Mha) of the world’s total oil palm cultivated area, expansion dynamics in sub-Saharan Africa have been overlooked. We show that in Southwest Cameroon, a top producing region of Africa, 67% of oil palm expansion from 2000–2015 occurred at the expense of forest. Contrary to the publicized narrative of industrial-scale expansion, most oil palm expansion and associated deforestation is occurring outside large agro-industrial concessions. Expansion and deforestation carried out by non-industrial producers is occurring near low-efficiency informal mills, unconstrained by the location of high-efficiency company-owned mills. These results highlight the key role of a booming informal economic sector in driving rapid land use change. High per capita consumption and rising palm oil demands in sub-Saharan Africa spotlight the need to consider informal economies when identifying regionally relevant sustainability pathways. Deforestation for palm oil production is often attributed to large-scale, agro-industrial expansion. Here, Ordway et al. show that much recent expansion in Southwest Cameroon can be attributed to an informal sector of non-industrial producers establishing near informal, non-industrial palm oil mills. Of the four most rapidly expanding oil crops , oil palm (Elaeis guineensis) is the second most significant driver of deforestation, accounting for 2 Mha of forest cleared in 2000–2010 and 1.77 GtCO2e of global greenhouse gas emissions during the same period3. Growing international attention focused on industrial-scale expansion led several corporations to commit to reducing or eliminating deforestation associated with palm oil production from their supply chains5. Because most rapid deforestation driven by oil palm growth has been concentrated in Indonesia and Malaysia, recent expansion in sub-Saharan Africa, the geographic origin of the crop, has largely been overlooked.Oil crops are the leading cause of global land use change. Between 1970 and 2016, oil crops expanded by 150 million hectares (Mha); resulting from a 280% increase in soybean production and 220% increase in palm oil production from 1990 to 20106. Expansion accelerated in several countries from 2000–2014, led by Cameroon7, coinciding with an increase in global palm oil trade due to increased profitability8. Palm oil has long been consumed throughout West and Central Africa. By 2050, edible oil consumption across the continent is projected to triple relative to 20131. This is due in part to high per capita consumption, population growth projections, and increases in per capita GDP. Areas of oil palm suitability in Africa overlap with Congo Basin tropical rainforests, which account for an estimated 25–30% of the world’s tropical forest carbon stocks11. Whether new oil palm plantations in the region are predominantly replacing forests or other crops on previously cleared lands is poorly understood.Although Africa’s contribution to global palm oil supplies atrophied from 77% in 1961 to 4% in 2014, the continent still holds 24% (4.5 Mha) of the world’s total oil palm cultivated area across climatically suitable regions of West and Central Africa12. These efforts draw on international standards established in response to extensive forest conversion in Indonesia and Malaysia, with the most notable examples being the Roundtable on Sustainable Palm Oil (RSPO) and the High Conservation Value (HCV) and High Carbon Stock (HCS) approaches15. Sustainability strategies to date have focused on industrial-scale oil palm expansion20, although research increasingly shows smallholders are an engine of growth23.Despite a lack of information on current oil palm expansion in Africa, 10 countries are proactively seeking strategies for sustainable development of their oil palm sectors through the Africa Palm Oil Initiative24. To prevent post-harvest losses, fruit is typically delivered to a mill within 48 h. Producers are significantly constrained by the location of milling facilities due to this time limit. Expansion pathways thus require consideration of both the producer and mill.Because milling constitutes a critical step in palm oil production, sustainable sourcing practices are targeting industrial mills as a strategic point for intervention. Upon harvest, oil palm fresh fruit bunches (FFB) rapidly decay, degrading the quality of the palm oil produced21.Economies of scale suggests that internal production or processing costs decline as the scale or output of a firm increases. Here, firm refers to an individual or company in the context of production, or a mill in the context of processing. Theoretically, large, well-organized agricultural companies are more likely to expand given their competitive advantage over individual producers cultivating at smaller scales. The prevalence of industrial-scale expansion has been demonstrated empirically in Southeast Asia and parts of South America26, while the clustering of the soybean industry in Mato Grosso, Brazil is a well-known agricultural case27. This density of industry is largely attributable to transportation cost savings and benefits from shared suppliers, labor, and knowledge29.Processing-related internal economies of scale imply that most expansion would occur near high-efficiency mills, given their greater milling capacity. Agglomeration economies, which arise from industry-level benefits that occur when different actors within an industry operate in close proximity, also supports the expectation that clustering is likely near high-efficiency mills. Silicon Valley is a widely cited example of this phenomenon30. Following a government-led rural financing program from 1978 to 1991, the area cultivated by non-industrial producers increased by 570%, now accounting for an estimated 70% of the oil palm planted in Cameroon32. The financing program, known as FONADER , expanded non-industrial oil palm plantations by providing credit, inputs, and technical support through relationships with companies33. To address a national vegetable oil deficit, efforts to support small-scale producers were renewed in 200334. Although oil palm cultivation in Cameroon is carried out across a range of production scales35, recent foreign investment in Southwest Cameroon by a third agro-industrial company  has led to concern of industrial-scale expansion36.In the 1970s, large, agro-industrial companies cultivated 90% of the oil palm in Cameroon38. Unlike industrial mills, which are more comparable to mills operating in Indonesia and Malaysia, most recently established non-industrial mills are unregulated and vary widely in scale and the quality of oil produced, ranging from completely manual to fully mechanized systems.Before government interventions, two companies (PAMOL and Cameroon Development Corporation) owned and operated nearly all palm oil mills in Southwest Cameroon. As the number of producers grew, niche milling opportunities emerged from inefficiencies including delayed payments to farmers, high transportation costs, and an inability of existing mills to process peak season productionHere, we explore whether recent patterns of oil palm expansion in Cameroon, Africa’s third largest palm oil producing country, conform to the widely publicized view that large companies drive most expansion and associated deforestation. We examine expansion in the context of producer decision-making from three angles: (1) internal economies of scale related to production costs at the farm level, (2) internal economies of scale related to milling and processing costs, and (3) agglomeration economies . This study presents a spatially explicit analysis of recent oil palm expansion in Southwest Cameroon, a major production region in the Congo Basin. Using Landsat satellite imagery, we measure oil palm expansion and associated deforestation inside and outside agro-industrial concessions from 2000–2015 and analyze the relationship between different milling systems and expansion.39. Expansion began accelerating around 2005 in Cameroon in parallel with production and consumption growth, while on-farm yields stagnated and declined  for every kilometer decrease in distance to an informal mill   was 4% greater for every km decrease in distance to an informal mill Fig. . Given tRapid expansion of oil palm plantations resulting in tropical deforestation in Southeast Asia has focused global attention on the sustainability of the sector. We set out to quantify the extent of deforestation associated with non-industrial oil palm production and explore spatial relationships with high-efficiency, industrial mills vs. other milling systems in Southwest Cameroon, a top producing region of Africa. Contrary to the widely publicized narrative of industrial-scale expansion, most oil palm expansion and associated deforestation did not occur inside large, agro-industrial concessions. Instead, over two-thirds of expansion and deforestation was carried out by non-industrial producers, near small-scale, low-efficiency, informal mills. Findings from this study also demonstrate that oil palm is expanding at the expense of forests throughout the region, unconstrained by the location of company-owned industrial mills. The increased odds of expansion near informal mills and deforestation near the lowest yielding informal mills highlight the key role of a booming informal economic sector in driving rapid land use change.16, we provide evidence that non-industrial producers accounted for twice the area of expansion carried out within industrial concessions in Southwest Cameroon, contributing substantially to deforestation. While we anticipated non-industrial oil palm expansion activity, the magnitude of its role was unexpected given the competitive advantage of large companies associated with economies of scale. The observed non-industrial producer proliferation is, however, consistent with their ability to navigate a complex land tenure system35. Like many West and Central African countries, customary and statutory land tenure systems in Cameroon create a complex legal pluralism under which land users operate42. For example, foreign investment in land for oil palm production in 2009 resulted in the allocation of 73,000 ha of land by the Government of Cameroon under a 99-year lease to a private New York-based firm, Sithe Global Sustainable Oils Cameroon, Ltd. This land was already inhabited by more than 14,000 people, resulting in conflict and opposition that led to a substantial reduction in the lease size and duration43. In contrast, non-industrial producers from Cameroon, who are familiar with customary land tenure systems in their region, are more capable of obtaining the necessary permissions to acquire land for cultivation. The concentration of this non-industrial expansion near informal milling facilities rather than near high-efficiency, industrial mills ran counter to expected patterns based on market efficiencies associated with economies of scale. However, it is consistent with research demonstrating the important role of informal economies in sub-Saharan Africa, which account for over 60% of the continent's total GDP44.Despite concerns that industrial-scale oil palm expansion threatens African tropical forests35. Although informal mills are highly labor intensive and low yielding, they appear to offer producers several benefits over the agro-industrial milling alternative, evidenced by the region’s boom in informal mills since 2000. Given relatively low installation costs, particularly for manual mills, the informal milling sector in Cameroon is far more dynamic than industrial milling operations which require significant investment. Several informal mill managers reported starting with manual presses and upgrading to semi- and fully-mechanized systems. Because of this dynamism, the expansion of oil palm cultivation and mills co-occur, whereby non-industrial producers become established in areas prior to informal mills in some cases, and producers establish near existing informal mills in other cases.Non-industrial producers actively expanding and clearing forest operate across a range of production scales, supplying to a variety of milling systems that provide palm oil to local and regional consumers through complex, dispersed supply chains45.In addition to our finding that non-industrial producers aggregate near informal mill operations, our results demonstrate that informal mill operations aggregate near company concessions where companies are actively clearing land explicitly for oil palm production. Agro-industrial companies exclusively use their high-efficiency mills. One possible explanation for this pattern relates to FFB theft. The companies that own actively expanding concessions have reported rampant FFB theft from their plantations, in some cases arguing that stolen FFB are supplied to nearby informal mills28. Poor road conditions in Southwest Cameroon and the lack of access of most farmers to transportation options meets the high transportation cost condition. The condition that input demand of an individual mill is low relative to production is supported by our observation that most informal mills operate at very low capacities. As a result, many informal mills report an inability to process the FFB production from their supply shed within the preferred 24–48 h window, particularly during the peak season. Industrial mill managers also cite a frequent inability to keep up with processing demand during the peak season30, suggesting excess FFB supply at least seasonally.Another possible explanation relates to agglomeration benefits derived by informal mills. Informal mill operators benefit from agglomeration through improved road conditions, a higher concentration of input suppliers, and greater crop-specific agronomic knowledge and informational exchange near large company concessions. Agglomeration theory supports the clustering of mills around shared input suppliers  if transportation costs are high and the input demand of an individual mill is not large enough to exploit the scale economies of oil palm productionThe establishment of non-industrial producers near agro-industrial concessions may also relate to direct contractual relationships with companies, in which case a producer may acquire access to land, transportation to the company’s industrial mill, high-yielding seedlings, or labor for harvesting. Because large companies face lower mill installation and processing costs relative to independent, informal operators stemming from milling-related scale economies, they should out-compete smaller mill operators. However, seasonal limitations to the benefits a producer gains from association with industrial mills appear to support a competitive advantage in small-scale milling alternatives.46. Strong seasonal precipitation trends result in fluctuating palm oil market prices based on peak and low production seasons. During the low period of oil palm production (June-September), which coincides with the short dry season, regional palm oil prices can increase substantially given restricted FFB supply. Despite this, agro-industrial mills buy at a fixed price, making them less competitive than informal mills whose oil prices are allowed to fluctuate between the low and peak seasons based on supply46. Producers and traders often retain palm oil produced during the peak season to sell during the low season, when prices are higher. Supplemental income from this type of storage is not possible when a producer sells their FFB to a high-efficiency industrial mill, since they do not recuperate any palm oil to be sold as a value-added product35. Additionally, as oil palm cultivation has become increasingly widespread, many producers face difficulties transporting their FFB to the five industrial mills concentrated in the southern third of the region, particularly during the rainy season on unpaved roads.The seasonality of FFB production, palm oil prices, and transport costs have been shown to incentivize producers supplying to agro-industrial mills in Cameroon to seek alternatives46. This needs to be further researched. Whether producers are seasonally taking advantage of the informal milling sector or abandoning their relationships with industrial mills altogether, high local and regional demand for red palm oil ensures a relatively stable and persistent market for palm oil produced by informal mills. Non-industrial mills also provide a major source of income to rural households, with job opportunities for both skilled and unskilled workers, including positions held by women, a feature absent from most industrial-scale operations47.It is likely that some producers supply to both industrial and informal mills, depending on seasonal processing demand, transportation costs, and palm oil pricesWhile these mills offer additional benefits for non-industrial producers, including an alternative source of income and greater autonomy, our findings shed light on the need to account for this informal economy when developing sustainable palm oil sector pathways. We found widespread expansion among non-industrial producers. This expansion, in combination with an increased need for milling alternatives, has led to a rapid rise in informal mills. We demonstrate that the proliferation of informal mills is buttressing oil palm expansion and associated deforestation throughout the region by reducing a producer’s geographic tie to the handful of existing high-efficiency industrial mills.1. Because both large and small-scale producers in Malaysia and Indonesia rely on industrial mills for processing, corporations attempting to eliminate deforestation from their supply chains have identified these mills as a key leverage point for regulating the land use practices of their suppliers. Although, comprehensively identifying all the producers who supply to each mill and tracking associated deforestation remains a challenge. In Southwest Cameroon, we found that industrial mills represent a mere 1% of all processing facilities in the region and only 28% of the regional processing capacity. Given the widespread use of informal mills, tracking deforestation through mill certification becomes an even greater hurdle, suggesting that current, non-state palm oil sustainability approaches  targeting industrial mills and their supply shed as a certifiable unit will fall short in this context. Additionally, many of these unregulated, low capacity mills have poor environmental management  and health standards .Unfortunately, the increase in cultivated area by non-industrial producers is unlikely to satiate increasing regional demand for palm oil and will likely result in further expansion given low on-farm yields combined with the limited capacity and low extraction rates of informal mills. Furthermore, our finding that non-industrial producers are actively expanding and clearing forest near low-efficiency, informal mills highlights the need to consider this informal sector in future sustainability solutions. By contrast, palm oil processing in Southeast Asia is dominated by industrial milling due to the relatively recent introduction and rapid modernization of the oil palm industry that began in Malaysia in the 1960s and expanded to Indonesia24. Given concerns about future oil palm expansion moving to Africa16, improved understanding of existing expansion dynamics offer insights into regionally relevant strategies for avoiding large-scale deforestation associated with commodity crop expansion. Although this study focused on Cameroon’s top producing Southwest region, oil palm has been produced and consumed widely across West and Central Africa for thousands of years24. Further research is necessary to verify whether our results are generalizable to other regions of Cameroon, and other African countries. However, our findings are generally consistent with recent research indicating that small-scale agricultural expansion has become the dominant driver of deforestation and disturbance in Congo Basin countries, doubling between 2000 and 201448.Our results point to the widespread use of non-industrial milling systems for oil palm production that is common across producing regions in Africa , owing to the long history of production and consumptionFar from a static system, the dynamic and evolving oil palm sector in sub-Saharan Africa presents unique sustainability challenges and opportunities. Findings from this research shed light on important land use change differences in the sector relative to its Southeast Asian counterparts, stemming from small-scale expansion associated with a dynamic informal milling system, linked to local and regional supply chains. Although our results highlight a connection between informal mills and unsustainable forest clearing, widespread use of these mills with low capacities and extraction rates presents a considerable opportunity to prevent further deforestation and increase palm oil yields at the processing stage and achieve major production gains from the existing cultivated area. High per capita consumption and rising palm oil demands in sub-Saharan Africa spotlight the need to consider these differences when identifying regionally relevant sustainability pathways.32. Across the study region, elevation increases from sea level (0 m) to more than 4000 m above sea level at the summit of Mount Cameroon. Mean annual precipitation averages 2900 mm, ranging from ~2100–3500 mm49. Rainfall is distributed during a short, wet season from September until late November and a long, wet season from late March until June, with air temperatures averaging ~23 °C annually. Estimates of average aboveground biomass in the region range from 209–300 Mg C ha−151.We mapped oil palm expansion in Cameroon’s top-producing Southwest Region. We restricted the analysis due to persistent, heavy cloud cover during the study period in the Littoral and Central Regions, preventing a comprehensive remote sensing analysis. In the Southwest, we limited our analysis to the humid forest zone agro-ecologically suitable for oil palm production according to Cameroon’s Research Institute for Agricultural DevelopmentOil palm expansion across Southwest Cameroon was mapped from 2000–2015, a period of national growth in production and area expansion of the crop  values <27 °C (drawn from ACCA)52. All bands were used in cloud and cloud shadow scoring. Scores were linearly rescaled to normalize values between 0–1. The algorithm selected sensor-radiance data identified as having the lowest TOA cloud and cloud shadow score on a pixel-by-pixel basis, resulting in nearly cloud free composites for each year.Each pixel was scored across all scenes within the filtered date-range based on the presence of cloud and cloud shadow contamination, defined by physical properties. Due to the bright and cold nature of clouds, all types of clouds should have Band 7  TOA reflectance larger than 0.03  and thermal infrared  softwareRandom Forest models (hereafter RF) were used to classify imagery in 2000 and 2015. Input data in the RF models included surface reflectance, sub-pixel information on fractional vegetation cover, topographical and texture data, and three vegetation indices (NDVI and Tasseled Cap greenness and wetness). The RF models were trained to classify the following land cover types: forest, mature oil palm, immature monoculture, and other land cover  were grouped into a single class. Image classification was conducted using the randomForest package in R. One-third of the training data were randomly selected and withheld from the model fitting process and used as a test dataset to estimate classification accuracy. Area weighted accuracies were calculated using methods described in Olofsson et al.n = 23,347). We visually identified whether these pixels classified as immature monoculture in 2015 were immature oil palm using high-resolution imagery from Google Earth and DigitalGlobe data from the Mapbox Editor. Despite being spectrally indistinguishable from other monoculture systems using Landsat data at 30 m resolution, we found that detection of immature oil palm plantations using the human-eye was straightforward at high spatial resolutions (roughly ≤5 m).The immature monoculture class in the Southwest Region of Cameroon is comprised of one of three crop types: oil palm, banana, or rubber. Owing to the high fraction of immature monoculture pixels in 2015, and because immature mono-cropped oil palm was not spectrally distinguishable from immature mono-cropped banana or rubber, we relied on a manual, visual interpretation method to estimate the fraction of pixels classified as immature monoculture that were immature oil palm. We estimated this fraction by sampling ten percent of all pixels characterized as forest or other in 2000, and immature monoculture in 2015  of the randomly sampled pixels that transitioned to immature monoculture in 2015 were immature oil palm. In contrast, 35% were either another type of immature monoculture system (banana or rubber) or were misclassified. Of the area forested in 2000 that transitioned to immature monoculture systems, 92.78% was a transition to immature oil palm, while 7.22% was a transition from forest to some other type of immature monoculture system. Based on this estimated fraction of immature oil palm within the immature monoculture class, 45.26% of land area converted to oil palm in 2015 was mature oil palm and 54.74% was immature oil palm.57. Image differencing provides a method for detecting biophysically relevant vegetated areas that underwent change. To conduct image differencing, we quantified changes in five spectral indices from 2000–2015: Tasseled Cap greenness and wetness, and the three sub-pixel bands on fractional vegetation cover. A change detection threshold at ±2 standard deviations around the mode was defined based on expert knowledge and previous studies58. Pixels were included if they exceeded this threshold for at least two indices.Rather than relying on the two classified maps to detect areas of oil palm expansion from 2000–2015, which can lead to error propagation, we used a hybrid approach that combined image differencing with post-classification results to characterize from-to land cover transitions60 included in this definition. Any change detection pixel that underwent a transition from forest to mature oil palm monoculture was considered deforestation due to oil palm expansion.This image differencing analysis identified locations of biophysical change across the landscape, resulting in a dataset of change pixels fewer in number compared to pixels identified as undergoing a transition based on a comparison of the classification maps alone. Within these change pixels, classification maps for 2000 and 2015 were used to determine the land cover transition from 2000–2015. Forest conversion to oil palm  was defined as a stand-replacement disturbance, with detectable forest degradation−1), extraction rate (%), and the year of establishment , capacity  and population density  as measures of market access, drawn from WRI61 and AfriPop62 respectively.Oil palm producers’ point of entry in the palm oil market is via mills. We included three mill covariates, two of which were measures of distance (km) distinguishing between high-efficiency industrial mills, and low-efficiency informal mills. Given the heterogeneity among informal mills, we also included extraction rate (%) as a proxy variable for mill type. Oil extraction rate is a widely used metric of mill performance within the oil palm industry relating to milling productivity. It is the percentage of the weight of palm oil recovered from a known weight of FFB processed. Thiessen polygons were used to construct a defined area of influence around each mill. Each Thiessen polygon was assigned the value of the mill extraction rate. The highest extraction rates correspond to mechanized, agro-industrial mills (20–22%), while manual mills have the lowest extraction rate (12%). In sub-Saharan Africa, an oil palm producer’s market access can also be influenced by their connection to informal supply chains, whereby producers sell directly to local consumers61. These data do not specify crop type and thus broadly refer to concession areas leased by agro-industries. Within Southwest Cameroon, they are used for cultivating rubber, banana, or oil palm. Distance to a community forest was included to control for the influence of land allocated by the government of Cameroon to communities within the non-permanent forest domain61. Beyond this high-level land allocation information, a lack of data made it impossible to include customary land tenure in the models, although we recognize that complex land tenure systems in the region likely influence land use decision-making64.Locations within agro-industrial concessions were identified using data from WRI−1), elevation (m) and topographic wetness index (unitless) were included as measures of agroecological suitability. Rainfall patterns, an important determinant of FFB yields, vary across the Southwest Region, with some coastal areas averaging over 3000 mm yr−1. Producers in Cameroon report locations with high rainfall, but less persistent cloud cover as ideal for achieving higher on-farm FFB yields. Across the tropics, lower elevation areas tend to be most susceptible to agricultural expansion given their greater accessibility65. We also included topographic wetness index (TWI) as an agricultural suitability measure, corresponding to a location’s hydrological propensity for inundation  or runoff . Elevation and TWI were estimated using Shuttle Radar Topography Mission (SRTM) data66, and mean annual precipitation was calculated using CHIRPS49.Finally, mean annual precipitation . The second estimated deforestation due to expansion, relative to the conversion of other land cover types, on a reduced dataset that included only grid cells where expansion occurred . Due to the rarity of expansion at the landscape scale, the expansion regression was fit using a weighted loss function. A weight variable was calculated by summing all no-expansion pixels and all expansion pixels and assigning no-expansion pixels a weight of the sum of expansion pixels divided by the sum of all pixels included in the analysis. Expansion pixels were assigned a weight equivalent to the sum of no-expansion pixels divided by the sum of all pixels in the analysis. The weight variable was included in the model by assigning the calculated weights within the glm function in R.Using results from the change detection analysis, we conducted two spatial analyses to evaluate the effect of the above variables on oil palm expansion. First, we developed a binomial logit model to estimate oil palm expansion across the entire Southwest Region. In areas where expansion took place, we then modeled deforestation due to oil palm expansion relative to expansion at the expense of other land cover types, for example replacing a rubber plantation or mixed crop farm. We fit two separate logit models. The first regression estimated oil palm expansion using all expansion and non-expansion grid cells , which was chosen to provide results at a regionally relevant scale, where farms range from one to thousands of hectares. To distinguish between milling effects on expansion occurring inside agro-industrial concessions compared to outside, we included a concession dummy variable with locations inside concessions equal to one. By interacting the concession dummy with distance to high-efficiency industrial and low-efficiency informal mills and mill extraction rate, we estimated their effects separately on land use change inside vs. outside an agro-industrial concession. This allowed us to identify differences in milling effects on oil palm expansion and deforestation depending on whether the expansion was carried out by agro-industries or non-industrial producers. Correlation analyses were performed between explanatory variables to ensure no collinearity existed in the dataset  for the non-spatial oil palm expansion model, and 0.102, relative to an expected value of −0.003  for the non-spatial deforestation model. To address the issue of spatial autocorrelation, autocovariate regressions were fit by including a spatial autocovariate term in each model. Dormann67 and Dormann et al.68. put forth the claim that autocovariate models can underestimate the effects of important parameters and generate bias in the estimates. Bardos and coauthors demonstrate, however, that this is not the case when a valid neighborhood weighting scheme is employed69. We used the spdep and lattice packages in R to calculate neighborhood weights using the method described in Bardos et al.69. Parameter estimates from the spatial autocovariate regression were comparable to the non-spatial models  and deforestation  models. To evaluate performance of the overall model, prediction error was calculated as the average area under the receiver operating characteristic (ROC) curve (AUC) across all cross validation test sets using the ROCR package in R  standard errors were calculated using White’s estimator via the foreign and sandwich packages in R. Results are reported from the spatial autocovariate oil palm expansion (Supplementary InformationPeer Review File


Reactive oxygen species (ROS) molecules are implicated in signal transduction pathways and thereby control a range of biological activities. Immune cells are constantly confronted with ROS molecules under both physiologic and pathogenic conditions. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive, immature myeloid cells and serve as major regulators of pathogenic and inflammatory immune responses. In addition to their own release of ROS, MDSCs often arise in oxidative-stress prone environments such as in tumors or during inflammation and infection. This evidently close relationship between MDSCs and ROS prompted us to summarize what is currently known about ROS signaling within MDSCs and to elucidate how MDSCs use ROS to modulate other immune cells. ROS not only activate anti-oxidative pathways but also induce transcriptional programs that regulate the fate and function of MDSCs. Furthermore, MDSCs release ROS molecules as part of a major mechanism to suppress T cell responses. Targeting redox-regulation of MDSCs thus presents a promising approach to cancer therapy and the role of redox-signaling in MDSCs in other disease states such as infection, inflammation and autoimmunity would appear to be well worth investigating. Thei+) MDSCs . The pol+) MDSCs . Althoug+) MDSCs , 7. In aA state of “oxidative stress” describes a situation where high levels of ROS -derived from cellular metabolism, toxic insults, or oxidative burst- outbalance the anti-oxidative system . This brThe most prevalent intracellular sources of ROS are mitochondria and NADPH oxidases (Nox) but beyond this, the ER and also the peroxisome (organelle that metabolizes long chain fatty acids) generate ROS molecules. Nox-mediated release of ROS induces the so-called oxidative burst and eliminates invading microorganisms . The relMitochondrial ROS are central regulators of the innate immune system. They are indispensable for Toll-like receptor (TLR)-initiated pathways . In detaFurthermore, mitochondrial ROS and ROS derived from other sources and cellular metabolism are intimately linked. Oxidative phosphorylation (OXPHOS) is a major cellular source of ROS and requires adequate availability of antioxidants to prevent apoptosis. One advantage of glycolysis over OXPHOS lies therefore in a better maintenance of the redox balance. Lian et al. recently observed that MDSCs counteract OXPHOS-derived ROS by upregulation of glycolysis, thereby protecting MDSCs from apoptosis Figure  23). We. We23). Redox signaling is moreover involved in several signal transduction pathways. In most cases cystein (Cys) residues serve as redox-dependent switches and the oxidation/reduction of specific amino acids, that bear reactive Cys residues, induces activation, or inactivation of target proteins such as phosphatases. Moreover, ROS modulate antioxidant enzymes that not only serve as scavengers but also transduce redox-dependent signals . GSH is 2O2 with catalase induces differentiation of immature myeloid cells into macrophages in mice bearing tumors  in cancer, and also in inflammatory conditions  M-MDSC suppressed B cell responses at least in part by ROS mediated suppression , 53. AstIt is of note that HIF-1α and Nrf2, which are both involved in redox-signaling and oxidative stress responses, emerge as critical regulators of MDSCs. Beyond redox regulation; both factors control other mechanisms and thereby regulate MDSC fate and function.A critical role of HIF-1α signaling in MDSCs is described in murine cancer models, such as hepatocellular carcinoma (HCC) , 55, 56 202 production. Intracellular oxidative stress and apoptosis were enhanced in the absence of Nrf2. However, myeloid-lineage specific Nrf2 deficiency enhances lung metastasis and has been shown to lead to an aberrant ROS accumulation in myeloid cells  is a potent Nrf2 activator and has been found to reduce MDSC production of ROS and tumor growth in mouse tumor models . CDDO-MeKO and KT both researched data for the article, contributed to discussion of the content as well as writing and reviewing of 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.


A total of 125 adult consumers from a rural setting in Malawi evaluated maize-based stiff porridges made thereof using a 7-point hedonic scale. Subsequently, the participants were asked to guess an ingredient that was added to some of the test samples. The 10% and 20% soybean-enriched maize-based stiff porridges scored 5/7 and above, with some being statistically similar to plain maize-based stiff porridges. No participant recognized that soybeans were incorporated into the maize-based stiff porridges. The study has clearly demonstrated the potential of enriching maize-based stiff porridge with hydrothermally treated soybeans without compromising consumer acceptability. This innovation could significantly contribute towards reducing the burden of energy-protein under-nutrition in SSA.Maize-based stiff porridge, a starchy protein-deficient staple food, dominates among the populations in sub-Saharan Africa (SSA). Unfortunately, this is often consumed along with leafy vegetables since the majority of the population in this region lack resources for the purchase of high protein animal source foods, a situation that exacerbates protein-energy malnutrition. Considering this, the current study evaluated the effect of enriching maize-based stiff porridge with flour made from hydrothermally treated soybeans on consumer acceptability. A total of nine experimental flours were prepared from maize and maize-soybean mixtures following a 3 Zea mays L.), a cereal with low protein content (10%), is the key staple crop in SSA which is largely consumed as a main dish during lunch and dinner in the form of a stiff porridge. The stiff porridge is usually prepared using flour made from whole maize, non-fermented degermed-dehulled maize or fermented degermed-dehulled maize and is called nsima in Malawi, nshima in Zambia, sadza in Zimbabwe, ugali in Kenya and Tanzania, mielie pap in South Africa, and many other names across SSA. Unfortunately, the majority of the population in SSA lack resources for the purchase of high protein animal source foods such as meat, milk, eggs, and fish protein [Protein-energy malnutrition is a major public health concern in sub-Saharan Africa (SSA) ,2. Besid protein . Consequ protein .Legumes are nutritionally valuable protein sources 20–45%) that offer a cheap option for upgrading the nutritive value of cereal-based foods. Owing to the high protein content, soybeans are the most popular legume used to enrich porridge served as breakfast for the whole family, and as a complementary food for infants and young children in SSA % that of. The soyOff-beany flavors in soybeans described as ‘‘painty, bean, green, and unpleasant’’ are an activity of endogenous lipoxygenase enzymes which catalyze the insertion of oxygen into polyunsaturated fatty acids producing hydroperoxides, which subsequently participate in autoxidation process leading to the production of off-flavor compounds—particularly hexanal and heptanal . LipoxygDespite the feasibility and widespread application of hydrothermal deactivation of lipoxygenase in soymilk industry, no report is available about the evaluation of this technique in the preparation of odorless products for the enrichment of protein-deficient maize stiff porridge. Therefore, the objective of this study was to investigate the effect enriching maize-based stiff porridge with flour made from hydrothermally treated soybeans on consumer acceptability. In this study, the effect of soybean proportion and the maize flour type are investigated, and the nutrition implication of soybean enrichment is discussed. 2 factorial design involving two factors, namely maize flour type  and soybean proportion  as summarized in A total of nine experimental flours were prepared from maize and maize-soybean mixtures following a 3The soybeans  were first hydrothermally treated to take care of the beany-grassy flavor in the following manner: Clean soybeans were gradually introduced into boiling water without causing the water to stop boiling (one part soybean to three parts water) for an hour, cooled in water, and manually dehulled by means of scrubbing the soybeans between two hands to force the hulls from the cotyledons. The dehulled soybeans were then washed and sundried for two days. To ensure homogeneity of the maize-soybean flour mixtures, the dried thermally processed soybean beans were thoroughly mixed with the maize portion (dry maize or dry dehulled maize grits) wherever applicable before the milling process see . In thisFive experienced women were engaged to jointly prepare nine maize stiff porridges, using each of the nine flours described in A total of 125 adult consumers (aged 18 years and above), without soy allergy, who regularly consume maize-based stiff porridge, were recruited from Lilongwe, rural Malawi, for this study after giving their informed consent. The recruits (participants) were predominantly female (63.2%), and more information about the participants is given in Considering that consumer opinions are influenced by how much information has been presented to them about the products before tasting ,18, the Each participant independently evaluated all of the nine maize-based stiff porridge samples (~8 g of each sample). The samples were presented one after the other, coded with random 4-digit numbers. The samples were served on white plates using a completely randomized balanced block design. In additional to asking the participants to rinse their palates with distilled water, five-minute breaks were also included between sample evaluations to minimize carry-over effects. A 7-point facial hedonic scale  was used to score the participant’s overall acceptability of each sample to accommodate those who did not attend any form of education or had low-level education attainment . A scoreUpon evaluating the nine test samples, the participants were asked to guess an ingredient that was added to some of the test samples. Finally, the participants were informed about the inclusion of soybean and the processes involved. p < 0.05). All statistical analyses were done in XLSTAT 2017 .A two-way ANOVA was used to test the main effects and interactions among the independent variables (maize flour type and soybean proportion). Post-hoc mean separations were carried out using Tukey’s honestly significant difference test at a significance level of 0.05 . It is therefore not surprising that maize flour type, soybean proportion, and the interaction between maize flour type and soybean proportion had a significant effect on the acceptability of the resultant stiff porridges as shown in However, stiff porridges made from blended flours of non-soaked dehulled maize (DM), irrespective of soybean proportion, had relatively higher acceptability scores that were not significantly different from soaked dehulled flour (SDM) and whole maize (WM) plain flours, respectively  more often than from dehulled maize flour (DM) , in this2. The novel maize-soybean stiff porridge provides a viable nutritious alternative staple for people living in the SSA. The stiff porridge made from maize-soybean blended flour not only contains higher amounts of protein, but also a higher content of lipids and micronutrients than the common maize-based stiff porridge. Since soybeans contain approximately 40% proteins and 20% lipids , while mIt is worth highlighting here that there have been exploratory initiatives aimed at enriching staple foods with legumes before. Notably, Bressani et al.  evaluateThe study had certain limitations in that it did not systematically optimize the maize stiff porridges as it only investigated products with soybean proportions of 0, 20, and 30%. While stiff porridges containing 30% of soybean were less liked by the participants, it is possible that higher proportions of soybean between 20% and 30% would give a favorable outcome. Further, the study did not investigate the effect of various processes involved in the preparation of the soybean on nutrient retention and bioavailability. Such information would help to optimize nutrient losses and improve nutrient use efficiency. Nonetheless, given the positive outcome recorded in our research with HIV-positive women , there iThe present study has demonstrated that it is possible to enrich maize-based stiff porridge with hydrothermally treated soybeans without compromising acceptability. Although the study involved participants from a single locality , the results herein may have wide application across SSA, particularly among the resource-limited poor who have minimal access to animal source protein foods, considering that soybeans potentially grow almost everywhere across the region. Unlike soybean-based ordinary porridges that are served as breakfast for the whole family and as complementary food for infants and young children, soybean-enriched maize stiff porridges have the potential of significantly contributing to the fight of energy-protein under-nutrition as stiff porridges are consumed by almost everyone in optimal quantities (dry matter basis) and regularly during lunch and supper. Future efforts should assess the feasibility of this innovation based on cost.


A woven coronary artery is a rare congenital coronary anomaly and incidentally found in coronary angiogram. Coronary angiography is the major diagnostic modality, which shows the main trunk of coronary divides into several channels which later reconnect with normal blood flow (J Int Cardiol 113:121-123 2006). However, some cases and reviews inferred that this characteristic might be mimicked by recanalized coronary thrombus, which occurs following thrombotic occlusion. In some case, the multiple intraluminal channels have a ‘Swiss cheese’, a ‘Spider web-like’, a ‘Honeycomb’ or a ‘Lotus root’ appearance and most of them appear in local segment . As these images are nonspecific findings, there is no angiographic uniform definition of intracoronary thrombus. More information about the characteristics and the development of this woven-like structure is needed.A 67-year-old male patient was admitted to our hospital because of chest pain. Coronary artery angiogram revealed that the right coronary artery (RCA) divided into multiple thin channels from proximal to distal, which was similar to the so-called woven coronary artery. Compared with his prior coronary angiograms which showed a tiny hazy lesion in distal segment of RCA, we found the woven-like phenomena should be caused by a late-stage recanalized coronary thrombus. Percutaneous coronary intervention (PCI) was performed to restore the RCA flow, and the angina symptom was extremely improved during clinical follow-up.The diagnostic criteria of woven coronary artery was based on angiographic image. However, some cases and reviews inferred that thrombotic recanalization might also share the same characteristic. In this case, we collected the baseline angiograms and intracoronary images then successfully diagnosed the woven-like RCA as thrombotic recanalization. For this kind of woven-like coronary artery, PCI could be a better treatment strategy. Detailed history collection and intracoronary image techniques should be emphasized in future clinical practice in the differentiating and treatment of woven-like phenomena. Woven coronary artery was described by Sane for the first time in 1988 [A 67-year-old male patient was admitted to our hospital for chest pain in August 2018. The electrocardiograph showed atrial fibrillation in rhythm and Q wave in the inferior leads. Transthoracic echocardiography showed inferior wall with decreased left ventricular ejection fraction (LVEF) of 40%. The patient was admitted in hospital 6 years ago. Unluckily, all the information was untraceable. Coronary angiography (CAG) was suggested and performed on 31st July 2018. We found that his main trunk of RCA was divided into multiple twisting small channels from proximal to distal, which reconnected at the level of posterior descending artery (PDA) with normal blood flow, the posterior lateral branch (PLB) was totally occluded and supplied by contra-lateral collaterals. The LCA was normal  was normal  overlapping from the proximal of first PDA to the ostium of RCA, rivaroxaban (2.5 mg bid) and metoprolol (47.5 mg q d). During 9-months clinical follow-up, the patient had no angina episode, the echocardiography showed systolic function of inferior wall was improved and LVEF was 44%.A woven coronary artery is characterized by branching the coronary artery into several smaller vessels, which reconnect distally after twisting along the coronary axis with normal blood flow. As there are very few numbers of woven coronary artery cases, the etiology of this anomaly is not fully explained yet. One case report examining the histopathology of woven coronary artery showed that these lumina shared a coat of elastic tunica and each of them had endothelial coat . BecauseThrombotic recanalization is an entity occurs after thrombotic occlusion. It is rarely recognized in clinical practice and often misdiagnosed because the angiographic image has nonspecific characteristic. As angiographic findings such as irregular filling defects and intraluminal haziness are not specific, there is no angiographic uniform definition of intracoronary thrombotic recanalization. Intravascular imaging and prior angiographic image should be helpful for the diagnosis.Most cases of thrombotic recanalization show it happens in a local or short lesion. Our case reported an extremely long segment of woven-like coronary change derived from a previous coronary thrombus event. Differential diagnosis of such woven-like images has significant therapeutic consequence. As the lumina of woven coronary artery has endothelial coat which could be identified by Intravascular imaging, Intravascular ultrasound (IVUS) and Optical coherence tomography (OCT) had been reported to be helpful in differentiating thrombus, dissection or woven structures . OCT hasAdditional file 1. The angiogram of RCA before PCI. Contralateral angiogram showed the woven-like change in RCA and the PLB was chronic total occlusion.Additional file 2. The angiogram of RCA after PCI. Final result showed that the side-branches were still intact.


Indicators of resting cardiac autonomic nervous system activity , heart rate, and blood pressure were measured at age 5–6 years. Data on oxytocin receptor gene polymorphisms rs53576, rs2268498 and oxytocin polymorphisms rs2740210, rs4813627, were collected (N = 966 included). If the child was carrier of the rs53576 GG variant, exposure to maternal verbally aggressive behavior (10.6%) was associated with increased systolic blood pressure at age 5–6 . If the child was carrier of the rs2268498 TT/TC variant, exposure to maternal verbally aggressive behavior was associated with increased systolic blood pressure at age 5–6 . No significant interactions of maternal verbally aggressive behavior with oxytocin gene polymorphisms on heart rate or cardiac autonomic nervous system activity were found. In conclusion, oxytocin receptor gene polymorphisms may partly determine a child’s vulnerability to develop increased systolic blood pressure after being exposed to maternal verbally aggressive behavior in early infancy.Early life stress has been shown to contribute to alterations in biobehavioral regulation. Genetic make-up, especially related to social sensitivity, might affect the child’s vulnerability to these alterations. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in changing resting cardiovascular outcomes at age 5–6. In the Amsterdam-Born-Children-and-their-Development-(ABCD)-study, a large prospective, observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13 Infancy is a highly critical period for brain development. During the first months of life, essential brain structures are evolving and in basic structures synaptogenesis is accelerating . ExposurMaternal verbally aggressive behavior in early infancy can be considered a profound early life stressor, as soothing maternal behavior would be more appropriate at this young age. We have recently shown that exposure to maternal verbally aggressive behavior at the age of 3 months is associated with increased systolic blood pressure (SBP) at age 5–6 years . The extOXT) gene and in the oxytocin receptor (OXTR) gene are potential candidates for gene-environment (GxE) interaction due to their differential associations with social sensitivity. Oxytocin is a neuropeptide, predominantly expressed in magnocellular neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei [OXT and OXTR gene polymorphisms may affect the infant’s perception of the social environment.Single nucleotide polymorphisms (SNPs) in the oxytocin  nuclei , which h) nuclei ,7. In ad) nuclei  and ment) nuclei . An impo) nuclei . AlthougOXT and OXTR polymorphisms associated with social sensitivity, such as facial emotion recognition or vocalizing, could be relevant in the context of maternal verbally aggressive behavior. At first, a SNP located in the third intron of the OXTR gene, rs53576, involving a guanine (G) to adenine (A) substitution, has been associated with diminished prosocial features. Individuals with the GG genotype (i.e. the absence of the polymorphism or wild type) display beneficial prosocial traits including enhanced trust, self-esteem and empathic abilities [rs53576 G-allele has been associated with increased amygdala responsiveness to emotional facial expressions [GG carriers were demonstrated to be more sensitive to the social stressor of rejection as indicated by increased stress reactivity of BP and cortisol levels [G-carriers are potentially more socially sensitive, this may render them more vulnerable to a negative social stressor. The second OXTR polymorphism of interest is rs2268498, upstream variant 2KB, located in the promoter region of the OXTR gene. T-allele carriers, both the wild homozygote and the heterozygote type, have been shown to perform better at facial emotion recognition [C-allele carriers.A number of different bilities . Recentlressions , implical levels . Becauseognition  and seemognition ,16, compOXT polymorphisms, rs2740210, located in the 3′ flanking region, upstream variant 2KB, and rs4813627, located 56kb downstream the OXT gene, have been found associated with the duration of maternal infant-directed vocalizing, a measure of maternal engagement [rs2740210 and rs4813627 are related to infant’s social sensitivity.Additionally, two particular gagement . It is nOXTR and OXT SNPs enhancing social sensitivity are more vulnerable to a negative social stressor and display increased stress responses programming biobehavioural regulation with adverse cardiovascular consequences on the long term. Therefore, we aimed to test whether our previously demonstrated association between exposure to maternal verbally aggressive behavior in early infancy and increased SBP in children at age 5–6 [OXTR and OXT SNPs. In addition, we included the cardiovascular outcomes heart rate (HR) and resting autonomic nervous system (ANS) activity at age 5–6. We expected that infants carrying OXTR rs53576 GG or rs2268498 T-allele, who are more apt at recognizing facial emotions, experience more stress in response to maternal verbally aggressive behavior and display more adverse cardiovascular outcomes at age 5–6, compared to infants carrying respectively GA/AA or CC variants. Additionally, we explored whether carriers of one of the different variants of OXT rs2740210 or rs4813627 are more or less vulnerable to adverse cardiovascular outcomes after experiencing maternal verbally aggressive behavior in infancy, compared to carriers of the other variant. As these OXT variants were only investigated in mothers and shown to be associated with maternal duration of vocalizing, of which it is not known which duration is related to social sensitivity, we did not hypothesize beforehand which allele of OXT rs2740210 or rs4813627 would be the risk allele for social sensitivity. Our hypotheses are visualized in Ample evidence has shown that stressful experiences early in life can increase the risk of cardiovascular health problems and diseases in later life through programming of the biobehavioral response to stress, with altered activity of the stress systems, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system ,19,20,21 age 5–6  is moderth week, range 11–25 weeks, SD 2 weeks). Compared to children not exposed to maternal verbally aggressive behaviour, exposed children were slightly taller, had a mother who reported more postnatal depressive symptoms, less pleasure in infant care and more physically aggressive behaviour. When the children were 5–6, their mothers reported more depressive symptoms, more parenting stress, and more often used an authoritarian parenting style, compared to the mothers from the non-exposed children.The characteristics of both the mothers and the children are presented in OXTR and OXT genotype variant of the infant  and in HR of 2.3 bpm  compared to the homozygote rs2268498 TT (wild type) variant. Genotype variant rs2740210 AA was associated with a larger pre-ejection period (PEP) of 2.8 msec  compared to the rs2740210 CC (wild type) variant. Genotype variants rs53576 and rs4813627 were not associated with cardiovascular outcomes   at age 5–6. Adjustment for potential confounding factors (Model 2) only slightly attenuated the association . Maternal verbally aggressive behavior in infancy was not associated with diastolic blood pressure (DBP), HR, PEP or respiratory sinus arrhythmia (RSA) at age 5–6.rs53576GG having experienced maternal verbally aggressive behavior in infancy, showed an increased SBP of 4.9 mmHg  at the age of 5–6 . Secondly, carriers of rs2268498 TT/TC having experienced maternal verbally aggressive behavior in infancy, showed an increased SBP of 3.0 mmHg  at the age of 5–6 . Carriers of rs2268498 CC having experienced maternal verbally aggressive behavior in infancy showed a decrease in DBP of -3.9 mmHg , compared to unexposed carriers of rs2268498 CC  at the age of 5–6  having experienced maternal verbally aggressive behavior in infancy. Although the exposed risk allele carriers display increased DBP, as compared to the exposed non-risk allele carriers, the DBP of the exposed risk allele carriers is comparable to the DBP of the non-exposed infants (and therefore not increased in absolute terms). Nonetheless, our findings could be interpreted being in the direction of the hypothesis: within infants exposed to maternal verbal aggression, those with risk genotype rs2268498 TT/TC display increased DBP as compared to non-risk-carriers rs2268498 CC.An unexpected finding was a decrease in DBP of -3.9 mmHg in carriers of OXT and OXTR polymorphisms. In our study, some genotype variants showed direct effects on cardiovascular outcomes. Replication is needed of both the direct effect of rs2268498 on SBP and HR and the direct effect of rs2740210 on PEP in order to further study the function of these SNPs in cardiovascular regulation.As yet, no literature exists on possible differences in BP, HR and ANS activity directly due to presence or absence of OXTR variant rs2268498 related to vulnerability to increases in SBP after a context of early life stress is highly novel. Our results suggest that an infant’s genetic requisites of better facial emotion recognition, and higher social sensitivity, increases the vulnerability of the exposed child to an increase in SBP at age 5–6. Interestingly, from an evolutionary perspective, OXTR variants rs53576 GG (the wild type) and rs2268498 TT/TC, being more sensitive to the social environment, might create more cardiac output to support a necessary fight or flight response, an adequate environmental adaptation. However, an increased SBP in the long term carries a cardiovascular health risk. Since BP has been shown to track into adulthood, with tracking coefficients larger for SBP than DBP [Our finding of than DBP .Strengths of this study are the large population-based birth cohort, the prospective study design, the extensive data collection from early infancy onwards and BP, HR and ANS measurements according to a standardized protocol. Importantly, we were able to control for a large number of potentially confounding stressors, such as maternal physical aggressive behavior in infancy and authoritarian parenting style at age 5–6. We specifically excluded participants with previously known physiological variables of influence on the ANS and BP such as preterm birth, which is associated with increased sympatho-adrenal activity in childhood .Based on literature on sample size, statistics and selection of SNPs in genetic epidemiologic studies –32, a maMaternal verbally aggressive behavior was considered present if speaking angrily had been present twice or more, at the infant’s age of 3 months. This definition of maternal verbally aggressive behavior seems quite narrow, but, at the same time, encloses all from only twice to frequent exposure to maternal verbally aggressive behavior in early infancy. Face validity of maternal self-reported verbally aggressive behavior will depend on maternal self-reflection. In our study, we did not have information on maternal self-reflection. Therefore, we could not include this covariate in our analyses. Importantly, self-reflection can be influenced by depressive symptoms in a way that it could lead to overestimation of behavior. However, we do not expect mothers to overestimate verbally aggressive behavior. On the contrary, possible social desirability could lead to underestimation of the true frequency of maternal verbally aggressive behavior. Importantly, self-report is the only way to measure verbally aggressive behavior, as continuous observation of the mother-infant dyad is not feasible. In our analyses we did adjust for maternal depressive symptoms both in infancy and at age 5–6. A limitation is that the distinction between temporary, frequent or persistent maternal verbally aggressive behavior to the infant, thus creating chronic stress in the first years, could not be made based on our data. Due to small numbers we were not able to investigate a possible dose-response relationship. Also, we could not assess the possible contribution of paternal aggressive behavior. We suspect that experience of simultaneous other adverse events will probably increase the gene-environment interaction effect.OXTR rs53576 GG (wild type); 19 exposed children with OXTR rs2268498 CC (homozygote recessive type); 44 exposed children OXT rs2740210 CC (wild type); 30 exposed children with OXT rs4813627 GG (wild type)). In order to follow the recommendations of Keller (2014) to properly control for potential confounders [p-values for interaction of the SNPs and maternal verbal aggression in association to SBP minimally changed, and remained significant ; rs2268498* verbal aggression: p = 0.026 (instead of 0.021). We aimed to replicate the results in an independent cohort, but, as far as we know, no other cohort study exists in which both maternal verbally aggressive behaviour at the age of 3 months and blood pressure at age 5 were assessed. Nevertheless, this is an exploratory analysis and our findings on gene-environment interaction by OXTR polymorphisms should be replicated in independent samples.Although the study population was large, the numbers of subjects in various groups in the studied interactions was fairly small 1a and AVPR1b [A first mechanism explaining our findings could be a direct effect of the gene- environment interaction on programming of OXT levels. In a retrospective study, multiple stressful early life events have been linked to reduced OXT levels in the Cerebro Spinal Fluid (CSF) , suggest systems  through d AVPR1b . Some evd AVPR1b , which ad AVPR1b  and poters53576 GG homozygotes, carriers of risk alleles enhancing social sensitivity, display a strong gray matter reduction of bilateral ventral striatum with increasing Childhood Trauma Questionnaire (CTQ) scores as adults [G-allele carriers, being socially sensitive, who had been exposed to early life adverse events [Secondly, striatal volume may be differentially affected by exposure to stress in early life depending on whether the child is a risk-carrier or not. The striatum consists of the ventral striatum (nucleus accumbens and olfactory tubercle) and dorsal striatum (caudate nucleus and putamen) and is activated by unexpected or intense stimuli . Betweens adults , implyine events .Finally, programming of striatal systems, such as the renin-angiotensin system (RAS) and dopaminergic system could differ between the risk and the non-risk carriers. Major components of the RAS, a BP regulator, have been shown to exist in striatal astrocytes and microglial cells . Hyperacrs53576 G-carriers only, peripheral oxytocin level has been negatively correlated with striatal DAT availability [rs53576 variants might be causing an additional difference between carriers and non-carriers of the risk allele. Although speculative, G-carriers might not be able to lower an increased SBP due to programming effects in several systems.Essentially, in lability . This spOXTR related genes are suggested to be a significant factor of vulnerability to increases in SBP at age 5–6. Future studies may address whether the GxE interactions we demonstrated, can be replicated in larger birth cohort studies, in adolescence and adulthood, whether differences between boys and girls exist and whether other cardiovascular outcomes are affected when stress is induced. Finally, studies of possible genetic overlapping functions are needed to further explore the relevance of these promising genetic markers.Concluding, maternal verbally aggressive behavior may be an important early life stressor with negative impact on cardiovascular health later in life. Infant’s variation of The study sample is part of a large prospective, observational, population-based multiethnic birth cohort, the Amsterdam Born Children and their Development (ABCD) study, which started in 2003. Extensive information about the cohort and procedures regarding data collection has been published elsewhere . Data weBetween January 2003 and March 2004, all pregnant women living in Amsterdam were asked to participate in the ABCD study during their first prenatal visit to an obstetric care provider . Of the 12373 women approached, 8266 women filled out the pregnancy questionnaire  (response rate: 67%)). A total of 6735 women gave permission for follow-up. Three months after birth, 5131 women filled out the infancy questionnaire. For the questionnaire at the child’s age of 5–6, addresses of 6161 mothers were retrieved; 4488 mothers returned the questionnaire. Attrition in this follow-up number was due to withdrawal, unknown address, infant or maternal death. Multiple births were excluded from the cohort preceding the third phase. The health check at 5–6 years consisted of various health measurements in 3287 children aged 5–6 years . For the ABCD-Genetic Enrichment (ABCD-GE) study, blood of the child was collected from a simple finger prick during the 5-year health check-up in 1192 children of Dutch descent. DNA was extracted from the dried blood spots. Data on all three measurements  had to be available to be included in the present study. We excluded preterm births  and congenital diseases (N = 966 included). The flow chart of participants included in the present study is shown in th week after birth . Maternal verbally aggressive behavior was assessed using a question about the frequency of speaking angrily to the infant on a six-point scale: ‘Have you ever spoken angrily to your baby in order to diminish the crying?’ The histogram of the answers to this question is shown in Maternal verbally aggressive behavior was assessed by a maternal self-report questionnaire completed in the 13Cardiac ANS activity was assessed at the age 5 health check, using the VU University Ambulatory Monitoring System . Reliability and validity aspects and recording methodology of the VU-AMS have been described previously . The sysRespiratory Sinus Arrhythmia (RSA), a time domain index of Heart Rate Variability (HRV) in the respiratory frequency range, was automatically obtained as derivate of parasympathetic nervous system activity. RSA was taken as the peak valley estimation (pvRSA) which was obtained automatically by subtracting the shortest inter beat interval during HR acceleration in the inspirational phase from the longest inter beat interval during deceleration in the expirational phase. Decreased parasympathetic activity is indicated by a shorter RSA. Pre-ejection period (PEP) is a measure of sympathetic activity. PEP can reliably be measured in children . PEP is Children’s BP was measured twice both in supine and sitting position after a test reading and 5 minutes of rest. BP was measured with the automatic oscillometric method, using the Omron 705 IT  with a small cuff (arm circumference 17–22 cm) on the non-dominant arm. When either the systolic (SBP) or diastolic pressure (DBP) differed more than 10 mmHg between the two measurements, a third measurement was taken (17%). The average of the two measurements closest together was used in the supine and sitting position. For this study we used PEP, RSA, HR and BP in sitting position.−6), or low minor allele frequencies (MAF) (<1%). Moreover, if mismatch in heterozygosity, gender or relatedness existed, individuals were excluded. Genetic markers were imputed using the IMPUTE2 software and the 1000 Genomes References Panel . Genotypes for the SNPs of interest were extracted from the imputed GWAS data set. The final number of SNPs was 277,644. The total of SNPs after imputation was 27,448,454. The mean quality of the imputed genotypes (r2) of the 4 SNPs included in this study  was 0.82, ranging from 0.75 to 0.87 .The finger prick yielded fasting capillary blood samples for DNA extraction. Subsequently, the DNA samples were genotyped, using the Illumina Human Core Exom Beadchip . The Illumina Human Core Exom Beadchip includes over 540,000 genetic markers. Before imputation, SNPs were excluded if they had high levels of missing data   (best approximation of the Wessel’s criteria) [The following child characteristics during infancy were included from youth health care services: sex, birth weight, and gestational age. Excessive infant crying was assessed by questionnaire. Excessive infant crying was considered present if mothers estimated their infant to cry for three or more hours per 24 hour day on average in the 13riteria) .The following maternal characteristics were included during pregnancy: age, parity (0 or > = 1), cohabitation status (single or living together with partner), and level of education (years after primary school). During infancy, maternal depressive symptoms, maternal physically aggressive behavior and maternal smoking at home were included. Maternal postnatal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D) . The sumwww.perinatreg.nl) and classified in accordance with the guidelines of the International Society for the Study of Hypertension in Pregnancy (www.isshp.com). Paternal hypertension and family  hypertension were derived from a questionnaire previously described elsewhere [Additionally the following characteristics were included: maternal pre-pregnancy BMI (kg/m2) and preexistent hypertension (yes or no). Pregnancy-induced hypertension (yes or no) was available by combining data from the questionnaire and the Dutch Perinatal Registration   and analrs53576 (GG vs. GA/AA) or rs2268498 (TT/TC vs. CC) and maternal verbally aggressive behavior and OXT rs2740210 (CC vs. CA/AA) or rs4813627 (GG vs GA/AA) were added to the fully adjusted models to test interaction in risk alleles. Additionally, the data were stratified into two groups  and analyzed separately according to the above model. The statistical analyses were performed by IBM SPSS Statistics software version 20.0 . The significance level we used in the study was 5%.All variables were inspected for outliers and checked on normality. Descriptive statistics were used to describe maternal and child characteristics. Associations between these characteristics and maternal verbally aggressive behavior were tested using analysis of variance for continuous variables and Chi square tests for categorical variables. Associations between the different polymorphisms and maternal verbally aggressive behavior, SBP, DBP, HR, RSA and PEP were tested using analysis of variance for continuous variables and Chi square tests for categorical variables. The associations of maternal verbally aggressive behavior and ANS, BP and HR were analyzed by means of multivariable linear regression analysis. Potential confounders were selected a priori from S1 FigFrequency of speaking angrily = ‘Have you ever spoken angrily to your baby in order to diminish the crying?’ . Maternal verbally aggressive behavior was considered present if speaking angrily to the infant had been present twice or more.(TIF)Click here for additional data file.S2 Figrs2740210. Carriers of rs2740210 CA/AA exposed to maternal verbally aggressive behavior in early infancy have a higher SBP of 3.9 mmHg  than unexposed carriers of rs2740210 CA/AA . (b) Systolic blood pressure (mmHg) according to maternal verbally aggressive behavior, stratified by rs4813627. Carriers of rs4813627 GA/AA exposed to maternal verbally aggressive behavior in early infancy have a higher SBP of 2.8 mmHg  than unexposed carriers of rs4813627 GA/AA .(a) Systolic blood pressure (mmHg) according to maternal verbally aggressive behavior, stratified by (ZIP)Click here for additional data file.S1 TableModel 1: adjusted for sex, height and age of the child; Model 2: Model 1, additionally adjusted for maternal depressive symptoms, pleasure in infant care, maternal physical aggression in infancy, authoritarian parenting style, maternal depressive symptoms and parenting stress (NOSI-K) at the child’s age of 5–6. *Interaction between maternal verbal aggressive behavior in infancy and oxytocin polymorphism *<0.05; **<0.01; ***<0.001(PDF)Click here for additional data file.


This factor may correspond to peptides/proteins , exosomes and their cargo, and metabolites. We hereby review the most remarkable evidence encouraging the possibility of such inter-organ communication, with special focus on muscle-derived factors that may potentially mediate such skeletal muscle-pancreas crosstalk.Skeletal muscle is a main target of insulin action that plays a pivotal role in postprandial glucose disposal. Importantly, skeletal muscle insulin sensitivity relates inversely with pancreatic insulin secretion, which prompted the hypothesis of the existence of a skeletal muscle-pancreas crosstalk mediated through an endocrine factor. The observation that changes in skeletal muscle glucose metabolism are accompanied by altered insulin secretion supports this hypothesis. Meanwhile, a muscle-derived circulating factor affecting  Skeletal muscle is the largest organ in lean humans that plays a main physiological role in insulin-stimulated glucose disposal . To accoAmong muscle-targeted organs, a crosstalk between skeletal muscle and the pancreas has been proposed . Pancrea Whether a similar mechanism is activated under conditions of high glycemia  is unknown. Since skeletal muscle is the main tissue responsible for insulin-mediated glucose disposal , it is iPancreatic insulin secretion must tightly match insulin demands for proper glycemic control. Upon glucose ingestion, the increase in glycemia and glucose transport into pancreatic beta cells may suffice to adapt insulin secretion to insulin demand. In turn, higher glycemia often observed in insulin resistance, especially in postprandial conditions , may alsHowever, convincing evidence shows that blood glucose concentration cannot entirely accommodate insulin secretion to insulin demand , 1990. AA large-scale, multi-center study investigated which factors determine the change in insulin secretion (by plasma C-peptide concentration) during an isoglycemic-hyperinsulinemic clamp . The anain vitro data showing that insulin stimulates its secretion  in individuals with normal and abnormal glycemic control . Blood gecretion .in vitro) stimulates its secretion   and a gac islets . Moreovec islets , adding Myokines having influence on insulin secretion should express their receptors in pancreatic islets. Because dozens and even hundreds of proteins have been detected in conditioned media from human muscle cells , we firsThe effect of specific myokines on beta cell function has been assessed by using their recombinant forms. IL-6 showed a stimulatory action on GSIS in mice after an acute injection (400 ng) that emulated its circulating concentration in response to exercise or high-fat diet . By contAdditional cytokine assessment includes IL-12, CXCL10 and fractalkine (CX3CL1). Both IL-12 and CXCL10 have shown to impair GSIS in INS-1 cells  and in hAn additional aspect to take into account when searching for potential endocrine mediators is to distinguish among proteins released from cell lysis vs. an active, regulated secretion process. In fact, many detected proteins do not seem to be secreted as they have no signal peptide, known receptor and their described function is at the intracellular level . Thus, tExtracellular vesicles are a heterogeneous population of cell-derived membranous structures including microvesicles and exosomes. Exosomes are the smallest vesicles (ranging from 30 to 100 nm of diameter) formed by the fusion of multivesicular endosomes with the plasma membrane . ExosomeSkeletal muscle cells can release exosomes  and miRNBesides myomiRs expression being affected by exercise or diabetic status, exosome-associated miRNAs can also be transferred to other cell types. In this regard, in vitro insulin secretion  prevented the decrease in visceral fat mass as detected in participants receiving vehicle infusion (The definition of myokine also needs to be revisited. At present, many muscle cell-derived proteins are named myokines. However, there is no evidence that those factors can indeed affect the function of any organ infusion . Authorsinfusion . CertainFinally, one should bear in mind that besides skeletal muscle, organs such as the liver and adipose tissue, may also secrete a number of factors into circulation. Those factors may play a role in mediating the interaction between insulin sensitivity and its secretion. Identifying the mechanism linking insulin sensitivity with insulin secretion, in particular in dynamic states such as the transition from fasting to postprandial conditions, may have a strong impact on designing therapies for improving insulin secretion in pre-diabetic and diabetic individuals.MM and JG conceived the present idea and drafted the manuscript. All authors revised and approved the final version of 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.