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Clemente, C.

Publications and source records attributed to Clemente, C..

5 recordsLinked to original sources
bioRxiv2026

MT4-MMP/NRP1 axis is required for balanced angiogenesis in the embryonic brain

Angiogenesis is essential for embryonic brain development and tissue repair, yet the mechanisms that spatiotemporally coordinate endothelial behavior to ensure balanced vascular remodeling remain elusive. Here, we identify the glycosylphosphatidylinositol (GPI)-anchored protease MT4-MMP as a critical, context-dependent determinant of angiogenic growth. Global loss of MT4-MMP transiently impairs vascular network formation in the embryonic hindbrain, whereas endothelial-specific deletion triggers an aberrant angiogenesis characterized by increased vessel density, branching, and a profound loss of vascular organization. This dual phenotype reveals MT4-MMP as a fundamental coordinator of neurovascular development. Consistently, MT4-MMP expression was dynamically regulated during wound repair, and its absence amplifies angiogenesis and accelerates wound closure in adult skin, highlighting its role in maintaining vascular homeostasis postnatally. Mechanistically, MT4-MMP-deficient endothelial cells exhibit impaired polarization and sustained, rather than transient, VEGFA-induced ERK activation. We identify NRP1 as a novel substrate of MT4-MMP and demonstrate that MT4-MMP-mediated NRP1 cleavage restricts NRP1 surface availability to tune the intensity of VEGFA signaling. Furthermore, pharmacological blockade of VEGFA-NRP1 binding partially rescues the vascular defects caused by endothelial MT4-MMP loss in vivo. Together, these findings uncover the MT4-MMP/NRP1 axis as a pivotal control point that prevents aberrant vessel expansion, establishing membrane-anchored proteolysis as a primary regulator across developmental and reparative contexts. TeaserThe proteolytic constraint exerted by MT4-MMP dictates neurovascular development and wound repair through the spatial control of NRP1-VEGFA signaling.

cell biology↗
bioRxiv2024

Unlocking the secrets of kangaroo locomotor energetics: Postural adaptations underpin increased tendon stress in hopping kangaroos

Hopping kangaroos exhibit remarkably little change in their rate of metabolic energy expenditure with locomotor speed compared to other running animals. This phenomenon may be related to greater elastic energy savings due to increasing tendon stress; however, the mechanisms which enable the rise in stress without additional muscle work remain poorly understood. In this study, we created a three-dimensional (3D) kangaroo musculoskeletal model, integrating 3D motion capture and force plate data, to analyse the kinematics and kinetics of hopping red and grey kangaroos. Using our model, we evaluated how body mass and speed influence (i) hindlimb posture, (ii) effective mechanical advantage (EMA), (iii) the associated tendon stress in the ankle extensors, and (iv) ankle work during hopping. We found that increasing ankle dorsiflexion and metatarsophalangeal plantarflexion likely played an important role in decreasing ankle EMA by altering both the muscle and external moment arms, which subsequently increased energy absorption and peak tendon stress at the ankle. Surprisingly, kangaroo hindlimb posture changes appeared to contribute to increased tendon stress, allowing more elastic energy storage at faster speeds. These posture-mediated increases in elastic energy storage and return could be a key factor enabling kangaroos to achieve energetic benefits at faster hopping speeds, but may limit the performance of large kangaroos due to the risk of tendon rupture.

zoology↗
bioRxiv2020

Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ after myocardial infarction

Macrophages produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. In this study, we demonstrated that cardiac macrophages increased expression of Mmp14 (MT1-MMP) 7 days post-MI. Specific macrophage-targeting of MT1-MMP (MT1-MMP{Delta}LysM mice) attenuates post-MI cardiac dysfunction, reduces fibrosis, and preserves the cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGF{beta}1 in macrophages, leading to paracrine SMAD2-mediated signaling in endothelial cells and endothelial-to-mesenchymal transition (EndMT). Post-MI MT1-MMP{Delta}LysM hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and MT1-MMP-deficient macrophages showed a reduced ability to induce EndMT in co-cultures with endothelial cells. Our results demonstrate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify macrophage MT1-MMP as a key regulator of this process. The identified mechanism has potential as a therapeutic target in ischemic heart disease.

immunology↗
bioRxiv2019

Emergence of the Zika virus Asian lineage in Angola

Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed without language restrictions using the keywords Zika and Africa for papers published to October 2018. We also checked available Situation Report publications from WHO for evidence of Zika virus (ZIKV) or congenital Zika disease in Africa. ZIKV African lineage has been detected within Africa since the mid 20th century, yet evidence for spread of the ZIKV Asian lineage within Africa is limited. Two countries in Africa (Cabo Verde and Angola) have reported ZIKV cases that are believed to be caused by a newly introduced Asian lineage virus. Sequence data are critical for confirming and understanding the spread of ZIKV Asian lineage within Africa, but these data are currently limited to a single 193bp fragment of the ZIKV NS1 gene from Angola. In addition, whilst epidemiological data on ZIKV and suspected microcephaly cases have been reported in detail from Cabo Verde, data from Angola are extremely limited.\n\nAdded value of this studyWe provide a detailed report of detected ZIKV acute cases and suspected microcephaly cases in Angola. We sequence ZIKV genomes from three acutely infected cases. These represent the first three Asian lineage genomes available from Africa, one of which was acquired from a baby with confirmed microcephaly. Analysis of these sequences suggests that ZIKV may have been introduced to Angola between July 2015 and June 2016, after which it likely circulated for at least one year. This provides the first genetic confirmation of autochthonous ZIKV Asian lineage transmission within Africa. We suggest that the virus was more likely introduced to Angola directly from Brazil, rather than from Cabo Verde. Our analyses from Angola, only the second African country to report presence of the Asian virus lineage, therefore improve our understanding of the extent and clinical impact of ZIKV Asian lineage in the continent.\n\nImplications of all the available evidenceThe circulation of ZIKV Asian lineage within parts of sub-Saharan Africa is concerning given the potential for continued viral spread across much of the continent. Available evidence suggests that ZIKV has circulated and caused cases of microcephaly in Cabo Verde and in Angola. Detecting additional ZIKV transmission using only clinical data on suspected microcephaly or clusters of mild illness may be challenging in countries where systems for reporting birth defects are limited and infectious disease burden is high. Further spread of the ZIKV Asian lineage would likely not be detected unless molecular surveillance systems for ZIKV are implemented to routinely monitor ZIKV transmission in Africa. Implementation of such a surveillance system is especially important in countries that are linked by high human mobility to areas that have experienced recent or ongoing outbreaks of ZIKV.\n\nAbstractO_ST_ABSBackgroundC_ST_ABSZika virus (ZIKV) infections and suspected microcephaly cases have been recently reported in Angola, but no data are available on the origins, epidemiology, and diversity of the virus.\n\nMethodsSerum samples from 54 suspected ZIKV cases, 76 suspected microcephaly cases, and 24 mothers of infants with suspected microcephaly were received by the Angolan Ministry of Health. Computed tomographic brain imaging and serological assays (PRNT) were conducted on one microcephalic infant. All sera were tested for ZIKV by RT-qPCR. 349 samples from HIV+ patients and 336 samples from patients suspected of chikungunya virus or dengue virus infection were also tested. Portable sequencing was used to generate Angolan ZIKV genome sequences, including from a ZIKV+ neonate with microcephaly born in Portugal to an Angolan resident. Genetic and mobility data were analysed to investigate the date of introduction and geographic origin of ZIKV in Angola.\n\nFindingsFour autochthonous cases were ZIKV positive via RT-qPCR, with all positive samples collected between December 2016 and June 2017. Viral genomes were generated for two of these cases, and from the neonate with microcephaly identified in Portugal. Genetic analyses and other data indicate that ZIKV was introduced to Angola from Brazil between July 2015 and June 2016. This introduction likely initiated local ZIKV circulation in Angola that continued until June 2017. The scanned microcephaly case showed brain abnormalities consistent with congenital Zika syndrome and serological evidence for maternal ZIKV infection.\n\nInterpretationOur analyses confirm the autochthonous transmission of the ZIKV Asian lineage in continental Africa. Conducting ZIKV surveillance throughout Africa is critical in the light of presented evidence for autochthonous ZIKV transmission in Angola, and associated microcephaly cases.\n\nFundingRoyal Society, Wellcome Trust, CNPq, CAPES, ERC, Oxford Martin School, Global Challenges Research Fund, Africa Oxford, and John Fell Fund.

epidemiology↗