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Enterovirus genomic replication initiates at a predicted RNA cloverleaf (5'CL) at the 5' end of the RNA genome. The 5'CL contains one stem (SA) and three stem-loops (SLB, SLC, SLD). Here, we present an analysis of 5'CL conservation and divergence for 209 human health-related serotypes from the enterovirus genus, including enterovirus and rhinovirus species. Phylogenetic analysis indicates six distinct 5'CL serotypes that only partially correlate with the species definition. Additional findings include that 5'CL sequence conservation is higher between the EV species than between the RV species, the 5'CL of EVA and EVB are nearly identical, and RVC has the lowest 5'CL conservation. Regions of high conservation throughout all species include SA and the loop and nearby bases of SLB, which is consistent with known protein interactions at these sites. In addition to the known protein binding site for the Poly-C binding protein in the loop of SLB, other conserved consecutive cytosines in the stems of SLB and SLC provide additional potential interaction sites that have not yet been explored. Other sites of conservation, including the predicted bulge of SLD and other conserved stem, loop, and junction regions, are more difficult to explain and suggest additional interactions or structural requirements that are not yet fully understood. This more intricate understanding of sequence and structure conservation and variability in the 5'CL may assist in the development of broad-spectrum antivirals against a wide range of enteroviruses, while better defining the range of virus isotypes expected to be affected by a particular antiviral.

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Cloverleaf skull deformity or Kleeblattschadel syndrome is a severe condition where multiple cranial sutures are absent and prematurely fused, leading to a trilobate head shape. The remaining open sutures or fontanelles compensate for rapid brain expansion, while the constricted fused calvarium restricts brain growth and results in increased intracranial pressure. Recent data show that early posterior cranial and foramen magnum decompression positively affects infants with cloverleaf skulls. However, long-term sequelae are still rarely discussed. We hereby report a child who developed secondary metopic craniosynostosis after posterior cranial decompression, which required a front-orbital advancement and cranial remodelling as a definitive procedure.

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The cloverleaf skull deformity remains among the most complicated craniofacial conditions to successfully manage. Many cases achieve largely unsatisfactory outcomes due to the requirement for frequent reoperation on the cranial vault and failure to deal with all the elements of the craniofaciostenosis in a timely fashion. Early cranial vault surgery without addressing the cranial base deformity and its attendant cerebrospinal fluid flow changes is invariably challenging and disappointing. A recent focus on the expansion of the posterior cranial vault as a primary procedure with the greater volume change allows a delay in fronto-orbital advancement and reduced need for repeat surgery. We herein describe three cases of complex multisuture craniosynostosis with cloverleaf skull deformity who underwent neonatal posterior cranial vault decompression along with foramen magnum decompression. Our report examines the safety and rationale for this pre-emptive surgical approach to simultaneously deal with the cranial vault and craniocervical junction abnormalities and thus change the early trajectory of these complex cases.

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Cortical processing pathways for sensory information in the mammalian brain tend to be organized into topographical representations that encode various fundamental sensory dimensions. Numerous laboratories have now shown how these representations are organized into numerous cortical field maps (CMFs) across visual and auditory cortex, with each CFM supporting a specialized computation or set of computations that underlie the associated perceptual behaviors. An individual CFM is defined by two orthogonal topographical gradients that reflect two essential aspects of feature space for that sense. Multiple adjacent CFMs are then organized across visual and auditory cortex into macrostructural patterns termed cloverleaf clusters. CFMs within cloverleaf clusters are thought to share properties such as receptive field distribution, cortical magnification, and processing specialization. Recent measurements point to the likely existence of CFMs in the other senses, as well, with topographical representations of at least one sensory dimension demonstrated in somatosensory, gustatory, and possibly olfactory cortical pathways. Here we discuss the evidence for CFM and cloverleaf cluster organization across human sensory cortex as well as approaches used to identify such organizational patterns. Knowledge of how these topographical representations are organized across cortex provides us with insight into how our conscious perceptions are created from our basic sensory inputs. In addition, studying how these representations change during development, trauma, and disease serves as an important tool for developing improvements in clinical therapies and rehabilitation for sensory deficits.

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El cráneo en trébol es una malformación rara asociada al cierre temprano de múltiples suturas; se presenta con alteraciones en el desarrollo neurológico y una alta mortalidad. El tratamiento quirúrgico tiene como objetivo restaurar la forma y función del cráneo, en lo posible con el menor número de procedimientos.Este trabajo tiene como objetivo la presentación del caso de un lactante con deformidad de cráneo en trébol, caracterizado con el uso de ayudas diagnósticas e intervenido en un único tiempo quirúrgico con distracción de fosa posterior y remodelación de la bóveda craneal. (AU)

Cloverleaf skull is a rare malformation associated with early closure of multiple sutures; it presents with alterations in neurological development and high mortality. Surgical treatment aims to restore the shape and function of the skull, if possible with the fewest number of procedures.This paper aims to present the case of an infant with a cloverleaf skull deformity, characterized with the use of diagnostic aids and operated on in a single surgical stage with distraction of the posterior fossa and remodeling of the cranial vault. (AU)

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BACKGROUND: The question of whether the coronavirus genome contain as-yetununderstood genetic component. PURPOSE (OBJECTIVE): Elucidate the novel functions of the discovered tRNA-like base sequence and lead to the development of novel therapeutic agents. METHODS: A novel tRNA-like base sequence was found in the sequences complementary to the genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV. By comparing mutations in the tRNA-like base sequences of these two viruses, it was found that base pairing in the cloverleaf model of SARS-CoV-2 was more robust than that of SARS-CoV. RESULTS: The results of homology search between a short sequence of the coronavirus tRNA-like base sequence and human genes suggest that the molecule produced by this novel tRNA-like sequence may be involved in the splicing of human messenger RNA. CONCLUSIONS: Experimental molecular evidence of the tRNA-like base sequence discovered in this study is urgently needed.

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El síndrome de Pfeiffer es una enfermedad autosómica dominante con una incidencia mundial estimada de 1 por cada 100 000 recién nacidos vivos. Se caracteriza principalmente por craneosinostosis, hipoplasia mediofacial, extremidades con gruesos artejos prominentes y sindactilia. Es causada por mutaciones alélicas en los genes del receptor del factor de crecimiento de fibroblastos 1 y 2.Presentamos el caso clínico de una recién nacida con cráneo en trébol, hipoplasia mediofacial, dentición congénita, proptosis bilateral severa, extremidades con dedos prominentes, sindactilia en pie izquierdo y fístula rectovaginal. A los 10 días de vida presenta perforación ocular derecha que requirió enucleación completa. Progresa con deterioro hemodinámico y respiratorio y fallece a los 11 días de edad.El diagnóstico clínico y molecular fue de síndrome de Pfeiffer tipo 2a con mutación Trp290Cys del gen FRFG2, que presentó fístula rectovaginal como asociación no descrita, constituyéndose en el primer caso reportado en el lugar de procedencia, pudiendo ser la primera manifestación de una mutación en el gen del receptor FGFR 2 en su área geográfica.

Pfeiffer syndrome is an autosomal dominant disease with an estimated worldwide incidence of 1 per 100,000 live births. It is mainly characterized by craniosynostosis, midface hypoplasia, great toes, and syndactyly. It is caused by allelic mutations in the fibroblast growth factor receptor 1 and 2 genes. We present a clinical case of female newborn with cloverleaf skull, mediofacial hypoplasia, congenital dentition, severe bilateral proptosis, limbs with prominent fingers, syndactyly in the left foot, and rectovaginal fistula. At 10 days old, she developed ocular perforation in the right eye and required enucleation. Subsequently, progressed with hemodynamic and respiratory deterioration and died at 11 days of age.In the present study, we report on a sporadic case of severe Pfeiffer syndrome type 2 in a Colombian infant who had a Trp290Cys mutation in the FRFG2 gene that presented rectovaginal fistula as non-described association, which makes it the first case reported in the place of origin. It could be the first appearance of a mutation in the gene of the FGFR 2 receptor in the geographical area.

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INTRODUCTION: Partial cloverleaf (parclo) interchanges with closely spaced parallel entrance and exit ramps are more prone to wrong-way driving (WWD) compared to other interchange types. In this study, a logistic regression model was developed to predict the risk of WWD at the exit ramp terminals of parclo interchanges. METHOD: The logistic regression model was developed using Firth's penalized likelihood techniques based on the predictor variables such as exit ramp geometric design features, wrong-way related traffic control devices, area type, and traffic volume. RESULTS: According to the model, the significant predictors of WWD at parclo exit ramp terminals include corner radius from crossroad to entrance ramp, type of median on crossroad, width of median on two-way ramp, channelizing island, distance to the nearest access point, "Keep Right" sign, wrong-way arrow, intersection signalization, and traffic volume at the exit and entrance ramps. This model was used to conduct network screening for all the exit ramp terminals of parclo interchanges in Alabama and Georgia to identify high-risk locations in these two states. Seven high-risk locations were monitored by video cameras for 48-hours to observe the occurrences of WWD incidents. Results suggest that two locations in Alabama and two locations in Georgia experienced multiple WWD incidents within 48-hours of a typical weekend. CONCLUSION: The observation of WWD incidents at high-risk locations demonstrates strong evidence that the model could identify the exit ramp terminals with high risk of WWD. PRACTICAL APPLICATIONS: Transportation agencies can use this model to assess the risk of WWD at the exit ramp terminals within their jurisdictions and identify the high-risk locations for countermeasures implementation.

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Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

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Purpose/aim of the study: We report a rare case of autosomal dominant genetic syndrome "Pfeiffer", which is part of the group of acrocephalosyndactyly, with an annual incidence <1/100,000. Three forms are known. Type I is the less common form and it is characterized by moderate-severe mediofacial hypoplasia usually with normal cognitive development. Conversely, types 2 and 3 are more common and they are associated with more severe signs and complications with a more unfavorable prognosis. The type 3 form due to the presence of a cloverleaf skull distinguishes type 2.Materials and methods: Thirty-eight-year-old primigravida was referred to our center, at 28 weeks of gestation due to borderline ventriculomegaly, macrocrania, and a short femur. First trimester screening for chromosomopathies and CF-DNA was low risk; II trimester screening ultrasound showed the presence of "short femur" and macrocrania.Result: Our ultrasound evaluation, assisted by 3D ultrasound, showed cloverleaf skull, turricephaly, moderate ventriculomegaly (13 mm), hypertelorism and exophthalmos, low ear implantation, mild rhizomelia. Ultrasound depicts Pfeiffer syndrome or other acrocephalosyndactyly syndromes (Apert syndromes, Saethre-Chotzen) or other syndromic forms of craniosynostosis like Crouzon syndrome. The NGS panel for molecular analysis of genes involved in skeletal dysplasias showed the mutation of the FGFR2 gene, de novo.Conclusions: Using three-dimensional (3D) ultrasound, it is easier to distinguish rare syndromes characterized by facial dysmorphisms such as exophthalmos, mediofacial hypoplasia, and craniosynostosis.

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Pfeiffer syndrome, affecting roughly 1 in 100,000 individuals is characterized by acrocephalosyndactyly - the premature closure of skull sutures (craniosynostosis). These acrocephalosyndactyly syndromes which are often sporadic de novo but also autosomal dominant in inheritance can be characterized by the fact that they often involve FGFR and TWIST genes. In the presented case, a 27-year old male level three trauma admission displayed skull abnormalities on physical examination that history taking confirmed was the result of pediatric surgically corrected Pfeiffer syndrome. Noncontrast brain CT as part of his trauma work-up revealed characteristic Pfeiffer syndrome imaging pattern of midface hypoplasia, nonvisualization of coronal and sagittal sutures, and a degree of obstructive hydrocephalus. Pfeiffer syndrome requires extensive pediatric surgery often with poor adult follow up. The case presented provides good visualization of characteristic skull abnormalities in a surgically corrected adult. By virtue of imaging an adult, this provides readers with a unique look at the long-term viability and the body's resulting physiological adaptations of the extensive mandatory pediatric surgery these patients undergo.

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INTRODUCTION: Early decompressive posterior linear craniectomy (PLC) can be indicated in very young infants with complex multisuture synostosis, which often involve the lambdoid suture (LS). The literature data on the surgical technique and its results are scarce. MATERIAL AND METHODS: Based on our experience with PLC during the last 10 years, we detail our surgical technique for PLC, the possible pitfalls, and complication avoidance. RESULTS: We review seven observations, 5 girls and 2 boys, 6 of these with identified mutations, operated for PLC at a mean age of 3.19 months (6 days to 6.1 months). One patient died of unexplained cardiac arrest on postoperative day two, the others had a favorable outcome with good development and no visual loss. Three of these required additional cranioplasty at a later age, one of these with craniofacial distraction. DISCUSSION: PLC can be a salvage operation in very young patients with complex synostosis involving the LS, and with proper preparation and careful technique, allows favorable outcome. The approach must be versatile in order to anticipate further surgeries in these complex, most often syndromic cases.

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The importance of tongue mobility on speech, oral food transport, and swallowing is well recognized. However, whether the individual tongue mobility influences postoperative function in oral cancer treatment remains to be elucidated. This study assesses the ability to perform five tongue movements as rolling, twisting (two sides), folding, and the 'cloverleaf' in a healthy population. Because a tumor in oral cancer patients often restricts the mobility of the tongue, it might be helpful to know if it is possible to recall any of those movements without demonstrating it. Two observers asked 387 Dutch healthy adults if they could perform one of the five specific tongue movements and were subsequently asked to demonstrate the five movements. The distribution in the Dutch population is: rolling: 83.7%, cloverleaf: 14.7%, folding: 27.5%, twisting left: 36.1% and twisting right: 35.6%. The percentage of people that can fold their tongue is almost ten times higher (3% versus 27.5%) than in previous research, and it was found that the ability to roll the tongue is not a prerequisite for folding of the tongue. A relationship between gender or right-handedness and the ability to perform certain tongue movements could not be found. Of the participants, 9.9% and 13.1% incorrectly assumed that they could demonstrate tongue rolling and cloverleaf. Tongue folding and twisting (left or right) were incorrectly assumed in 36.9%, 24.1%, and 25.4% of the cases. Rolling and cloverleaf are preferred for future prediction models because these movements are easy to recall without demonstrating.

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Pfeiffer syndrome is a rare genetic disorder with heterogenous phenotype and prognosis. Due to its diverse clinical presentation, it can easily be misdiagnosed. Where genetic testing still remains a challenge, antenatal sonogram can aid in early diagnosis. The cranioorbito-faciostenosis demands aggressive management to permit survival instead of uniform early demise.

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Paper-based nucleic acid testing techniques are increasingly in demand. Hence, we have developed a simple and cheap paper fluidic device to detect multiple gene targets in Leptospira. Fluidic channels of the penta-clover device are drawn using a correction pen on Whatman filter paper 1. The fluid blocks the pores of the paper, avoiding leakage and ensuring the equal flow of sample to the reaction pads. The target genes are amplified by performing Loop-Mediated Isothermal Amplification (LAMP) with dry reaction components. Thecolor change of leuco crystal violetallows real-time monitoring of a positive amplification. The difference in color intensity is captured with a smartphone and analyzed using image processing software. The device amplifies the target within 15 min, detects the pathogen at a concentration as low as 50 attogram µL-1, detects Leptospira in blood samples without prior treatment and differentiates the Leptospira species even after 21 days of storage at room temperature.

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A 12-year-old female Shih-tzu dog was presented with a 2-month history of cutaneous non-pruritic multiple ulcerated or crusted nodules of less than 1.5 cm in diameter on eyelids, lips, abdomen, groin, thighs and perianal region. Several diagnostic tests were performed, including fine needle aspiration and skin biopsy of the cutaneous nodules. Cytologic interpretation was round cell neoplasm with multilobated (clover-leaf shaped) nuclei. Histopathology revealed round neoplastic cells with prominent anisocytosis and anisokaryosis, and numerous mitotic figures; however, the origin of the cells was not identified. Immunohistochemical evaluation indicated that these cells were positive for CD79a and MUM-1, but negative for CD3, CD20 and Pax 5. The patient was treated with chemotherapy, and the skin condition improved. Despite good response to chemotherapy, the patient was euthanized due to poor general health.

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INTRODUCTION: Pfeiffer syndrome is a rare autosomal dominant inherited disorder associated with craniosynostosis, midfacial hypoplasia, and broad thumbs and toes. The syndrome has been divided into three clinical subtypes based on clinical findings. METHODS: This review will specifically examine the most severe type, Pfeiffer syndrome type 2, focusing on its genetics and molecular biology. CONCLUSION: This subtype of the syndrome is caused by de novo sporadic mutations, the majority of which occur in the fibroblast growth factor receptor type 1 and 2 (FGFR1/2) genes. There is not one specific mutation, however. This disorder is genetically heterogeneous and may have varying phenotypic expressions that in various cases have overlapped with other similar craniosynostoses. A specific missense mutation of FGFR2 causing both Pfeiffer and Crouzon syndromes has been identified, with findings suggesting that gene expression may be affected by polymorphism within the same gene. Compared to other craniosynostosis-related disorders, Pfeiffer syndrome is the most extreme phenotype, as the underlying mutations cause wider effects on the secondary and tertiary protein structures and exhibit harsher clinical findings.

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Aminoacyl tRNA synthetases ligate tRNAs specifically with their cognate amino acid. These synthetases are among life's earliest proteins, class II tRNA synthetases (cognates A, D, F, G, H, K, N, P, S, and T) presumably preceding class I tRNA synthetases (cognates C, E, I, L, M, Q, R, V, W, and Y). Classification of codons into palindromic (structure XYX), 5'-dominant (YXX), and 3'-dominant (XXY) (Codon Directional Asymmetry [CDA]) shows that class II tRNA synthetases aminoacylate amino acids associated with XXY. Our working hypothesis expects bias for XXY codons in primordial RNAs, such as theoretical minimal RNA rings, designed in silico to mimic life's earliest RNAs. Twenty-five RNA rings have been computed, which code over a minimal length (22 nucleotides) for a start codon, stop codon, and one and only one codon for each of the 20 amino acids, and form stem-loop hairpins preventing degradation; these 25 minimal RNAs are the only ones matching these constraints and they seem homologous to consensus tRNA sequences. This similarity defined candidate RNA ring anticodons and corresponding cognate amino acids. Here, analyses of RNA ring codon contents confirm bias for XXY codons in 13 among 14 RNA rings with unequal XXY and YXX codon numbers. This bias increases with the genetic code integration order of the RNA ring's cognate amino acid across and within tRNA synthetase classes, suggesting that evolutionary processes, and not physicochemical constraints, produced the association between CDA and tRNA synthetase classes. The self-referential hypothesis for genetic code origin, a very complete genetic code evolutionary hypothesis integrating many translational machinery components, predicts best among genetic code evolutionary hypotheses CDA biases in RNA rings. The RNA rings' simple design inadvertently reproduces CDAs predicted by the genetic code's structure, confirming theoretical minimal RNA rings as good proxies for life's earliest RNAs.

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Small circular RNAs occur in many cells. Theoretical considerations designed to mimick primordial RNAs designed 25 theoretical, minimal 22-nucleotide long circular RNAs (RNA rings) forming stem-loop hairpins, including one codon per amino acid, a start and a stop codon. These RNA rings resemble consensus tRNAs, whose predicted anticodons assign to each RNA ring a potential cognate amino acid. Assuming dual translator and messenger roles, three consecutive translation rounds produce 21-residue-long peptides, seven codons at each round. In these conditions, steric hindrances between tRNA(-like) translators competing for partially overlapping nucleotide triplets can be reduced if none of the seven codons produces by circular permutation (position 1 → 3, or position 3 → 1) any of the six others. This non-permutability of codon sets is one of the conditions that define potential circular codes regulating translational frame. A near-universal maximal self-complementary circular code exists in reading frames of natural genes, and permutations of this circular code define maximal circular codes in each +1, +2 gene frames. Chronologically scaling RNA rings according to the genetic code inclusion order of their cognate amino acid, codon numbers belonging to the natural frame +1 circular code X1 decrease with cognate amino acid inclusion order, those belonging to the natural frame 0 circular code X0 increase. RNA rings with early cognates apparently reflect pre-(tRNA-like)-adaptor translation by direct codon-amino acid affinity with partially overlapping consecutive codons where X1 regulated translation. Translation of non-overlapping consecutive codons evolved in parallel with RNA rings' cognate inclusion in the genetic code and with X0. Hence the complex "multi-frame" natural circular codes potentially evolved spontaneously from small coding circular RNAs mimicked by theoretical minimal RNA rings. Modern reading frames evolved from earlier reading frames corresponding to modern +1 frames.

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INTRODUCTION: Pfeiffer syndrome is a rare autosomal dominant inherited disorder associated with craniosynostosis, midfacial hypoplasia, and broad thumbs and toes. The syndrome has been divided into three clinical subtypes based on clinical findings. METHODS: This review will specifically examine the most severe type, Pfeiffer syndrome type 2, focusing on its genetics and molecular biology. CONCLUSION: This subtype of the syndrome is caused by de novo sporadic mutations, the majority of which occur in the fibroblast growth factor receptor type 1 and 2 (FGFR1/2) genes. There is not one specific mutation, however. This disorder is genetically heterogeneous and may have varying phenotypic expressions that in various cases have overlapped with other similar craniosynostoses. A specific missense mutation of FGFR2 causing both Pfeiffer and Crouzon syndromes has been identified, with findings suggesting that gene expression may be affected by polymorphism within the same gene. Compared to other craniosynostosis-related disorders, Pfeiffer syndrome is the most extreme phenotype, as the underlying mutations cause wider effects on the secondary and tertiary protein structures and exhibit harsher clinical findings.