Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

Leishmania genetic exchange is mediated by IgM natural antibodies.

Host factors that mediate Leishmania genetic exchange are not well defined. Here we demonstrate that natural IgM (IgMn)1-4 antibodies mediate parasite genetic exchange by inducing the transient formation of a spherical parasite clump that promotes parasite fusion and hybrid formation. We establish that IgMn from Leishmania-free animals binds to the surface of Leishmania parasites to induce significant changes in the expression of parasite transcripts and proteins. Leishmania binding to IgMn is partially lost after glycosidase treatment, although parasite surface phosphoglycans, including lipophosphoglycan, are not required for IgMn-induced parasite clumping. Notably, the transient formation of parasite clumps is essential for Leishmania hybridization in vitro. In vivo, we observed a 12-fold increase in hybrid formation in sand flies provided a second blood meal containing IgMn compared with controls. Furthermore, the generation of recombinant progeny from mating hybrids and parental lines were only observed in sand flies provided with IgMn. Both in vitro and in vivo IgM-induced Leishmania crosses resulted in full genome hybrids that show equal patterns of biparental contribution. Leishmania co-option of a host natural antibody to facilitate mating in the insect vector establishes a new paradigm of parasite-host-vector interdependence that contributes to parasite diversity and fitness by promoting genetic exchange.

Author Correction: The evolutionary history of lethal metastatic prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism.

Inhibitors of complement and coagulation are present in the saliva of a variety of blood-feeding arthropods that transmit parasitic and viral pathogens. Here, we describe the structure and mechanism of action of the sand fly salivary protein lufaxin, which inhibits the formation of the central alternative C3 convertase (C3bBb) and inhibits coagulation factor Xa (fXa). Surface plasmon resonance experiments show that lufaxin stabilizes the binding of serine protease factor B (FB) to C3b but does not detectably bind either C3b or FB alone. The crystal structure of the inhibitor reveals a novel all ß-sheet fold containing 2 domains. A structure of the lufaxin-C3bB complex obtained via cryo-electron microscopy (EM) shows that lufaxin binds via its N-terminal domain at an interface containing elements of both C3b and FB. By occupying this spot, the inhibitor locks FB into a closed conformation in which proteolytic activation of FB by FD cannot occur. C3bB-bound lufaxin binds fXa at a separate site in its C-terminal domain. In the cryo-EM structure of a C3bB-lufaxin-fXa complex, the inhibitor binds to both targets simultaneously, and lufaxin inhibits fXa through substrate-like binding of a C-terminal peptide at the active site as well as other interactions in this region. Lufaxin inhibits complement activation in ex vivo models of atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH) as well as thrombin generation in plasma, providing a rationale for the development of a bispecific inhibitor to treat complement-related diseases in which thrombosis is a prominent manifestation.

Comprehensive Proteomics Analysis of the Hemolymph Composition of Sugar-Fed Aedes aegypti Female and Male Mosquitoes.

In arthropods, hemolymph carries immune cells and solubilizes and transports nutrients, hormones, and other molecules that are involved in diverse physiological processes including immunity, metabolism, and reproduction. However, despite such physiological importance, little is known about its composition. We applied mass spectrometry-based label-free quantification approaches to study the proteome of hemolymph perfused from sugar-fed female and male Aedes aegypti mosquitoes. A total of 1403 proteins were identified, out of which 447 of them were predicted to be extracellular. In both sexes, almost half of these extracellular proteins were predicted to be involved in defense/immune response, and their relative abundances (based on their intensity-based absolute quantification, iBAQ) were 37.9 and 33.2%, respectively. Interestingly, among them, 102 serine proteases/serine protease-homologues were identified, with almost half of them containing CLIP regulatory domains. Moreover, proteins belonging to families classically described as chemoreceptors, such as odorant-binding proteins (OBPs) and chemosensory proteins (CSPs), were also highly abundant in the hemolymph of both sexes. Our data provide a comprehensive catalogue of A. aegypti hemolymph basal protein content, revealing numerous unexplored targets for future research on mosquito physiology and disease transmission. It also provides a reference for future studies on the effect of blood meal and infection on hemolymph composition.

Unravelling epigenetic mechanisms in Cerastoderma edule genome: a comparison of healthy and neoplastic cockles.

Cancer is a multifaceted genetic disease characterized by the acquisition of several essential hallmarks. Notably, certain cancers exhibit horizontal transmissibility, observed across mammalian species and diverse bivalves, the latter referred to as hemic neoplasia. Within this complex landscape, epigenetic mechanisms such as histone modifications and cytosine methylation emerge as fundamental contributors to the pathogenesis of these transmissible cancers. Our study delves into the epigenetic landscape of Cerastoderma edule, focusing on whole-genome methylation and hydroxymethylation profiles in heathy specimens and transmissible neoplasias by means of Nanopore long-read sequencing. Our results unveiled a global hypomethylation in the neoplastic specimens compared to their healthy counterparts, emphasizing the role of DNA methylation in these tumorigenic processes. Furthermore, we verified that intragenic CpG methylation positively correlated with gene expression, emphasizing its role in modulating transcription in healthy and neoplastic cockles, as also highlighted by some up-methylated oncogenic genes. Hydroxymethylation levels were significantly more elevated in the neoplastic samples, particularly within satellites and complex repeats, likely related to structural functions. Additionally, our analysis also revealed distinct methylation and activity patterns in retrotransposons, providing additional insights into bivalve neoplastic processes. Altogether, these findings contribute to understanding the epigenetic dynamics of bivalve neoplasias and shed light on the roles of DNA methylation and hydroxymethylation in tumorigenesis. Understanding these epigenetic alterations holds promise for advancing our broader understanding of cancer epigenetics.

Dispersal history of SARS-CoV-2 in Galicia, Spain.

The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron-BA.1 variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the United States became increasingly significant. The number of detected introductions varied from 96 and 101 for Alpha and Delta to 39 for Omicron-BA.1. Most of these introductions left a low number of descendants (<10), suggesting a limited impact on the evolution of the pandemic in Galicia. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.

Pyricularia Are Mostly Host-Specialized with Limited Reciprocal Cross-Infection Between Wheat and Endemic Grasses in Minas Gerais, Brazil.

Wheat blast, caused by Pyricularia oryzae Triticum (PoT), is an emerging threat to global wheat production. The current understanding of the population biology of the pathogen and epidemiology of the disease has been based on phylogenomic studies that compared the wheat blast pathogen with isolates collected from grasses that were invasive to Brazilian wheat fields. In this study, we performed a comprehensive sampling of blast lesions in wheat crops and endemic grasses found in and away from wheat fields in Minas Gerais. A total of 1,368 diseased samples were collected (976 leaves of wheat and grasses and 392 wheat heads), which yielded a working collection of 564 Pyricularia isolates. We show that, contrary to earlier implications, PoT was rarely found on endemic grasses, and, conversely, members of grass-adapted lineages were rarely found on wheat. Instead, most lineages were host-specialized, with constituent isolates usually grouping according to their host of origin. With regard to the dominant role proposed for signalgrass in wheat blast epidemiology, we found only one PoT member in 67 isolates collected from signalgrass grown away from wheat fields and only three members of Urochloa-adapted lineages among hundreds of isolates from wheat. Cross-inoculation assays on wheat and a signalgrass used in pastures (U. brizantha) suggested that the limited cross-infection observed in the field may be due to innate compatibility differences. Whether or not the observed level of cross-infection would be sufficient to provide an inoculum reservoir, or serve as a bridge between wheat growing regions, is questionable and, therefore, deserves further investigation.

Ascending aortic aneurysm and histopathology in Alport syndrome: a case report.

BACKGROUND: Alport syndrome (AS) is caused by mutations in type IV collagen genes that typically target and compromise the integrity of basement membranes in kidney, ocular, and sensorineural cochlear tissues. Type IV and V collagens are also integral components of arterial walls, and whereas collagenopathies including AS are implicated in aortic disease, the incidence of aortic aneurysm in AS is unknown probably because of underreporting. Consequently, AS is not presently considered an independent risk factor for aortic aneurysm and more detailed case studies including histological evidence of basement membrane abnormalities are needed to determine such a possible linkage. CASE PRESENTATION: Here, we present unique histopathological findings of an ascending aortic aneurysm collected at the time of surgery from an AS patient wherein hypertension was the only other known risk factor. CONCLUSIONS: The studies reveal classical histological features of aortic aneurysm, including atheroma, lymphocytic infiltration, elastin disruption, and myxoid degeneration with probable AS association.

A mosquito juvenile hormone binding protein (mJHBP) regulates the activation of innate immune defenses and hemocyte development.

Insects rely on the innate immune system for defense against pathogens, some aspects of which are under hormonal control. Here we provide direct experimental evidence showing that the juvenile hormone-binding protein (mJHBP) of Aedes aegypti is required for the regulation of innate immune responses and the development of mosquito blood cells (hemocytes). Using an mJHBP-deficient mosquito line generated by means of CRISPR-Cas9 gene editing technology we uncovered a mutant phenotype characterized by immunosuppression at the humoral and cellular levels, which profoundly affected susceptibility to bacterial infection. Bacteria-challenged mosquitoes exhibited significantly higher levels of septicemia and mortality relative to the wild type (WT) strain, delayed expression of antimicrobial peptides (AMPs), severe developmental dysregulation of embryonic and larval hemocytes (reduction in the total number of hemocytes) and increased differentiation of the granulocyte lineage. Interestingly, injection of recombinant wild type mJHBP protein into adult females three-days before infection was sufficient to restore normal immune function. Similarly, injection of mJHBP into fourth-instar larvae fully restored normal larval/pupal hemocyte populations in emerging adults. More importantly, the recovery of normal immuno-activation and hemocyte development requires the capability of mJHBP to bind JH III. These results strongly suggest that JH III functions in mosquito immunity and hemocyte development in a manner that is perhaps independent of canonical JH signaling, given the lack of developmental and reproductive abnormalities. Because of the prominent role of hemocytes as regulators of mosquito immunity, this novel discovery may have broader implications for the understanding of vector endocrinology, hemocyte development, vector competence and disease transmission.

Wild, tamed, and domesticated: Three fire macroregimes for global pyrogeography in the Anthropocene.

Climate and natural vegetation dynamics are key drivers of global vegetation fire, but anthropogenic burning now prevails over vast areas of the planet. Fire regime classification and mapping may contribute towards improved understanding of relationships between those fire drivers. We used 15 years of daily active fire data from the MODIS fire product (MCD14ML, collection 6) to create global maps of six fire descriptors (incidence, size inequality, season length, interannual variability, intensity, and fire season modality). Using multiple correspondence analysis (MCA) and hierarchical agglomerative clustering, we identified three fire macroregimes: Wild, Tamed, and Domesticated, each of which splitting into prototypical and transitional regimes. Interpretation of the six fire regimes in terms of their main drivers relied on the global maps of anthromes and Köppen climate types. The analysis yielded a two-dimensional space where the principal dimension of variability is primarily defined by interannual variability in fire activity and fire season length, and the secondary axis is based mainly on fire incidence. The Wild fire macroregime occurs mostly in cold wildlands, where burning is sporadic and fire seasons are short. Tamed fires predominate in seasonally dry tropical rangelands and croplands with high fire incidence. Domesticated fires are characteristic of humid, warm temperate and tropical croplands and villages with low fire incidence. The Tamed and Domesticated fire macroregimes, representing managed burning, account for 86% of all active fires in our dataset and for 70% of the global burnable area. Fourteen percent of active fires were found in the cold wildlands, and in the rangelands and forests of steppe and desert climates of the Wild macroregime. These results highlight the extent of human control over global pyrogeography in the Anthropocene.

What to consider when implementing a tool for timely recognition of palliative care needs in heart failure: a context-based qualitative study.

BACKGROUND: Needs assessment tools can facilitate healthcare professionals in timely recognition of palliative care needs. Despite the increased attention for implementation of such tools, most studies provide little or no attention to the context of implementation. The aim of this study was to explore factors that contribute positively and negatively to timely screening of palliative care needs in advanced chronic heart failure. METHODS: Qualitative study using individual interviews and focus groups with healthcare professionals. The data were analysed using a deductive approach. The Consolidated Framework for Implementation Research was used to conceptualise the contextual factors. RESULTS: Twenty nine healthcare professionals with different backgrounds and working in heart failure care in the Southern and Eastern parts of the Netherlands participated. Several factors were perceived to play a role, such as perception and knowledge about palliative care, awareness of palliative care needs in advanced chronic heart failure, perceived difficulty when and how to start palliative care, limited acceptance to treatment boundaries in cardiology, limited communication and collaboration between healthcare professionals, and need for education and increased attention for palliative care in advanced chronic heart failure guidelines. CONCLUSIONS: This study clarified critical factors targeting patients, healthcare professionals, organisations to implement a needs assessment tool for timely recognition of palliative care needs in the context of advanced chronic heart failure. A multifaceted implementation strategy is needed which has attention for education, patient empowerment, interdisciplinary collaboration, identification of local champions, chronic heart failure specific guidelines and culture.

The genome of the stable fly, Stomoxys calcitrans, reveals potential mechanisms underlying reproduction, host interactions, and novel targets for pest control.

BACKGROUND: The stable fly, Stomoxys calcitrans, is a major blood-feeding pest of livestock that has near worldwide distribution, causing an annual cost of over $2 billion for control and product loss in the USA alone. Control of these flies has been limited to increased sanitary management practices and insecticide application for suppressing larval stages. Few genetic and molecular resources are available to help in developing novel methods for controlling stable flies. RESULTS: This study examines stable fly biology by utilizing a combination of high-quality genome sequencing and RNA-Seq analyses targeting multiple developmental stages and tissues. In conjunction, 1600 genes were manually curated to characterize genetic features related to stable fly reproduction, vector host interactions, host-microbe dynamics, and putative targets for control. Most notable was characterization of genes associated with reproduction and identification of expanded gene families with functional associations to vision, chemosensation, immunity, and metabolic detoxification pathways. CONCLUSIONS: The combined sequencing, assembly, and curation of the male stable fly genome followed by RNA-Seq and downstream analyses provide insights necessary to understand the biology of this important pest. These resources and new data will provide the groundwork for expanding the tools available to control stable fly infestations. The close relationship of Stomoxys to other blood-feeding (horn flies and Glossina) and non-blood-feeding flies (house flies, medflies, Drosophila) will facilitate understanding of the evolutionary processes associated with development of blood feeding among the Cyclorrhapha.

A Deeper Insight into the Tick Salivary Protein Families under the Light of Alphafold2 and Dali: Introducing the TickSialoFam 2.0 Database.

Hard ticks feed for several days or weeks on their hosts and their saliva contains thousands of polypeptides belonging to dozens of families, as identified by salivary transcriptomes. Comparison of the coding sequences to protein databases helps to identify putative secreted proteins and their potential functions, directing and focusing future studies, usually done with recombinant proteins that are tested in different bioassays. However, many families of putative secreted peptides have a unique character, not providing significant matches to known sequences. The availability of the Alphafold2 program, which provides in silico predictions of the 3D polypeptide structure, coupled with the Dali program which uses the atomic coordinates of a structural model to search the Protein Data Bank (PDB) allows another layer of investigation to annotate and ascribe a functional role to proteins having so far being characterized as "unique". In this study, we analyzed the classification of tick salivary proteins under the light of the Alphafold2/Dali programs, detecting novel protein families and gaining new insights relating the structure and function of tick salivary proteins.

Evaluating priority locations and potential benefits for building a nation-wide fuel break network in Portugal.

Despite growing interest in developing extensive fuel treatment programs to prevent catastrophic wildfires in the Mediterranean region, there is little information on the projected effectiveness of fuel treatments in terms of avoided exposure and risk. In Portugal, a fuel management plan aiming to prevent loss of lives, reduce large fires (>500 ha), and reduce annual burned area is under implementation, with particular emphasis on the nation-wide fuel break network (FBN). In this study, we evaluated the effectiveness of the planned FBN in terms of meeting fire management objectives, costs, and benefits. We first estimated the overall effectiveness of the FBN at intersecting modeled large fires (>500 ha) and at reducing exposure to protected areas and residential buildings using wildfire simulation modeling. Then, the fuel break burn-over percentage, i.e. the percentage of fires that are not contained at the FBN, was modeled as a function of pre-defined flame length thresholds for individual FBN segments. For the planned FBN, the results suggested a potential reduction of up to 13% in the annual burned area due to large fires (ca. 13,000 ha), of up to 8% in the annual number of residential buildings exposed (ca. 100 residential buildings), and up to 14% in the annual burned area in protected areas (ca. 2400 ha). The expected burn-over percentage was highly variable among the segments in response to estimated fire intensity, and an average decrease of 40% of the total benefits was estimated. The most important fuel breaks typically showed a higher percentage of fire burn-over, and hence reduction in effectiveness. We also showed that the current implementation of FBN follows a random sequence, suboptimal for all objectives. Our results suggest that additional landscape-scale fuel reduction strategies are required to meet short-term national wildfire management targets.

CDKN2A deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).

Nodal peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNAs) with prognostic significance. Here, investigating 5 formalin-fixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing (WGS), we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNAs. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCL-NOS with absolute specificity. In contrast, these deletions were rare and never co-occurred in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, IPI, transplant eligibility and GATA3 expression (adjusted HR =2.53; 95% CI 1.006-6.3; p=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCL-NOS and their significance should be evaluated in prospective trials.

The evolutionary history of lethal metastatic prostate cancer.

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.

PfCDPK1 is critical for malaria parasite gametogenesis and mosquito infection.

Efforts to knock out Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) from asexual erythrocytic stage have not been successful, indicating an indispensable role of the enzyme in asexual growth. We recently reported generation of a transgenic parasite with mutant CDPK1 [Bansal A, et al. (2016) MBio 7:e02011-16]. The mutant CDPK1 (T145M) had reduced activity of transphosphorylation. We reasoned that CDPK1 could be disrupted in the mutant parasites. Consistent with this assumption, CDPK1 was successfully disrupted in the mutant parasites using CRISPR/Cas9. We and others could not disrupt PfCDPK1 in the WT parasites. The CDPK1 KO parasites show a slow growth rate compared with the WT and the CDPK1 T145M parasites. Additionally, the CDPK1 KO parasites show a defect in both male and female gametogenesis and could not establish an infection in mosquitoes. Complementation of the KO parasite with full-length PfCDPK1 partially rescued the asexual growth defect and mosquito infection. Comparative global transcriptomics of WT and the CDPK1 KO schizonts using RNA-seq show significantly high transcript expression of gametocyte-specific genes in the CDPK1 KO parasites. This study conclusively demonstrates that CDPK1 is a good target for developing transmission-blocking drugs.

Putting fire on the map of Brazilian savanna ecoregions.

The Brazilian savanna (Cerrado) is considered the most floristically diverse savanna in the world, home to more than seven thousand species. The region is a mosaic of savannas, grasslands and forests whose unique biophysical and landscape attributes are on the basis of a recent ecoregional map, paving the way to improved region-based strategies for land management actions. However, as a fire-prone ecosystem, Cerrado owes much of its distribution and ecological properties to the fire regime and contributes to an important parcel of South America burned area. Accordingly, any attempt to use ecoregion geography as a guide for management strategies should take fire into account, as an essential variable. The main aim of this study is to complement the ecoregional map of the Cerrado with information related to the fire component. Using remotely sensed information, we identify patterns and trends of fire frequency, intensity, seasonality, extent and scar size, and combine this information for each ecoregion, relying on a simple classification that summarizes the main fire characteristics over the last two decades. Results show a marked north-south fire activity gradient, with increased contributions from MATOPIBA, the latest agricultural frontier. Five ecoregions alone account for two thirds of yearly burned area. More intense fires are found in the Arc of Deforestation and eastern ecoregions, while ecoregions in MATOPIBA display decreasing fire intensity. An innovative analysis of fire scars stratified by size class shows that infrequent large fires are responsible for the majority of burned area. These large fires display positive trends over many ecoregions, whereas smaller fires, albeit more frequent, have been decreasing in number. The final fire classification scheme shows well defined spatially-aggregated groups, where trends are found to be the key factor to evaluate fire within their regional contexts. Results presented here provide new insights to improve fire management strategies under a changing climate.

Progenitor-cell-enriched micrografts as a novel option for the management of androgenetic alopecia.

Regenerative medicine is a multidisciplinary field that combines engineering and life science principles to promote regeneration, potentially restoring the physiological condition in diseased tissues. Specifically, the developments of complex grafts enhance the intrinsic regenerative capacity of the host by altering its environment. Autologous micrografts obtained through Rigenera® micrografting technology are able to promote derma and bone regeneration. Androgenetic alopecia (AGA) leads to a progressive thinning of scalp hair affecting 60-70% of the adult population worldwide. Pharmacological treatment offers moderate results and hair transplantation represents the only permanent treatment option. The aim of this study was to demonstrate the role of dermis micrografting in the treatment of AGA by clinical and histological evaluations after 4, 6, and 12 months. Hair growth and density were improved at all indicated times. Those outcomes were also confirmed by the TrichoScan® analysis, reporting an increase of total hair count and density with an increase and reduction of anagen and telogen phases, respectively. Scalp dermoscopic analysis showed an improvement of hair density and histological analysis indicated a clear amelioration of the scalp, development of hair follicles, and a beginning of cuticle formation. Collectively, those results suggest a possible use of the micrografts as a novel therapeutic option in the management of AGA.