Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters ; 2 disorders of the pentose phosphate pathway ; 9 diseases of glycogen metabolism ; 29 congenital disorders of glycosylation ; 15 carbohydrate-linked lysosomal storage diseases . With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications. Heart failure (HF) is a chronic, progressive condition in which heart functionality becomes heavily compromised and cannot sustain the oxygen demands of the body, ultimately resulting in death. Several studies have established that 40–50% of patients with HF die within 5 years from diagnosis . It has The pathogenesis of HF is extremely complex, heterogeneous and multifactorial. HF can result from environmental factors , genetic predisposition, hereditary disorders or a combination of these three. Nonetheless, the most common causes of HF are cardiomyopathies (CMs) and congenital cardiac defects .CMs represent a clinically heterogeneous group of disorders resulting in abnormal heart structure and functionality . They arA relevant portion of genetic cardiomyopathies are monogenic. Considering the two most frequent forms of CMs, it has been estimated that over 60% of hypertrophic cardiomyopathies (HCMs) and 30–35% of dilated cardiomyopathies (DCMs) have monogenic etiology  is caused by an AR mutation in the piration . We founutations ,27,28,29utations ,25. Otheutations . In our utations  . Thiamine is important for the oxidation of carbohydrates, especially glucose. Upon its conversion to thiamine–pyrophosphate, thiamine acts as a coenzyme for three key enzymes involved in carbohydrate metabolism: transketolase (TK) in the pentose phosphate pathway (PPP), pyruvate dehydrogenase (PDH) in the terminal part of glycolysis and α-ketoglutarate dehydrogenase complex (α-KDH) in the tricarboxylic acid cycle. Moreover, thiamine is involved in reduced glutathione generation and thus contributes to the counteraction of oxidative stress [situs inversus totalis) [Thiamine-responsive megaloblastic anemia (TRMA) syndrome [OMIM:249270] is an AR disorder of the thiamine  transporter. It is caused by homozygous mutations of the e stress . We idene stress ,45,46,47totalis) . We identotalis) ,45,46,472 and NADPH. The non-oxidative branch yields glycolytic intermediates, such as fructose 6-phosphate and glyceraldehyde 3-phosphate and sedoheptulose sugars, which contribute to the production of sugar phosphate precursors to amino acid synthesis and ribose-5-phosphate  is caused by AR-inherited homozygous or compound heterozygous mutations affecting the ketolase ,52,53. Tketolase . Specifiketolase . Fewer tketolase ,56,57 , they may develop life threatening acute hemolytic anemia. Our literature search produced several reports of single or few G6PH-deficient patients describing with cardiac symptoms, which included: CD, HF, TVR, severe MVS, PVSD, PDA, coronary artery disease and ST-segment elevation [Glucose-6-phosphate dehydrogenase (G6PDH) deficiency [OMIM:300908] is one of the most common forms of enzyme deficiency and although prevalence estimations vary in different studies, it is considered to affect over 400 million people worldwide . It is aactivity . The laclevation ,64,65,66levation , 324 eldlevation  found thlevation ,69. Thislevation . DefinitGlycogen storage diseases (GSDs) are a group of IMDs which arise from congenital defects that affect glycogen synthesis (glycogenesis) or breakdown (glycogenolysis) primarily in hepatic and muscle tissues . GlycogeGAA gene, localized on chromosome 17q25.3. Its prevalence is estimated at between 1/30,000–140,000 births worldwide, depending on the form [GAA mutations result in the loss of function of the acid maltase enzyme and ultimately in intra-lysosomal accumulation [Pompe disease is an AR GSD type IIa [OMIM:232300] with infantile onset, caused by acid maltase deficiency (AMD). AMD is due to a homozygous or compound heterozygous mutations in the the form . GAA mutmulation . Classicmulation ,73,74. Tmulation . Lastly,mulation .Focusing on the non-classical form of Pompe disease, a comprehensive systematic review from van Kooten et al.  collecteEnzyme replacement therapy (ERT) is now a consolidated treatment for Pompe disease and can efficiently prevent deterioration of cardiac symptoms while partially helping to recover some functional dysfunction .GBE1 gene at location 3p12, which encodes the glycogen branching enzyme . This disorder alone accounts for 3% of all GSDs [Andersen’s disease [OMIM:232500], or AR GSD type IV, is caused by mutations in the all GSDs ,77. Lossall GSDs . After ball GSDs ,100,101 all GSDs ,103.AGL) gene located on chromosome 1p21. This gene encodes the glycogen debrancher enzyme (GDE), which is involved in glycogen degradation. This enzyme has two independent catalytic activities that occur at different sites on the protein: a 4-α-glucotransferase activity and an amylo-1,6-glucosidase activity. When genetic mutations cause a loss of function of GDE, accumulation of abnormal glycogen with short outer chains occurs, which often cause hypertrophy in the affected tissues. GSDIII has been traditionally divided into two subtypes: in GSDIIIa, the most common, the enzymatic deficiency affects the liver, heart and skeletal muscle, while in GSDIIIb, only the liver is affected [Cori–Forbes disease [OMIM:232400] is an AR glycogen storage disorder (type III) caused by homozygous or compound heterozygous mutations affecting the amylo-α-1,6-glucosidase/4-α-glucanotransferase  gene on chromosome 3q24. The prevalence of GSD type XV is estimated to be at lower than 1/1,000,000. Glycogenin 1 is a glycosyltransferase that catalyzes the synthesis of short glucose polymers, indicated as n or polyglucosans, from UDP-glucose. These short polymers act as substrates for glycogen synthase and branching enzyme for the synthesis of new glycogen macro-polymers [GSD type XV [OMIM:613507] is a rare AR disorder caused by compound heterozygous mutations in the glycogenin type 1  gene, located at 19q13.33 and has an estimated prevalence of <1/1,000,000 [GSD type 0b [OMIM:611556] is an AR disorder caused by homozygous mutations in the muscle glycogen synthase type 1   is a variant of Pompe disease with XLD inheritance, characterized by severe cardiac manifestations, along with skeletal and neurological symptoms, with estimated prevalence of <1/1,000,000. Genetically, it is caused by mutations of the on (LMP) ,156. Itson (LMP) . Two speon (LMP) ,158. Ouron (LMP) ,191,192 PRKAG2) gene on chromosome 7q36.1, which is associated with Wolff–Parkinson–White syndrome (WPW) [OMIM:194200]. The affected protein is a serine/threonine AMP-activated protein kinase (AMPK) that in response to activation by several cellular stressors induces increased AMP production and ATP catabolism [PRKAG2 mutations [Glycogen glycogen-associated cardiomyopathy [OMIM:602743] is an autosomal dominant GSD caused by mutations in the protein kinase, AMP-activated, noncatalytic, gamma-2 (tabolism . In 2001PW) OMIM:200. The utations ,204,205.RBCK1) gene located on chromosome 20p13 , is an AR GSD caused by mutations on the RANBP-type and C3HC4-type zinc finger-containing 1  and as congenital disorder of glycosylation type IIw (CDG2W) [OMIM:619525]. This gene encodes glucose 6-phosphate translocase type I (G6PT1), which is responsible for regulating the rate-limiting step of glucose 6-phosphate transport through the membrane of the ER. Hence, G6PT1 functions as a glucose 6-phosphate receptor/sensor in ATP-mediated calcium sequestration in the ER lumen  is a CDG (type 1d) with AR inheritance and an estimated prevalence of <1/1,000,000 live births . It is ceticulum . About 4eticulum , with a eticulum . We ideneticulum ,219,220 ALG6 gene, located on chromosome 1p31. ALG6 enzyme, also called glucosyltransferase 1, catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. The CDG resulting from this deficiency manifests in muscular hypotonia, ataxia, motor developmental retardation and severe neurological involvement and more rarely retinal degeneration, deep vein thrombosis and pseudotumor cerebri  is a hyper-rare CDG (type Ic) caused by the loss of function of the enzyme encoded by the  cerebri . However cerebri  , catalyzes the transfer of the 7th and 9th mannose residues to the growing lipid-linked glycan chains in the endoplasmic reticulum  is a CDG (type Il) has a prevalence of <1/1,000,000 live births. It is caused by an AR loss-of-function mutation in the 143 is a eticulum , of whiceticulum ,225,226 ALG12 gene on chromosome 22q13.33. The encoded protein is Dolichol-P-mannose: Man7GlcNAc2-PP-Dol-alpha-6-mannosyltransferase, responsible for the addition of the 8th mannose residue on the immature glycan chain Man7GlcNAc2-PP-Dol. This CDG is characterized by generalized hypotonia, feeding difficulties and facial dysmorphism, which can present along with skeletal anomalies, seizures, and cardiac anomalies in some cases  is another very rare AR (CDG type Ig) caused by a loss-of-function mutation in the 3 is anotme cases ,228,229.me cases ,228,230 me cases .GMPPB gene on chromosome 3p21.31. This gene encodes the beta subunit of the enzyme that catalyzes the conversion of mannose-1-phosphate and GTP to inorganic diphosphate and GDP-mannose (GDP-Man), which is an essential mannosyl-donor required for N-, O- and C-linked glycosylation [GDP-mannose pyrophosphorylase B (GMPPB) deficiency [OMIM:615320] is an AR-inherited CDG caused by homozygous or compound heterozygous mutations in the sylation . Patholosylation . To datesylation ,233  and pyruvate. Sialic acids are essential components of glycoproteins and glycolipids, which enable critical cellular processes. Sialic acid catabolism has been proven recently to be important for cardiac and skeletal muscle function and development  is a very rare CDG with AR inheritance due to compound heterozygous mutations resulting in the loss of function of the elopment . In factelopment . ManNAc tabolism . Cardiactabolism  (Table 5tabolism .PGM1) gene located on chromosome 1p31.3 are causative of CDG type It [OMIM:614921], a rare disorder with AR inheritance and unknown prevalence in the population. PGM1 protein is an enzyme belonging to the phosphohexose mutase family. Although several PGM isoenzymes have been described in humans, PGM1 alone accounts for 90% of phosphoglucomutase activity in the body  is the most frequently diagnosed CDG. It has AR inheritance and its estimated incidence reaches up to 1/20,000 newborns and it affects over 800 patients worldwide ,240. It reported ,283,284 B3GALTL, sometimes referred to as B3GLCT or B3GTL) [OMIM:261540], also known as Peters plus syndrome, is a rare AR disorder that presents with syndromic developmental defects mostly affecting the eye. It is caused by mutations in the B3GALTL gene that encodes an O-Fucose-specific β-1,3-N-glucosyltransferase responsible for transferring glucose to fucose with a β-1,3 linkage, thus contributing to the elongation of O-linked fucosylglycans on thrombospondin type-1 repeats (TSRs) of several proteins , also known as Larsen-like syndrome, is a rare AR and idiopathic CDG with a mutation in the  11q12.3 . The aff 11q12.3 . Overall 11q12.3 ,300,301 FKRP) on chromosome 19q13.32. The encoded protein, FKRP, is a ribitol-5-phosphate transferase involved in the functional glycosylation of α-dystroglycan (α-DG), which is a significant component in the link between the cytoskeleton and the extracellular matrix [Muscular dystrophy–dystroglycanopathy type C5 [OMIM:607155] , muscular dystrophy–dystroglycanopathy type A5  OMIM:613153] and muscular dystrophy–dystroglycanopathy type B5 [OMIM:606612] are AR dystroglycanopathies caused by mutations in the fukutin-related protein gene  gene located on chromosome 9q31.2. The estimated prevalence of this disorder has been estimated in Japan at between 6–11/100,000 live births, while estimations for other countries are still not available. Fukutin is responsible for the addition of ribitol-5-phosphate to a special type of glycan named called α-dystroglycan, which is usually conjugated to membrane proteins and lipids. α-dystroglycans are essential for the maintenance of muscle integrity, cortical histogenesis and normal ocular development. Therefore, defects in the FKTN gene lead to a congenital progressive muscular dystrophy characterized by brain malformation, dystrophic changes in skeletal muscle, severe intellectual deficit, epilepsy, and motor impairment [Fukuyama congenital muscular dystrophy [OMIM:253800] is a rare AR CDG originating from mutations in the fukutin  via O-glycosyl linkage [Muscular dystrophy–dystroglycanopathy type A1 [OMIM:236670] is another severe AR congenital muscular dystrophy with a prevalence of <1/1,000,000. The mutation is found in the  linkage . O-manno linkage . Symptom linkage . In tota linkage , only on linkage . Instead linkage  reportedPOMT2) gene on chromosome 14q24.3. This gene encodes a protein called O-mannosyltransferase 2, which requires the activity of its homolog, POMT1, to initiate O-mannosylglycan synthesis in the endoplasmic reticulum, making it essential for the glycosylation of α-DGs [Muscular dystrophy–dystroglycanopathy type A2 [OMIM:613150] is a rare AR dystrophy that occurs as result of mutations in the O-mannosyltransferase 2 , catalyzes the first step in the biosynthesis of chondroitin sulfate, heparan sulfate and dermatan sulfate proteoglycans. Proteoglycans are present in almost all ECMs of connective tissues and derive their major biochemical function from the physiochemical characteristics of the glycosaminoglycan component of the molecule, which provide hydration and swelling pressure to the tissue to withstand compressional forces [Spondyloocular syndrome (SOS) [OMIM:605822] is a rare AR CDG caused by mutations in the l forces ,351. Chal forces . Of thesl forces ,353,354 DOLK gene on chromosome 9q34.11. Its prevalence is estimated as <1/1,000,000 live births. DOLK is one of the enzymes involved in the de novo biosynthesis of dolichol phosphate mannose (Dol-P-Man). Dol-P-Man is an essential glycosyl carrier lipid for C- and O-mannosylation and N- and O-linked glycosylation of proteins and for the biosynthesis of glycosyl phosphatidylinositol anchors in the ER. Loss of function of this kinase clinically manifests with muscular hypotonia, ichthyosis, nervous system symptoms, and cardiac defects, predominantly CMs [Dolichol kinase 1  deficiency [OMIM:610768] is an AR CDG caused by homozygous or heterozygous compound mutations in the ntly CMs . In mostntly CMs ,359,360 DPM3) gene on chromosome 1q22. DPM3, together with DPM1 and DPM2, forms the DPM complex, which is responsible for the production of mannosyl donors for glycosylphosphatidylinositols, N-glycan synthesis, and protein O-/C-mannosylation  is an AR CDG caused by mutation on the dolichol-phosphate mannose synthase subunits 3  gene lead to a very rare AR CDG (type If). This gene, located on chromosome 17p13, encodes an ER membrane protein essential for the flipping of DPM and dolichol-phosphate-glucose (DPG) across the ER membrane and for the regulation of DPM and DPG within the ER lumen [truncus arteriosus communis) that died during neonatal cardiac surgery.Mutations in the mannose-phosphate-dolichol utilization defect 1  deficiency [OMIM:612379] is a rare X-linked CDG resulting from mutations in the rocesses . Phenotyrocesses ,370,371 PIGA) gene, is an idiopathic X-linked recessive (XL) neurodevelopmental disorder. Mutations in the PIGA gene on chromosome Xp22.2 2 lead to the loss of function of the PIGA protein, which participates in the synthesis of N-acetylglucosaminyl phosphatidylinositol on the ER membrane. This reaction represents the first step in the GPI anchor synthesis, and when deficient, it results in defective glycan synthesis [Multiple congenital anomalies–hypotonia–seizures syndrome-2 (MCAHS2) [OMIM: 300868], caused by mutations on the phosphatidylinositol-glycan-anchor biosynthesis class A  gene on chromosome 17p11.2. The loss of function of PIGL enzyme disrupts the second step of GPI synthesis in the ER, namely the de-N-acetylation of the N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI), which results in the disruption of glycan synthesis and unoccupied glycosylation sites on proteins and other molecules. PIGL-CDG presents as a multisystemic disorder clinically characterized by colobomas, migratory ichthyosiform dermatosis, mental retardation, ear anomalies and congenital heart defects. Concerning the latter, to date eight patients have been reported with cardiac manifestations, ranging from TGA, HSS and ToF to VSD with pulmonary hypertension, DOV, PPS and systolic murmur [Coloboma–congenital heart disease–ichthyosiform dermatitis–mental retardation–ear anomalies (CHIME) syndrome [OMIM:280000] is an AR CDG resulting from mutations in the phosphatidylinositol glycan anchor biosynthesis class L  gene. This gene encodes the GPI ethanolamine phosphate tranferase-1, which is also involved in GPI-anchor synthesis on the ER membrane. The backbone of GPI synthesis is assembled by the coordinated addition of sugar and phosphoethanolamine (EtNP) components to phosphatidylinositol. The disruption of this reaction leads to neonatal hypotonia, seizures, multiple congenital anomalies, and often premature death [Multiple congenital anomalies–hypotonia–seizures syndrome 1 (MCAHS1) OMIM:614080] is an AR CDG due to mutations in the phosphatidylinositol glycan anchor biosynthesis class N  gene. The encoded enzyme is a subunit of a heteropentameric transamidase complex involved in the attachment of proteins to the GPI anchor, which functions as a plasma membrane anchor for extracellular proteins [Multiple congenital anomalies–hypotonia–seizures syndrome 3 (MCAHS3) [OMIM:615398] is an AR CDG that originates from homozygous mutations on chromosome 20q13.12 in the phosphatidylinositol-glycan biosynthesis class T  and class O  cause two very rare CDGs that manifest with facial dysmorphism, skin abnormalities, mental retardation, epilepsy and gastrointestinal defects. PIGV is localized in the ER, where it transfers the second mannose to the GPI backbone  and complex 7 (COG-7) [OMIM:608779] genes lead to AR CDG type IIg and CDG type IIe, respectively. The rtension ,400,401 rtension ,403,404 +-transporting V1 subunit A (ATP6V1A) gene on chromosome 3q13.31 are causative of an AR CDG also known as cutis laxa type IId [OMIM:617403]. The acidification of endosomes, lysosomes, GA and other intracellular organelles are dependent on the vacuolar-type H+-ATPase (V-ATPase), a multimeric complex acting as an ATP-dependent protein pump, of which the protein encoded by ATP6V1A is a subunit. This complex is critical for the transport of hydrogen ions across the plasma membrane into the extracellular space and protein glycosylation. An imbalance in this process leads to acidification. So far, 4 patients have been reported, of which two exhibited SD (with tortuous aortic arch), LQTS with incomplete RBBB, HCM and progressive cardiac failure . This CDG presents more severe cardiac manifestations. Out of six reported patients, five were described with a variety of cardiac symptoms: severe DAR, PFO, SD, MVR, TVR, HCM, AI and TI, RHHS with HoRV, TVS, small PDA, MVP, RVD with reduced diastolic compliance (DI) and RBBB , is an AR LSD caused by homozygous or compound heterozygous mutations affecting the gene encoding cathepsin A  on chromosome 20q13. CTSA is a carboxypeptidase exerting a protective and stabilizing function on β-galactosidase and neuraminidase. In fact, GSL is associated with a combined loss of function of these two enzymes and manifests in three different phenotypic subtypes: early infantile form, late infantile form and juvenile/adult form. Although the three forms share some clinical features , they display some phenotypic differences and very different levels of severity and life expectancy. Cardiac involvement is usually reported in the infantile forms, which are also the most severe. Through our search, we identified 10 GLS patients, 8 infantile and 2 older in age , described with cardiac involvement, specifically DC, heart murmur, SD (mainly thickened cardiac septa), altered LV wall thickness (with decreased ventricular function), CM, HF, VDL, arterial hypertension and presence of vacuolated myocardial fibers  411,412,419,420.GBA1, also known as acid beta-glucosidase) gene on chromosome 1q22. Within the lysosomal lumen, this enzyme hydrolyzes glucosylceramides, playing a central role in the glucosylation of cholesterol, degradation of complex lipids and turnover of the cellular membrane. This results in the accumulation of glucocerebrosides within cells such as immune cells, which can infiltrate several tissues such as heart, liver and muscles  is a rare AR subtype of the classical subacute/chronic neuronopathic GD caused by homozygous or compound heterozygous mutations affecting the glucosylceramidase-beta type 1 ( muscles . In addi muscles . GD typely GD3c) ,463,464.GLA) gene on chromosome Xq22. It has an estimated prevalence of approximately 1–5/10 000 live births. Genetic mutations on this gene induce deficient or absent activity of lysosomal enzyme GLA, which mediates glycosphingolipid catabolism. As a result, accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids have been detected in the plasma and cellular lysosomes of vessels, nerves, and other tissues . I. I470]. Enzyme replacement therapy (ERT) is an established treatment for GLA LSD, with or without chaperone therapy , which helps in preventing or delaying the progression of some complications such as LV mass increase; however, its effects on other cardiac symptoms such as LVH and on fibrotic damage are less clear .GLB1) on chromosome 3p22.3 can originate two clinically distinct, albeit allelic, disorders: GM1-gangliosidosis type 1 and mucopolysacharidosis type IVB, also known by the eponym Morquio syndrome type B.Homozygous or compound heterozygous mutations of the gene encoding for beta-galactosidase-1 (GLB1 gene generates an elastin-binding protein (EBP), and some EBP mutations that compromise elastin fiber assembly have been associated with the development of cardiovascular symptoms  is an AR LSD with an estimated prevalence of about 1/100,000–200,000 live births. Clinically, GM1G1 is characterized by variable degrees of neurodegeneration and skeletal abnormalities, while cardiac symptoms are a less common occurrence, mostly associated with the infantile form and with specific c plaque . Later rc plaque ,477,478.c plaque ,479,480 Morquio syndrome type B [OMIM: 253010] is an AR LSD with a prevalence of 1/250,000–1,000,000 live births, with multiorgan involvement due to compromised keratan sulfate catabolism which results in intralysosomal accumulation in connective tissues and several other organs . ClinicaHEXB) gene on chromosome 5q13. It has an estimated prevalence of 1–9/1,000,000 live births. This lysosomal hexosaminidase after activation catalyzes the degradation of the ganglioside GM2 and other molecules containing terminal N-acetyl hexosamines. In the case of HEXB loss of function, GM2 ganglioside is abnormally stored in several tissues, primarily neurons and peripheral nervous tissues . This translates to early blindness, progressive central nervous system degeneration, hepatosplenomegaly, macrocephaly and cherry red spots on the macula. Although less common in Sandhoff disease, nine infantile patients have been reported with cardiac manifestations [Sandhoff disease [OMIM:268800] is an AR LSD caused by mutations in the beta-hexosaminidase  on chromosome 4p16. IDUA hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans , dermatan sulfate and heparan sulfate. From a clinical standpoint, MPS-I has been traditionally classified in subtypes based on the severity of the symptoms: the mild subtype called Scheie syndrome (MPS-IS) [OMIM: 607016], the moderate form called Hurler–Scheie syndrome (MPS-IH/S) [OMIM:607015] and the severe form called Hurler syndrome MPS-IH [OMIM:607014]. At present, however, MPS-I is considered a spectrum of disorders from attenuated to severe with many phenotypes in between , also known by the eponym Hunter syndrome, is an XLR LSD resulting from mutations of the gene encoding the enzyme iduronate 2-sulfatase (IDS), located on chromosome Xq28. IDS hydrolyzes the 2-sulfate groups of the g., ERT) . Pneumong., ERT) ,553. Thrg., ERT) ,597,598 g., ERT) . HSCT ing., ERT) .N-sulfoglucosamine sulfohydrolase (SGSH) on chromosome 17q25. It is the most common subtype of MPS-III, with a prevalence of 1–1.62/100,000 newborns, depending on ethnicity and country [Mucopolysaccharidosis type III subtype A [OMIM:252900], or Sanfilippo syndrome subtype A, is an AR LSD caused by homozygous or compound heterozygous mutations in the gene encoding  country ,601. The country . Death u country . Through country ,608,609  country ,600,610.N-alpha-acetylglucosaminidase (NAGLU) gene, located on chromosome 17q21. Its prevalence is estimated to be 0.5–1/100,000 live births [Mucopolysaccharidosis type III subtype B [OMIM:252920], or Sanfilippo syndrome subtype B, is another AR LSD caused by compromised GAG degradation due to mutations affecting the e births . Similare births . Howevere births . Our syse births ,613,614 e births ,600,610.HGSNAT gene (8p11.2-p11.1) and the GNS gene (12q14.3), respectively. The HGSNAT gene encodes heparan acetyl-CoA:alpha-glucosaminide N-acetyltransferase, while the GNS gene encodes N-acetylglucosamine-6-sulfatase. The rarest subtypes of mucopolysaccharidosis type III, namely subtype C [OMIM:252930] and D [OMIM:252940], are both hyper-rare AR LSDs with an unknown prevalence, caused by genetic mutations of two different genes: the HGSNAT is a lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of heparin and heparan sulfate in the presence of acetyl-CoA. When defective, intralysosomal GAG accumulation occurs and compromises the functionality of multiple organs, resulting in MPS-IIIC. This subtype has an estimated prevalence of 0.07–0.42/100,000 live births, depending on ethnicity and country ,615. MPSN-acetyl)-6-sulfatase that hydrolyzes N-sulfate esters from heparin, heparan sulphate and keratan sulphate. This subtype has a prevalence estimated at around 0.10/100,000 , also known as Maroteaux–Lamy syndrome, is a progressive AR LSD with an estimated prevalence of 1/43,000–1,500,000 ,625, cauwith age . Our sea00, also with age ,662,663 with age ,664.Mucopolysaccharidosis type VII [OMIM:253220], also called Sly syndrome, is an ultra-rare AR LSD caused by mutations affecting the gene encoding beta-glucuronidase (GUSB) located on chromosome 7q11. The loss of function of GUSB results in the lysosomal accumulation of three main GAGs, dermatan sulfate, heparan sulfate and chondroitin sulfate, leading to tissue hypertrophy and function disruption of many organs . MPS-VIIARSK gene on chromosome 5q15. This gene encodes arylsulfatase K, which is responsible for the hydrolysis of N-sulfate esters from sulfated multiple substrates such as GAGs, steroids, carbohydrates, proteoglycans and glycolipids. When loss of function occurs, the catabolism of GAGs  and other substrates is compromised, and they accumulate in peripheral tissues disrupting their functionality [Mucopolysaccharidosis type X [OMIM:619698] is a very recently described type of AR LSD caused by homozygous or compound heterozygous mutations of the ionality . Thus faionality  (Table 6The heart is the organ responsible for providing and maintaining the blood supply to all tissues of the body. Its muscular component, called myocardium, is formed by highly specialized contractile cells, extremely resistant to fatigue and characterized by unparalleled metabolic plasticity. To meet the high energy demand required by the contractile machinery of these cells, the biochemistry of the human myocardium has evolved to ensure constant energy production from a variety of substrates, mainly lipids and carbohydrates ,680. CarWith this systematic review, on one hand, we intend to raise awareness among clinicians about the potential association between rare IMDs and cardiac symptoms, as aid for diagnostics and therapeutics. On the other hand, by systematically gathering information on the enzymatic deficiencies that lead to cardiac manifestations, we aim to provide relevant knowledge on the molecular mechanisms underlying specific processes involved in cardiac development and functionality, which could be targeted for pharmacologic therapy and metabolic interventions.


Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention. Non-infectious manifestations were the initial presenting feature in 25% of IEI patients in the European Society for Immunodeficiencies Registry, which includes over 16,000 entries (This is no exception for the combined immunodeficiency activated phosphoinositide 3-kinase δ syndrome (APDS) first described in 2013 , 5. Auto2.A 16-year-old African American female was hospitalized with new-onset petechial rash and palpable purpura. A skin biopsy demonstrated superficial dermal perivascular lymphocytes, neutrophils, eosinophils, and extravasation of red blood cells. Staining of vessels in the dermal papillary tips was positive for C3 and fibrinogen, suggestive of vasculitis . LaboratNotable prior history included developmental delay, seizures, recurrent infections, and lymphadenopathy. Between the ages of 2–10 years, she experienced recurrent sinusitis and otitis media requiring tonsillectomy, adenoidectomy with two revisions, and tympanostomy tube placement with yearly revisions between ages 7–10 years. Otitis media episodes continued despite these surgical interventions. Her infectious history was also notable for hospitalization at 2-years-old for cervical lymphadenitis attributed to Epstein-Barr virus (EBV) and at 3-years-old for a vesicular rash due to varicella zoster virus (VZV) infection.Chronic, unexplained lymphadenopathy first developed at age 4 years. She underwent an excisional biopsy of a deep right cervical lymph node, which demonstrated follicular hyperplasia with poorly formed germinal centers, mantle zone attenuation, and an irregularly expanded marginal zone . RoutineGiven the discovery of bronchiectasis on HRCT chest and previous history of lymphadenopathy and recurrent sinopulmonary and herpesvirus infections as noted above, a thorough immune evaluation  was condPIK3CD gene at c.3061G > A encoding the known pathogenic E1021K variant and confirming a diagnosis of APDS type I  are a group of lipid kinases critical to the normal functioning of widespread and diverse cellular processes. Of the three class IA PI3 kinases, PI3Kδ, a heterodimer consisting of a catalytic and regulatory subunit, is preferentially expressed in immune cells and functions downstream of varied cell-surface receptors, including cytokine receptors, T- and B-cell antigen receptors, costimulatory molecule receptors, growth receptors, and toll-like receptors. Signaling pathways downstream of PI3Kδ activation then orchestrate the growth, activation, proliferation, differentiation, and survival of immune cells –12.PIK3CD gene encoding the p110δ catalytic subunit  or the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits   and is not found in the healthy population  mutations in either the , APDS2) –15. The pulation . A heterS2 cases , 15.These mutations result in increased PI3Kδ pathway activity with upregulated phosphorylation of phosphatidylinositol-4,5-bisphosphate to form phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 in turn enhances activation of the AKT serine-threonine kinases , 12. ActThese dysregulated signaling pathways in APDS have diverse effects on T- and B-cells. B-cells demonstrate increased apoptosis along with impaired maturation in the bone marrow beyond the transitional B-cell stage –18. IntaLike B-cells, T-cells also demonstrate increased apoptosis , 20. Whi4.Disease progression in APDS classically involves chronological development of infectious, benign lymphoproliferative, autoimmune, and malignant complications , 6 with Benign lymphoproliferation occurs in up to 87% of patients, manifesting as lymphadenopathy, splenomegaly, hepatomegaly, tonsillar/adenoid hypertrophy, and nodular hyperplasia within gastrointestinal and respiratory mucosa. Diffuse large B-cell lymphoma, CHL, and marginal zone B-cell lymphoma are the most common forms of malignant lymphoproliferation with an increased risk of development in those with previous or chronic EBV infection –6. Patie5.In the largest systematic review of APDS patients to date, autoimmune features were reported in 28% of 243 total patients , 40, 42.As noted in 6.Efforts to mitigate the infectious, lymphoproliferative , and autoimmune complications of APDS have centered on combination use of antibiotic prophylaxis, IRT, immunomodulators, selective PI3Kδ inhibitors, and hematopoietic stem cell transplant (HSCT) . While tSelective PI3Kδ inhibitors have been the focus for this search for treatments with greater efficacy and more favorable side effect profiles. Leniolisib (CDZ173) is a potent oral small molecule inhibitor of the p110δ catalytic subunit with promising results in APDS patients. Rao et al. recently published results from the global, phase 3, randomized (2:1), placebo-controlled trial of leniolisib in 31 APDS patients . LenioliFinally, HCST has been pursued in APDS patients with severe, treatment-refractory disease , 25. Sig7.Normal immune function depends on balanced PI3Kδ pathway signaling as evidenced by the immunodeficiency and immune dysregulatory features that develop from heterozygous GOF mutations in PI3Kδ. The clinical heterogeneity of APDS is likely due to a complex interplay between environmental and pathogen exposures and genetic predisposition. While APDS patients have wide-ranging clinical phenotypes from being asymptomatic to substantially severe , the oveOur case highlights cutaneous ANCA vasculitis as an underreported autoimmune manifestation of APDS while also demonstrating well-established features, such as recurrent sinopulmonary and herpesvirus infections, bronchiectasis, lymphadenopathy, increased transitional B-cells, total and naïve T-cell lymphopenia, and dysgammaglobulinemia. Spontaneous resolution of the vasculitis was observed similar to the clinical course of uncomplicated primary cutaneous vasculitis  though AVasculitis was reported in approximately 1% of the more than 5,000 IEI patients in the USIDNET registry, with the highest rates in interferonopathies and Wiskott–Aldrich syndrome. However, vasculitis occurs in several other immunodeficiencies, including HIGM, CVID, Hyper IgE-syndrome, complement deficiencies, chronic granulomatous disease, agammaglobulinemia, and autoimmune lymphoproliferative syndrome . The speDNA sequencing advancements and identification of monogenic defects underlying IEIs has led to a better understanding of the molecular pathways and mechanisms that result in their clinical manifestations. This, in turn, has allowed for significant advancements in developing precision-medicine therapeutics , includi


JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations , have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs , some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.Knowledge on the myeloproliferative neoplasms (MPNs) – polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) – has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs:  JAK2, MPL, CALR – and thus can be seen as clonal versions of myelopoiesis (JAK2 exon 14 (JAK2V617F) was discovered first, rapidly followed by the MPL exon 10  and CALR exon 9 mutations , in MPN disease initiation and progression have been extensively studied, in vitro and in murine models . MPN phenotypes clearly do not depend on JAK2V617F, since this mutation is found in all MPN subtypes , as well as in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and in splanchnic vein thrombosis (SVT) . Consequently, the size of JAK2V617F-mutated clones and the percentage (%) of JAK2V617F-mutated alleles varies widely, from 1% to 100%. Of note, 25-50% JAK2V617F-mutated alleles are observed in all MPN subtypes. Moreover, if homozygous JAK2V617F-mutated clones (JAK2V617F load ≥50%) are typical of PV, they are also found in PMF. Heterozygous JAK2V617F-mutated clones (JAK2V617F loads <50%) are typical of ET and RARS-T, but also observed in PMF, in SVT, and more rarely, in PV  and CALR exon 9 mutations – with mutated allele loads close to 50%. Again, MPL and CALR mutations are found in both ET and PMF, in 5-10% MPN cases for MPL mutations, and 25-30% MPN cases for CALR mutations  (CALR mutations (15.9 years) compared to patients with MPL or JAK2V617F mutation , and worse for patients with no mutation in the JAK2/CALR/MPL genes (2.3 years)  .JAK2, germline ATG2B and GSKIP duplication or mutations in RBBP6 or EPOR (EPOR-p.P488S), and single nucleotide polymorphisms (SNPs) in the TERT, MECOM, and CHEK2 genes   . As in sDNMT3A, TET2, ASXL1, EZH2, SRSF2 and SF3B1 genes  in JAK2, MPL or CALR. Concomitant mutations do not directly influence the MPN phenotype but are associated with clonal expansion and disease progression, notably secondary myelofibrosis and leukemic transformation , with myelodysplastic/myeloproliferative neoplasms with ringed sideroblasts and thrombocytosis (RARS-T), and also in up to 14% PMF patients , thus reinforcing chronic inflammation and the production of myeloid cells, and increasing the risk of mutation of myeloid progenitors , 78.JAK2V617F mutation in the MPN clone , or an early event predisposing patients to the acquisition of JAK/STAT-activating mutations in myeloid progenitors and the development of MPN  are typically produced by non-mutated T-cells . Causes of inflammation other than genetic alterations have been investigated in myeloid malignancies. These include smoking, chronic inflammatory diseases, auto-immunity, metabolism disorders  and transferrin (decreased). Thus, chronic inflammation is characterized by mild elevations of leukocyte and platelet counts, and impaired erythropoiesis despite important iron stocks, eventually resulting in anemia  and acute myeloid leukemia , polymyalgia rheumatica, giant cell arteritis –95, 97. leukemia , 99. Intc marker .DNMT3A mutations, hereby causing clonal myelopoiesis and further inflammation  . In addiammation , 69, 102Non-genetic pathogenic mechanisms such as chronic antigen stimulation and antigen-driven selection are implicated in the pathogenesis of blood malignancies. Prior history of any autoimmune disease confers a significant risk of developing a myeloid malignancy, notably a MPN; the autoimmune diseases concerned include immune thrombocytopenic purpura and aplastic anemia –93. In MGBA) gene; subsets of GD patients develop GlcSph-reactive autoantibodies. Interestingly, GD patients present with chronic inflammation , various clinical manifestations, and an increased risk of blood malignancies , also called lysoglucosylceramide (LGL1), were detected in 20% MPN  patients, and 40% myeloma patients, which implied that an auto-immune process accompanied the development of MPN or myeloma disease in these patients , 104. Acgnancies , 106. Ingnancies . One hypInflammation may also be diet-induced. The influence of dietary factors on the risk of MPN has been investigated: the only finding was that a high intake of caffeine protects against PV . In contAccording to present knowledge, MPNs result from the combination of acquired mutations (JAK2/STAT5 activating driving mutations and/or concomitant mutations), chronic inflammation  and for a minority of individuals, of germline genetic pre-disposition to MPNs. Hence, whenever possible, better addressing the causes of mutation-independent inflammation  and iron deficiency) should prevent or reduce the risk of MPN. Moreover, to be curative MPN treatments should target mutations, eliminate disease-initiating stem cells, and suppress the production of inflammatory cytokines and causes of mutation-independent inflammation. Among present treatments, IFN-α2 and JAK inhibitors counter both inflammation and JAK2/STAT5 driving mutations, with partial results for JAK1/2 inhibitors (which do not act on NF-κB-dependent inflammation) and complete remissions for IFN-α2 (which counters inflammation more broadly) , 48, 86.via phlebotomies; hepcidin mimetics and ferroportin inhibitors offer new therapeutic options (Presented in  options .via increased physical activity and an improved diet, would be expected to reduce the risk for ET. A more systematic search for and treatment of undiagnosed chronic inflammatory or/and autoimmune diseases should help reduce inflammation and the associated risk of acquired MPN-driving mutations in healthy myeloid cells, or additional mutations in the MPN clone. In patients with proven autoimmunity against GlcSph, GlcSph could become a new target in MPN therapy, since GlcSph can be reduced with existing treatments (Importantly, searching for causes of inflammation in patients other than mutations may contribute to improve their response to treatment in case of established MPN, and help reduce the risk of developing a MPN in older individuals. For instance, prevention of smoking should reduce the risk for PV, and prevention of obesity, eatments , 106.CALR exon 9 mutants, patients with CALR-mutated ET or PMF may benefit from CALR mutant peptide vaccination (Other new potential therapeutic targets in MPNs include certain cytokines, particularly IL-1β, which can be inhibited efficiently with IFN-α, and also with anti-IL-1β antibodies or NF-κB inhibitors. Finally, because of the immunogenicity of cination –113.The author confirms being the sole contributor of this work and has approved it for publication.


FW2.2 is a PLAC8 motif-containing gene that negatively controls fruit size by regulating cell division and expansion in the carpel ovary during fruit development. However, despite FW2.2, other FWL (FW2.2-Like) genes in tomatoes have not been investigated. In this study, we identified the 21 SlFWL genes, including FW2.2, examined their expression profiles under various abiotic adversity-related conditions. The SlFWL gene structures and motif compositions are conserved, indicating that tomato SlFWL genes may have similar roles. Cis-acting element analysis revealed that the SlFWL genes may participate in light and abiotic stress responses, and they also interacted with a variety of phytohormone-responsive proteins and plant development elements. Phylogenetic analyses were performed on five additional plant species, including Arabidopsis, pepper, soybean, rice and maize, these genes were classified into five subfamilies. Based on the results of collinearity analyses, the SlFWL genes have a tighter homologous evolutionary relationship with soybean, and these orthologous FWL gene pairs might have the common ancestor. Expression profiling of SlFWL genes show that they were all responsive to abiotic stresses, each subgroup of genes exhibited a different expression trend. Our findings provide a strong foundation for investigating the function and abiotic stress responses of the SlFWL family genes.PLAC8 is a cysteine-rich protein that serves as a central mediator of tumor evolution in mammals. PLAC8 motif-containing proteins widely distribute in fungi, algae, higher plants and animals that have been described to be implicated in fruit size, cell number and the transport of heavy metals such as cadmium or zinc. In tomatoes,  FW2.2 (fruit weight 2.2), the first locus identified as a significant QTL regulating tomato fruit weight, controls tomato fruit size by negatively regulating the number of cell divisions in the carpel ovary [FW2.2 is a member of a broad family of cysteine-rich eukaryotic proteins with a placenta-specific 8 conserved structure, originally discovered in mammalian placental proteins [FW2.2 gene primarily affects fruit size by regulating the number of cell divisions and expansions in the carpel ovary, and the allele variations in the expression of FW2.2 alleles manifest as differences in transcript levels and timing of expression [FW2.2 also affects other phenotypes, such as fruit number and photosynthate distribution [FW2.2 physically interacts with the CKII kinase, which is located in or around the plasma membrane and has been extensively studied in animals and yeast cells, where it forms part of the cell cycle-related signal transduction pathway [el ovary ,2. It plel ovary . FW2.2 iproteins ,4. In topression . Furtherribution . Further pathway .FW2.2 has numerous homologs in plants, animals, and fungi [FW2.2-like (FWL) genes serve significant roles in regulating the size of fruit and cell number [CNR1 (Cell Number Regulator 1) and CNR2, two of the FW2.2 orthologs in maize, act as negative growth regulators, reducing the size of the entire plant and its organs when CNR1 is overexpressed, whereas the expression of CNR2 was shown to be inversely linked with the vigor of hybrid seedlings and tissue growth activity [FWL gene family in rice has eight members. Among them, OsFWL3 has a negative correlation with the glume’s growth activity, the grain length of the osfwl3 mutant was longer than the wild type. Analysis of GUS activity revealed that the expression level of OsFWL3 in mature glume was significantly higher than that in developing glume. While OsFWL5 negatively regulated plant height, the plant height of the osfwl5 mutant was distinctly shorter than that of the control [FW2.2 gene was significantly up-regulated during nodule development and was named GmFWL1 [FWL gene family play significant roles in the translocation of cadmium and zinc [OsFWL4 expression in rice seedlings affects Cd resistance, when exposed to cadmium, the expression of OsFWL4 in rice seedlings considerably changed in their root and stem tissues, whereas their Cd concentration was significantly reduced in their above-ground tissues [OsFWL5/OsPCR1 and OsFWL2/OsPCR3 are closely associated with Cd accumulation. The cadmium buildup in the rice roots, stems, leaves and seeds was greatly enhanced in the RNAi plants of OsPCR1 and OsPCR3, however, this was not the case in the overexpressed plants, which displayed cadmium tolerance [Arabidopsis thaliana, the Cys-rich membrane protein AtPCR1 was first obtained from the cadmium-sensitive yeast strain ycf1, and overexpressing AtPCR1 exhibited increased Cd(II) resistance [AtPcr1, 2, 9 and 10 grew better than empty vector-expressing strains on Cd(II)-containing plates [Arabidopsis. Mutants with a loss of atpcr2 function are sensitive to zinc stress under zinc excess and deficiency conditions [OsFWL5/OsPCR1 expression was found to increase during seed development in GW2 (Grain Weight 2) loss-of-function mutants, which encode a protein that regulates seed weight [OsFWL5/OsPCR1 was found to be involved in both the control of controlling grain weight, length and breadth as well as for the resistance of rice to heavy metals like zinc, cadmium and lead, according to analysis of the OsFWL5/OsPCR1 knockout and overexpression lines [MCA1 and MCA2, two members of the Arabidopsis FWL family with PLAC8 motifs, are situated at the plasma membrane and take up Ca2+ as well as mediate the rise in cytosolic Ca2+, which is generated by cold and the development of cold tolerance in Arabidopsis [In addition, nd fungi ,8. In pll number ,9,10. CNactivity . The kno control . Numerou control . A homold GmFWL1 . Moreoved GmFWL1 ,15,16. Mand zinc ,14,17. O tissues . OsFWL5/olerance . In Arabnditions . Similard weight . OsFWL5/on lines ,22. It wbidopsis ,24. Thesbidopsis .Solanum lycopersicum), a widely cultivated vegetable crop, is highly susceptible to abiotic stresses, which can affect plant growth, reduce photosynthetic rate, disrupt ion balance and yield [FWL family members in tomatoes have not been well characterized, and few studies have been reported on their response to various abiotic stresses. In this study, we characterized the SlFWL gene family in tomatoes and performed a comprehensive analysis of their protein physicochemical properties, chromosomal localization, gene structure, protein motifs, phylogenetic relationships and subcellular localization predictions. We also analyzed their expression profiles in response to abiotic stress such as low temperature (4 °C), high temperature (42 °C), salt (NaCl) and drought (PEG) stimuli. This study provides a better understanding of the structural characteristics of tomato SlFWL genes and serves as a basis for the functional validation of SlFWL genes and their role in stress tolerance in tomato plants.Tomato  method and visualized the gene structure using TBtools (v1.09876)  A. The chromosome B. The seSlFWL genes in tomatoes were analyzed for conserved motifs using MEME , with the identification of 10 conserved motifs , GCN4_motif (sperm endosperm), and zein metabolism regulation response elements were also detected. These findings suggested that the SlFWL genes may participate in many complex regulatory pathways involved in plant development, metabolic processes, and stress responses.The 2 kb upstream sequences from the translation start sites of the esponses . The anaArabidopsis, pepper and soybean, as well as monocotyledonous plants such as rice and maize [In order to investigate the homology of FWL proteins across different plant species, FWL proteins from 68 other species were extracted from EnsemblPlant, including proteins from dicotyledonous plants such as nd maize ,13,15,27FWL genes in different plant species, we performed a synteny analysis of FWL genes between the genomes of tomato, Arabidopsis, rice (Oryza indica and Oryza japonica), maize, soybean and pepper . The results show that each SlFWL gene exhibited a distinct tissue expression pattern  after 1 h of heat treatment in comparison to the control (0 h). Under heat stress, the expression of SlFWL1 instantly rose 59-fold at 1 h. SlFWL19 did not respond to heat stress before 6 h, and then reached its highest expression level. The response of SlFWL20 to heat stress lasted long and was consistently up-regulated within 24 h. The expression of SlFWL6, SlFWL9, SlFWL10 and SlFWL12 was down-regulated in the short term but peaked within 6–12 h under heat stress. FW2.2, SlFWL14 and SlFWL18 were down-regulated at 1 h under heat stress, and, after a brief recovery, their expression was significantly suppressed after 6 h.Heat stress significantly altered the transcriptional profile of WL genes . SlFWL1,SlFWL genes responded to salt stress treatment  and Pafw2.2-like [FWL genes play a conserved role in repressing cell division or controlling cell number to control plant organ size [FWLs react to abiotic stress. In this study, we performed a genome-wide identification of the tomato FWL (FW2.2-Like) genes and thoroughly analyzed the gene structure, chromosomal localization, phylogeny, gene duplication, cis-regulatory elements, expression profiles in different tissues and in response to different abiotic stress treatments in tomatoes.FWL proteins with the PLAC8 structural domain are known to be universally present in plants, mammals, and fungi and have been found to play critical roles in regulating plant organ size, metal ion homeostasis and root tumor formation ,3,8,11. 2.2-like ,29,30. Tgan size . HoweverSlFWL genes, including the well-known gene FW2.2, which is distributed on 10 chromosomes in tomatoes  subunit of a CKII kinase at or near the plasma membrane. This discovery implied that FW2.2 may serve as a component of a signaling mechanism activated by extracellular signals that regulate fruit cell division [FW2.2 may function in a signaling pathway that connects hormone or sugar signals to the control of cell cycle machinery in developing flowers. This pathway may affect inflorescence number by the modulation of photosynthate partitioning in the plant and may act upstream of several genes associated with cell proliferation, such as CYCD3; 1 and KRP [FW2.2 is involved in the distribution and response of plant hormones is unknown, and the molecular mechanism by which FW2.2 connects hormone and sugar signals to regulate cell proliferation remains an open question.Our anticipated subcellular localizations demonstrate that the division ,7. Additdivision . The tomdivision . During division . Cell prdivision . For ins and KRP . HoweverFWL family are transmembrane domain proteins, and several investigations have shown that they are frequently found localized in the plasma membrane of cells [AtPCR1 was localized at the plasma membrane [2+ uptake and can function as intact membrane proteins [SlFWL genes that do not contain this structure. We speculated that the function of these genes may have also changed during evolution, which remains to be further verified. It is worth mentioning that cadmium resistance can be achieved by solely expressing the AtPCR1 N-terminal hydrophobic segment, which carries a CCXXXXCPC sequence conserved among various organisms [The majority of members of the of cells . In othemembrane . The amiproteins . A TM frproteins . Our trarganisms .SlFWL genes are very similar, except for SlFWL9, which has no coding region. The position and distribution of the coding region CDS of all SlFWL genes are relatively conserved  and monocotyledonous plants (rice and maize). These genes are distributed in five major branches  of colinear gene pairs between them, followed by pepper (17 pairs)  .SlFWL family genes. The promoter region contains multiple light-responsive elements and hormone-related action elements such as abscisic acid-responsive elements, jasmonic acid-responsive elements, gibberellin-responsive elements, and salicylic acid-responsive elements. In addition, these SlFWL genes also have stress-signaling elements such as TC-rich MYB- and MYC-binding sites  [SlFWL members feature MYB-binding elements. Additionally, the SlFWL gene family encompasses the GCN4 motif, which is developmentally significant and appears in numerous seed storage protein genes. Studies have demonstrated that promoter fragments carrying the GCN4 motif serve to regulate the seed-specific expression of genes related to germination [SlFWL genes may play an important role in light response, phytohormone signaling, and stress response.We analyzed 2000 bp of cis-regulatory elements (CREs) upstream of the translation start site of ng sites . These rt (ABRE) . MYB prot (ABRE) ,44. Our mination . The cisFWL genes in different tissues has been described in many species. For example, in Arabidopsis, reverse transcription PCR (RT-PCR) analysis shows that MCA2 was expressed in leaves, flowers, roots, angiosperms and stems, the GUS reporter gene for MCA1 was expressed in cotyledons, leaves, vascular tissues of the main roots and regions of the rosette center corresponding to the stem apical meristem [SlFWL does not have a uniform gene expression pattern in tomatoes. We obtained each SlFWL gene expression pattern in different tissues from public databases , hypocotyl (HYPO), nutritional meristem (MERI), cotyledon (COTYL), young leaf (YL), mature leaf (ML), young bud (YFB), flower (0 DPA), 10 days post-anthesis fruit (10 DPA), 20 days post-anthesis fruit (20 DPA) and ripe fruit (33 DPA). SlFWL1, 2, 3, 5, 10, 12, 16 and 19 were highly expressed in all tissues, with higher expression than other SlFWL genes. Expression clustering analysis revealed that SlFWL2, 9, 11, 12 and 21 were highly expressed in roots, followed by hypocotyl, and were relatively low in the fruiting stage. SlFWL1, 6, 7, 8, 13 and 20 were more highly expressed in cotyledons and roots than in any other tissues, and SlFWL14, 15, 17 and 19 were specifically expressed in mature flowers. The differential expression of these SlFWL genes in different tissues may indicate that they perform different functions in different parts of the plant and remains to be further investigated.The expression pattern of meristem . Howeveratabases . Ten SlFFWL family are focused on fruit and whole plant size and heavy metal resistance and allocation, but roles in abiotic stresses have not been reported [SlFWL family under cold temperature, high temperature, salt, and drought treatments  with a light intensity of 300 μmol·mhumidity .SlFWL genes under different abiotic stress conditions , we subjected 30-day-old (four-leaf-stage) tomato plants with relatively uniform growth conditions to stress treatments for three days and collected leaf samples at 0, 1, 3, 6, 12, and 24 h after the onset of stress [To investigate the expression pattern of the f stress . Plants f stress . For thef stress . The thi® Universal Blue qPCR SYBR Green Master Mix reagent , and primers were designed by NCBI Primer-BLAST   and then reverse transcribed to obtain cDNA by the HiScript II One Step RT-PCR Kit . Quantitst 2022) . The exphttps://plants.ensembl.org/index.html, accessed on 14 April 2022), and the hidden Markov model (HMM) of PLAC8 (PF04749), the FWL-conserved structural domain, was obtained from Pfam  [SlFWL candidate genes were searched in the tomato whole genome sequence using the Simple HMM search function of TBtools (v1.09876) software and filtered with the E-value 1 × 10−5 [SlFWL family genes, the FWL protein sequences containing the PLAC8 structural domain in Arabidopsis thaliana on NCBI were used as a query to perform a BLASTP search in the tomato protein sequence database with a maximum E-value of 1 × 10−5 to remove low similarity and duplicate sequences to find all remaining possible SlFWL genes [http://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi, accessed on 14 April 2022), and the SlFWL family genes were confirmed [SlFWL family genes was obtained by the online tool ExPASy  [http://www.csbio.sjtu.edu.cn/bioinf/Cell-PLoc-2/, accessed on 20 April 2022) and TMHMM Server v.2.0  were used for prediction of subcellular localization and the transmembrane structure of the SlFWL family members [Tomato genome, annotations, and protein sequence files (SL3.0) were downloaded from Ensemble Plants (il 2022) . Then, t1 × 10−5 . To obtaWL genes . Finallyonfirmed . All ideonfirmed . The calil 2022) . Cell-PL members ,58.SlFWL genes in tomatoes were aligned using ClustalW, and the phylogenetic tree of SlFWL genes was generated using the neighbor-joining (NJ) method, the 1000 bootstrap method, and the Poisson model on MEGA (Version 11) [SlFWL genes were visualized by TBtools ) [http://meme-suite.org, accessed on 16 May 2022), and the number of motif parameters was manually limited to 10 [SlFWL genes were extracted from the tomato genome sequence using TBtools (v1.09876) software [http://bioinformatics.psb.ugent, accessed on 12 May 2022), and these cis-regulatory elements were drawn by TBtools (v1.09876) [All identified sion 11) . The exo3 File)) . The coned to 10 . The prosoftware . The pro1.09876) ,61.Arabidopsis thaliana, rice, maize, pepper and soybean were performed using the MUSCLE alignment function in the MEGA (Version 11) with default settings [https://itol.embl.de/, accessed on 26 May 2022) to generate a phylogenetic tree [Multiple sequence alignment analyses of the FWL homologous family members in settings . The maxsettings . Then, ttic tree . The coltic tree .http://ted.bti.cornell.edu, accessed on 18 May 2022), which included the whole root (ROOT), hypocotyl (HYPO), vegetative meristems (MERI), cotyledons (COTYL), young leaves (YL), mature leaves (ML), young flower buds (YFB), anthesis flowers (0 DPA), 10 days post-anthesis fruit (10 DPA), 20 days post anthesis fruit (20 DPA), and ripening fruit (33 DPA) [SlFWL genes. The data for each row were normalized and plotted according to the average FPKM value for each gene. Heatmaps were generated using R software (v.4.2.2), and the package “pheatmap” (v.1.0.12) through Hiplot, a comprehensive web service for biomedical data analysis and visualization [We obtained tissue expression data of the wild tomato variety LA1589 from the publicly available transcriptome database, Tomato Functional Genomics Database ((33 DPA) . We retrlization . The qRTp < 0.05) indicating a significant difference. Drawing was conducted using GraphPad Prism 9 .Data was collated using Microsoft Excel 2016 and analyzed for statistics and significance using SPSS software 20.0 , with one-way ANOVA and Duncan’s test (FW2.2-like (FWL) gene family in tomatoes, including gene structure, chromosomal location, phylogeny, gene duplication, cis-regulatory elements and expression patterns in response to various abiotic stress treatments, is thoroughly analyzed in this paper. These findings imply that SlFWL genes may serve a variety of abiotic stress-related purposes. In addition to facilitating future functional research of this gene family in tomatoes and other plant species, the discovery and characterization of SlFWL genes in this work may have repercussions for the future creation of stress-tolerant crops.The


Cellular senescence describes a stable cell cycle arrest state with a characteristic phenotype. Senescent cells accumulate in the human body during normal aging, limiting the lifespan and promoting aging-related, but also several non-related, pathologies. We propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies”. Targeting senescent cells with senolytics or senomorphics is likely to mitigate these pathologies. Examples of senopathies include cardiovascular, metabolic, musculoskeletal, liver, kidney, and lung diseases and neurodegeneration. For all these pathologies, animal studies provide clear mechanistic evidence for a connection between senescent cell accumulation and disease progression. The major persisting challenge in developing novel senotherapies is the heterogeneity of senescence phenotypes, causing a lack of universal biomarkers and difficulties in discriminating senescent from non-senescent cells. Cellular senescence is a state of stable cell cycle arrest. It is, in vivo, most commonly induced in response to various physiological and pathological conditions through DNA damage signaling ,2,3,4 orThe SASP is considered the main trigger of tissue damage caused by SCs and is composed of pro-inflammatory cytokines, chemokines, and matrix-remodeling factors . In addiSimilarly, the contribution of cellular senescence to a wide range of pathological conditions is highly complex, combining beneficial and detrimental effects ,33. ManyWe propose to refer to all diseases whose pathogenesis or progression is associated with cellular senescence as “senopathies” and aim to provide examples and mechanistic explanations in this opinion paper. While, on the one hand, precision medicine identifies more and more subtypes of disease entities, senescence might, on the other hand, be a common denominator and therapeutic (co-) target for a variety of very different disease entities. Here, we do not cover the connection between cellular senescence, cancer, and senolytic cancer therapy. This topic has already been extensively reviewed elsewhere ,41,42 anIn 1995, Dimri and colleagues demonstrated that cellular senescence occurs in cultures of human cells and aging skin by developing a first biomarker, such as the activity of β-galactosidase at pH 6.0, referred to as SA-β-Gal . IncreasIn general, SCs are characterized by a stable cell cycle arrest primarily due to DNA damage signaling in response to the shortening of telomeres, exposure to growth factors and inflammatory cytokines, high levels of reactive oxygen species (ROS), and mitochondrial dysfunction. These cells are typically larger, displaying a flattened shape and extensive vacuolization. Disrupted integrity of the nuclear envelope is observed due to a loss of Lamin B1 protein, whose decreased expression is currently one of the most useful senescence biomarkers . SenesceChromatin reorganization in SCs provokes the formation of senescence-associated heterochromatin foci (SAHFs) to induce the silencing of genes that promote proliferation, including E2F target genes. SAHFs are characterized by extensive DAPI staining and immunoreactivity to macroH2A, heterochromatin protein 1 (HP1), and lysine 9 di-or-tri-methylated histone H3 (H3K9me2/3) .WAF1/CIP1 (CDKN1A) and p16INK4A (CDKN2A) to inhibit the activity of cyclin-dependent kinase [INK4A, and p21WAF1/CIP1, are extensively used to detect cellular senescence in vitro and in vivo [Moreover, SCs display a persistent DNA damage response (DDR) and contain nuclear foci called “DNA segments with chromatin alterations reinforcing senescence” (DNA-SCARS). DNA-SCARS in uncapped telomeres are called “telomere dysfunction-induced foci” (TIF). Another indicator of the DDR is the phosphorylated form of H2A.X or γ-H2A.X, a variant of a histone required for checkpoint-mediated cell cycle arrest and DNA repair of double-stranded DNA breaks. Regulatory protein p53, as a mediator of the DDR, promotes the activation of p21 in vivo ,47.Senescent cells maintain their metabolic activity and secrete inflammatory cytokines , growth factors such as TGFβ, chemokines, specific micro-RNAs, and matrix metalloproteinases, collectively known as the SASP . The SASINK4A, p21WAF1/CIP1) or absent ; and (3) identification of factors predicted to be altered in specific senescence contexts  [Manifestation of each senescence hallmark is context-dependent and varies according to the trigger, cell or tissue type, and time from induction of the senescence program . ChangesB1); and  identifiXO/mTOR) .Aging and related functional declines are strong drivers for many diseases and can be treated pharmacologically ,53,54,55p16-3MR [INK-ATTAC [INK4A-expressing cells.Several studies connecting SC accumulation to disease progression used the p16-3MR  or the INK-ATTAC  mouse moINK4A mRNA. Navitoclax effectively eliminated SCs from advanced atherosclerotic lesions in LDL receptor knockout mice exposed to a high-fat diet. Thereby, navitoclax prevented elastic fiber degradation and fibrous cap thinning through increased metalloprotease production [Improved cardiovascular function, increased regeneration, and prevention of hypertrophy and fibrosis were shown under the treatment of old animals with navitoclax or a combination of dasatinib and quercetin (D+Q) ,62. Thesoduction .WAF1/CIP1, and p16INK4A [NOD mouse model of type 1 diabetes, pointing toward diabetes as a potential senopathy [db/db diabetes-prone animals fed a high-fat diet were observed after treatment with D+Q [Ruxolitinib treatment enhanced adipogenesis, reduced fat tissue loss and lipotoxicity, and improved insulin sensitivity of old animals by reducing the amounts of SA-β-gal positive cells and transcription of IL-6, p21p16INK4A . Even moenopathy . Alleviawith D+Q . A subsewith D+Q . Metformwith D+Q  and extewith D+Q . Althougwith D+Q ,70, the with D+Q .−/−Zmpste24 progeroid mouse model [Significant reduction in SCs and SASP factors in old mice by treatment with Ruxolitinib or D+Q prevented loss of bone mass and increased their strength, effectively preventing osteoporosis and frailty . Moreovese model .INK-ATTAC and in the −/−Mdr2 mouse model of primary sclerosing cholangitis [Age-related liver steatosis and fibrosis were effectively treated with A-1331852 or D+Q by elimination of SCs with decreased production of the SASP, both in langitis ,77. Morelangitis .SAMP8 mice developing pathophysiological alterations similar to human AD and in the NFT-Mapt0/0tau model acquiring tau-related pathologies at a faster rate show that treatments with fisetin or D+Q decreased inflammation and stress with restored synaptic function, cognitive deficits, and cerebral blood flow [INK-ATTAC PS19 mice, which express high levels of human tau, specifically in neurons [Senopathies have detrimental effects on the nervous system by affecting both its structure and function. One prominent example of a neurodegenerative condition likely promoted by the accumulation of SCs and characterized by the expression of tau is AD. Studies in ood flow ,79. More neurons .INK4A, Bcl-2, IL-la, and IL-1β. It would be interesting if also chronic obstructive pulmonary disease (COPD), in which senescent cells are known to accumulate, were alleviated by senolytic treatment [An accumulation of senescent cells induces fibrotic pulmonary disease, especially in idiopathic pulmonary fibrosis . D+Q impreatment .In While we are moving towards precision medicine with more disease entities identified by molecular patterning than before by clinical phenotypic classification alone , one com


Proteus mirabilis is the one of most important pathogens of catheter-associated urinary tract infections. The emergence of multidrug-resistant (MDR) P. mirabilis severely limits antibiotic treatments, which poses a public health risk. This study aims to investigate the resistance characteristics and virulence potential for a collection of P. mirabilis clinical isolates.P. mirabilis isolates and highlights the possibility of clonal spread of them across China. Mobile genetic elements SXT/R391 ICEs were commonly (10/14) detected in these MDR P. mirabilis strains, whereas the presence of resistance island PmGRI1 and plasmid was sporadic. All ICEs except for ICEPmiChn31006 carried abundant antimicrobial resistance genes (ARGs) in the HS4 region, including the extended-spectrum β-lactamase (ESBL) gene blaCTX-M-65. ICEPmiChn31006 contained the sole ARG blaCMY-2 and was nearly identical to the global epidemic ICEPmiJpn1. The findings highlight the important roles of ICEs in mediating the spread of ARGs in P. mirabilis strains. Additionally, these MDR P. mirabilis strains have great virulence potential as they exhibited significant virulence-related phenotypes including strong crystalline biofilm, hemolysis, urease production, and robust swarming motility, and harbored abundant virulence genes.Antibiotic susceptibility testing revealed fourteen MDR strains, which showed high resistance to most β-lactams and trimethoprim/sulfamethoxazole, and a lesser extent to quinolones. All the MDR strains were sensitive to carbapenems (except imipenem), ceftazidime, and amikacin, and most of them were also sensitive to aminoglycosides. The obtained MDR isolates were sequenced using an Illumina HiSeq. The core genome-based phylogenetic tree reveals the high genetic diversity of these MDR P. mirabilis with high virulence potential poses an urgent threat to public health. Intensive monitoring is needed to reduce the incidence of infections by MDR P. mirabilis.In conclusion, the prevalence of MDR  Urease CDEFGHJ) . CAUTIs CDEFGHJ) . P. mirafimbriae . The forfimbriae .Proteus species possess intrinsic resistance to colistin, nitrofurantoin, tigecycline, and tetracycline  , play a central role in the acquisition and spread of ARGs in irabilis . ICE is irabilis . Especiabination . SXT/R39bination , and alsblaCMY-2 , tet(X6)(tet(X6) , and blablaNDM-1 . SXT/R393-toprJ1 .P. mirabilis isolates from a county hospital in the Sichuan province of China. Also, virulence characteristics including motility, urease production, hemolytic activity, and biofilm formation were determined to better understand the potential risk of these MDR P. mirabilis isolates.The present study was conducted to investigate the prevalence, resistance gene profiles, and virulence determinants for clinical 22.1P. mirabilis strains were isolated from different clinical samples of patients at the Hejiang County People’s Hospital, in Luzhou City, Sichuan Province of China, from January to December 2021. Written informed consent from the patients was exempted from this study since the present study only focused on bacteria, and the strains were isolated as a part of the routine hospital laboratory procedures. Isolates were initially identified with both the VITEK 2 system  and 16S rRNA gene sequencing analysis  (The minimum inhibitory concentrations (MICs) of 23 antimicrobial agents, including ampicillin, amikacin, ampicillin/sulbactam, azlocillin, aztreonam, cefazolin, cefepime, cefoxitin, cefixime, cefotetan, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, gentamicin, imipenem, meropenem, levofloxacin, nitrofurantoin, mezlocillin, piperacillin/tazobactam, tobramycin, and trimethoprim-sulfamethoxazole were automatically performed by the VITEK 2 system. MICs of ceftazidime, cefotaxime, and meropenem were manually confirmed using the broth microdilution method, and the susceptibility testing for ceftazidime was also performed by Kirby Bauer disk diffusion method, with I, M100) . MDR strI, M100) .2.3P. mirabilis were selected for genomic DNA extraction using the QIAamp DNA Mini Kit  following the manufacturer’s guidelines. Whole genome sequencing was performed on the HiSeq 2000  Sequencer with a 150 bp paired-end library and 200 × coverage by the Beijing Tsingke Bioinformatics Technology Co. Ltd. The raw reads were trimmed using Trimmomatic v0.38 before being assembled into draft genomes using SPAdes v3.12.0 program (P. mirabilis HI4320 (Accession no. NC_010554) was calculated with JSpeciesWS (intSXT). The contigs of SXT/R391 ICE were extracted and assembled against the reference ICE of FZP3105 from our previous study (PmGRI1 were extracted and assembled against the reference PmGRI1-CYPM1 (GenBank accession CP012674). Linear sequence alignment was carried out using BLAST and visualized with Easyfig 2.2.3 in their core genomes, as previously described with minor modification (The genome sequences of other representative fication . Brieflyfication . A maximfication .2.5E. coli strain J53 (sodium azide-resistant) or EC600 (rifampicin-resistant) as the recipient, as described previously with minor modification (intSXT (Conjugation experiments were carried out using broth-based method with the fication . After t (intSXT .2.62.6.1P. mirabilis (OD600~0.4) were diluted 1/100 into fresh LB broth containing 50% filter sterilized human urine prepared from a pool of urine from several healthy volunteers. 200 µl diluted bacterial cultures were incubated statically in sterile 96-well microtiter plates  for 24 h at 37°C. The culture supernatant was then removed and the biofilm production was quantified by the crystal violet staining method as described previously(Broth cultures of reviously. Negativreviously.2.6.2P. mirabilis was mixed with LB broth containing filter sterilized urea (20 g/L) in the ratio of 1:100. After incubation for 24 h at 37°C, the color change (orange to pink) was observed by adding 0.02% phenol red reagent (pH indicator). The hemolytic ability of P. mirabilis strains was determined by culturing on a 10% sheep blood plate for 24 h at 37 °C. For motility assays, 1 µl of culture was point inoculated onto the surface center of the solid LB agar plates. After incubation for 24 h at 37 °C in a lid-side-up position, motility was measured as the diameter across which P. mirabilis grew , hemolysin (hpmAB), Urease (ureC), biofilm formation , autotransporters , proteases (zapA), and siderophore (nrpR) were identified using the Virulence Factors of Pathogenic Bacteria Database (VFDB)  was performed in a pairwise BLASTn alignment.The presence of genes related to bacterial virulence factors including fimbriae (e (VFDB) . The ide33.1. mirabilis strains, 14 (43.8%) of them were identified as MDR, which were recovered from sputum , urine , stool , ascites , and wound secretion . Results of the antimicrobial susceptibility test indicated that all the MDR strains were resistant to ampicillin, azlocillin, cefazolin, cefixime, mezlocillin, ampicillin/sulbactam, and trimethoprim/sulfamethoxazole, in addition to their intrinsic resistance profiles (P. mirabilis possesses intrinsic decreased susceptibility to imipenem (but not meropenem and ertapenem), 92.9% of MDR strains (n=13) were resistant to imipenem in this study, which was thought to be caused by weak affinity with penicillin-binding proteins or porin loss  of them carried at least 15 ARGs -IV (n=11), aph(4)-Ia (n=11), aph(6)-Id (n=8), and aph(3’’)-Ib (n=8) being the most prevalent. Of the detected quinolone resistance genes, aac(6’)-Ib-cr  is the most common, followed by qnrD1 , and qnrS1 was only detected in one isolate. Furthermore, we found that genotypic and phenotypic resistance in these strains often does not match. Almost all the blaCTX-M-65-harboring isolates (except for HJP22016) remain sensitive to aztreonam. Also, the presence of aac(6’)-Ib-cr did not lead to quinolone resistance in several strains, such as HJP21048, HJP31010, and HJP31030. These findings suggest that the functions of these ARGs may be regulated by some unknown mechanisms in P. mirabilis strains , maintenance (topB), and conjugation (vir genes). The sole acquired resistance gene region was identified downstream of dnaA , wherein blaCTX-M-63 was present in an ISEcp1-blaCTX-M-63 transposition unit. The insertion sequence ISEcp1 is known to mobilize adjacent sequences, including blaCTX-M genes, by using its own left inverted repeat (IRL) in conjunction with alternative sequences resembling its right inverted repeat (IRR)  from China, and pPM64421b  from Brazil, indicating global spread of this type of plasmid.Only two types of plasmids, IncQ1 and Col3M, were identified in these at (IRR) . BLASTn aadA5, aph(6)-Id, aph(3’’)-Ib, aph(3’)-Ia, aac(3)-IIa, aph(6)-Id, aph(3’’)-Ib), β-lactam (blaTEM-1B), macrolide (mph(A)), amphenicol (catA1), sulphonamides , and trimethoprim (dfrA17) are clustered in a 39, 086-bp MDR region, wherein an IncQ1-type replication gene repA is present. The MDR region showed high similarity  to the one found in a P. mirabilis strain CY32 , and was partly similar  to the plasmid p24362-1 (CP051379) recovering from a Salmonella enterica strain from swine in the USA. The result reveals that the MDR regions on the chromosomes of P. mirabilis HJP16012 and CY32 seem to be derived from a p24362-1-like plasmid. Further sequence analysis showed that two copies of IS1 flanked the MDR region in CY32 and HJP16012 -relative elements, including SGI1(Proteus genomic island 1 (PGI1)(Proteus genomic island 2 (PGI2)(Pmi1(PmGRI1(P. mirabilis strains. The presence of SGI-relative elements in our P. mirabilis isolates was screened by searching the integrase gene of SGI1 (KM234279), PGI1(KJ411925), PGI2 (MG201402), GIPmi1 (MF490433), and PmGRI1(MW699445) from the whole sequenced genomes. As a result, five  strains contained the PmGRI1 integrase gene , Proteus 2 (PGI2), GIPmi1(GI2) was successfully assembled. PmGRI1-17012 is 40,678 bp in size, and catA1 is the only known and complete antimicrobial resistance gene , which was recovered from a clinical P. mirabilis strain from Taiwan, China, in 2012. Due to possible complex structures or high numbers of transposases and ISs, the complete sequences of PmGRI1 in HJP05004, HJP22021, and HJP20004 were fragmented in two or more contigs. PmGRI1-05004 and PmGRI1-20004 are also possible variants of PmGRI1-CYPM1 as revealed by the existing assembly. PmGRI1-22021 seems to have a more complex genetic structure, with a number of genes, including several ARGs, being inserted upstream and downstream of tnpA of Tn21, respectively  and found that ten out of the fourteen  MDR P. mirabilis strains were positive for the intSXT gene -Id gene (an aminoglycosides resistance gene). BLASTn analysis showed that ICEPmiChn21049 is similar  to ICEPmiChn-HERJC4 (MZ221994) recovering from P. mirabilis strain HERJC4 from chicken in China. ICEPmiChn20004 is closely related  to several ICEs of human and animal origins from different locations in China, such as those in P. mirabilis strain PM8762 , and P. mirabilis strain HBNNC12 . ICEPmiChn31006 is nearly identical  to the element ICEPmiJpn1 initially described in Japan  to ICEPmiChn3105 (Accession no. CP098444), while HJP31010  is genetically distant from FZP3105 according to the species tree  and one variable region (VR) III. Their HS4 (traN-s063) regions contain 15 to 19 ARGs  that are clustered together in an ISPpu12-mediated composite transposon (26-mediated excision/replacement upstream of tet(A) and ISCR2-mediated insertion of ARGs downstream of floR representing two major modular differences of them , ICEEcoChnXH1815 , and ICEKpnChnQD23 , suggesting that ICEs may sever as an important vehicle in mediating the accumulation and dissemination of ARGs across bacterial species from different sources. ICEPmiChn31006 carries no VRIII and MDR HS4, but an HS3 region, with inserted genes encoding a pair of methylcytosine-specific restriction enzyme mcrBC. The sole ARG blaCMY-2 (encoding β-lactam resistance) in ICEPmiChn31006 is present in the HS5 region and locates downstream of the truncated ISEcp1, the element assumed to be involved in mobilization and expression of blaCMY-2   . The fin3.7All the tested strains produce strong crystalline biofilm in the urine environment and all of them, except for HJP16012, are urease producers  strains contained the pmpA (encoding the P. mirabilis P-like fimbria) and 71.42% (10/14) of them contained the uroepithelial cell adhesin (UCA) fimbriae gene ucaA, while only two strains (14.29%) had the Proteus mirabilis fimbria (PMF) gene pmfA , and RcsD (flagellar regulation) , pst, and rcsD (P. mirabilis uropathogenesis (flhA (encoding the flagellar assembly protein), fliF (encoding the flagellar MS-ring protein), fliG (encoding the flagellar motor switch protein), fliP (encoding the flagellar biosynthetic protein), fliL , and flgN (encoding the flagella filament assembly) were identified in all the tested strains. flaD (encoding the flagellar capping protein) was absent in HJP05004, HJP17012, and HJP18031, whose swarming abilities, however, were not affected at all, suggesting that flaD maybe not very necessary for swarming motility. As previously reported (hpmAB (encoding the hemolysin HpmA and its secretion protein HpmB) is highly conserved across the tested P. mirabilis isolates, whereas only seven of them exhibited hemolytic activity, suggesting an unknown regulatory mechanism is involved. Besides, 78.57% (11/14) of these P. mirabilis strains contained the siderophore synthase gene nrpR, which is important for colonizing the urinary tract (Proteus toxic agglutinin) are required for invading and colonizing of P. mirabilis in the bladder  of them had aipA  . In addiogenesis . Some flreported , hpmAB  represent major vehicles in mediating the dissemination of ARGs in P. mirabilis isolates. Plasmids also contribute to the resistance spread but to a lesser extent. Worryingly, the revelation of virulence-related phenotypes and the presence of abundant virulence genes in these MDR P. mirabilis strains pose an urgent threat to public health. Therefore, to better deal with infections caused by this species, close surveillance of the prevalence of MDR strains and related mobile elements from clinical is urgently recommended.In conclusion, this study revealed that ESBL genes are commonly detected in MDR The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/YL: conceptualization, formal analysis and writing-original draft. MY, CF and YF: methodology, resources and formal analysis. XD: software. WZ: resources, writing-review and editing. LZ: conceptualization, writing-review and editing, and supervision. All authors contributed to the article and approved the submitted version.