Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice.

Background: SARS-CoV-2 Omicron variants are highly resistant to vaccine-induced immunity and human monoclonal antibodies.

Methods: We previously reported that two nanobodies, P17 and P86, potently neutralize SARS-CoV-2 VOCs. In this study, we modified these nanobodies into trimers, called TP17 and TP86 and tested their neutralization activities against Omicron BA.

Structural insights into the rational design of a nanobody that binds with high affinity to the SARS-CoV-2 spike variant.

The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants associated with the adaptive evolution of the virus is prolonging the global coronavirus disease 2019 (COVID-19) pandemic. The modification of neutralizing antibodies based on structural information is expected to be a useful approach to rapidly combat emerging variants. A dimerized variable domain of heavy chain of heavy chain antibody (VHH) P17 that has highly potent neutralizing activity against SARS-CoV-2 has been reported but the mode of interaction with the epitope remains unclear.

Isotope-dilution LC-MS/MS analysis of the elastin crosslinkers desmosine and isodesmosine in acute cerebral stroke patients.

Utilizing chemically synthesized an isotopically labeled internal standard, isodesmosine-C,N, an isotope-dilution LC-MS/MS method was established. Concentrations of desmosine and isodesmosine in plasma of acute cerebral stroke patients and healthy controls were determined. The concentration of desmosines was markedly higher in plasma from acute stroke patients compared with healthy controls.

Alignment of the metatarsal heads affects foot inversion/eversion during tiptoe standing on one leg in demi-pointe position: A cross-sectional study on recreational dancers.

Classical ballet dancers stand on tiptoe in the demi-pointe position where the ankle is plantarflexed, and the toes extend around a mediolateral axis passing through the second metatarsal head. Foot sickling, the foot inversion/eversion when the forefoot is grounded, should be avoided to achieve esthetics and prevent injuries during tiptoe standing. The foot inversion/eversion angle may change depending on the metatarsal heads through which the toe extension axis passes.

A panel of nanobodies recognizing conserved hidden clefts of all SARS-CoV-2 spike variants including Omicron.

We are amid the historic coronavirus infectious disease 2019 (COVID-19) pandemic. Imbalances in the accessibility of vaccines, medicines, and diagnostics among countries, regions, and populations, and those in war crises, have been problematic. Nanobodies are small, stable, customizable, and inexpensive to produce.

Dancers utilize a 'whip-like effect' to increase arm angular momentum during multiple-revolution .

A (PeDh) is multiple turns using the angular momentum generated by swinging the arms with both feet on the ground. The purpose of this study was to investigate how the arm swing facilitates increasing peak angular momenta of both arms during multiple PeDh. Upper body movements in single to six-revolutions clockwise (as seen from above) PeDhs were analysed to determine arm's angular momentum induced by the individual joint torque, gravitational force and motion-dependent terms.

Development of an Enterovirus 71 Vaccine Efficacy Test Using Human Scavenger Receptor B2 Transgenic Mice.

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks.

Dephosphorylation of protamine 2 at serine 56 is crucial for murine sperm maturation in vivo.

The posttranslational modification of histones is crucial in spermatogenesis, as in other tissues; however, during spermiogenesis, histones are replaced with protamines, which are critical for the tight packaging of the DNA in sperm cells. Protamines are also posttranslationally modified by phosphorylation and dephosphorylation, which prompted our investigation of the underlying mechanisms and biological consequences of their regulation. On the basis of a screen that implicated the heat shock protein Hspa4l in spermatogenesis, we generated mice deficient in Hspa4l (-null mice), which showed male infertility and the malformation of sperm heads.

Amino Acid Variation at VP1-145 of Enterovirus 71 Determines Attachment Receptor Usage and Neurovirulence in Human Scavenger Receptor B2 Transgenic Mice.

Infection by enterovirus 71 (EV71) is affected by cell surface receptors, including the human scavenger receptor B2 (hSCARB2), which are required for viral uncoating, and attachment receptors, such are heparan sulfate (HS), which bind virus but do not support uncoating. Amino acid residue 145 of the capsid protein VP1 affects viral binding to HS and virulence in mice. However, the contribution of this amino acid to pathogenicity in humans is not known.

Regulation of hip joint kinetics for increasing angular momentum during the initiation of a pirouette en dehors in classical ballet.

This study examined how dancers regulate the hip joint kinetics to coordinate the upper and lower body angular momenta with the increased rotation of pirouette en dehors (pirouette) during the preparation. During the preparation of the pirouette, the upper body rotates greatly about the vertical axis; however, the lower extremity remains relatively stationary. Therefore, there must be specific control at the hip to coordinate the upper and lower body angular momenta in turns of increased rotation.

Comparison of lower limb kinetics during vertical jumps in turnout and neutral foot positions by classical ballet dancers.

The purpose of this study was to investigate the effect of hip external rotation (turnout) on lower limb kinetics during vertical jumps by classical ballet dancers. Vertical jumps in a turnout (TJ) and a neutral hip position (NJ) performed by 12 classical female ballet dancers were analysed through motion capture, recording of the ground reaction forces, and inverse dynamics analysis. At push-off, the lower trunk leaned forward 18.

Calpain 1 inhibitor BDA-410 ameliorates α-klotho-deficiency phenotypes resembling human aging-related syndromes.

Taking good care of elderly is a major challenge of our society, and thus identification of potential drug targets to reduce age-associated disease burden is desirable. α-klotho(-/-) (α-kl) is a short-lived mouse model that displays multiple phenotypes resembling human aging-related syndromes. Such ageing phenotype of α-kl(-/-) mice is associated with activation of a proteolytic enzyme, Calpain-1.

Reduced renal α-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism.

Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL.

Transfer of momentum from different arm segments to a light movable target during a straight punch thrown by expert boxers.

The aim of this study was to determine the relationship between the reductions in momentum of punching arm segments and the impulse of the impact force when boxers throw a punch at a movable target with a mass almost equal to that of the human head. Nine male expert collegiate boxers threw a rear-hand straight punch at the target with their full effort. The reductions in momentum of the upper arm, forearm and fist plus glove of the punching arm during impact and the impulse were determined using a motion capture system and an accelerometer attached to the target.

[Updates on rickets and osteomalacia: various roles of Klotho and FGF23 in vivo ].

Recent understandings of phosphate regulation have, at least in part, depended upon the findings of fibroblast growth factor (FGF) 23, the hormone specific for phosphate regulation. Moreover, FGF23 would be the most important marker for prognosis in chronic kidney disease (CKD) . On the other hand, Klotho was firstly developed as a responsible gene for senescence.

Complex regulation and diverse functions of alpha-klotho.

It has been understood that the α-klotho gene, first identified as an aging-related gene, is actually necessary for regulating mineral homeostasis in vertebrates. All vertebrates, including humans, actively maintain calcium and phosphate ions in bones, circulating blood, and cerebrospinal fluid. Therefore, disruptions in homeostasis cause osteoporosis, ectopic calcification, and epilepsy.

Plasma soluble α-klotho protein levels in premature and term neonates: correlations with growth and metabolic parameters.

Objective: α-Klotho (α-KL), a protein with antiaging properties, regulates phosphate, calcium, and bone metabolism, induces resistance to oxidative stress, and may participate in insulin signaling. The role of α-KL in neonates, known to be prone to metabolic disturbances and oxidative stress, is not known. The aim of this study was to evaluate circulating soluble α-KL concentrations in preterm and full-term neonates and unravel possible correlations with growth, metabolism, and indices of oxidative stress.

Serum soluble α-klotho in hemodialysis patients.

Background: The extracellular domain of klotho is cleaved and released into various extracellular fluids, such as blood, urine, and cerebrospinal fluid, as soluble α-klotho (sαKl).

Methods: We measured sαKl in 53 hemodialysis patients and 20 healthy controls to examine its role in mineral metabolism.

Results: The sαKl level of the hemodialysis patients was 430 pg/ml (386 - 540 pg/ml, which was lower than that of healthy controls 740 pg/ml (550 - 913 pg/ml, p < 0.

Decreased renal α-Klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion.

Hypercalciuria is one of the early manifestations of diabetic nephropathy. We explored here the role of α-Klotho, a protein expressed predominantly in distal convoluted tubules that has a role in calcium reabsorption. We studied 31 patients with early diabetic nephropathy and compared them with 31 patients with IgA nephropathy and 7 with minimal change disease.

Circulating levels of soluble alpha-Klotho are markedly elevated in human umbilical cord blood.

Context: Fetal serum levels of calcium and phosphate are higher than those in the maternal levels. Although α-Klotho is known to participate in calcium and phosphate metabolism in adults, its role in the perinatal period remains unknown.

Objective: This study aimed to determine the baseline levels of soluble α-Klotho in fetuses and compare them with those in neonates, mothers, and adults to clarify whether α-Klotho is involved in the fetal-specific regulation of calcium and phosphate metabolism.

Nature versus nurture in two highly enantioselective esterases from Bacillus cereus and Thermoanaerobacter tengcongensis.

There is an increasing need for the use of biocatalysis to obtain enantiopure compounds as chiral building blocks for drug synthesis such as antibiotics. The principal findings of this study are: (i) the complete sequenced genomes of Bacillus cereus ATCC 14579 and Thermoanaerobacter tengcongensis MB4 contain a hitherto undescribed enantioselective and alkaliphilic esterase (BcEST and TtEST respectively) that is specific for the production of (R)-2-benzyloxy-propionic acid ethyl ester, a key intermediate in the synthesis of levofloxacin, a potent antibiotic; and (ii) directed evolution targeted for increased thermostability of BcEST produced two improved variants, but in either case the 3-5 °C increase in the apparent melting temperature (T(m)) of the mutants over the native BcEST that has a T(m) of 50 °C was outperformed by TtEST, a naturally occurring homologue with a T(m) of 65 °C. Protein modelling of BcEST mapped the S148C and K272R mutations at protein surface and the I88T and Q110L mutations at more buried locations.

Kinematic and kinetic analysis of the fouetté turn in classical ballet.

The fouetté turn in classical ballet dancing is a continuous turn with the whipping of the gesture leg and the arms and the bending and stretching of the supporting leg. The knowledge of the movement intensities of both legs for the turn would be favorable for the conditioning of the dancer's body. The purpose of this study was to estimate the intensities.

Mechanics of the Fouetté turn.

The Fouetté turn in classical ballet is performed repeatedly on one leg with swinging of the free limbs, producing a continued sequence of turns with one turn leading into the next. The purpose of this study was to determine the possible time history profiles of the twisting torque between the supporting leg and the remainder of the body that will allow continued performances of the Fouetté turn. Simulations were performed using a model which comprised the supporting leg and the remainder of the body to find torque profiles that maintain the initial angular velocity so that the state after one revolution is the same as the initial state.

Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects.

Background: Alpha-Klotho (alphaKl) regulates mineral metabolism such as calcium ion (Ca(2+)) and inorganic phosphate (Pi) in circulation. Defects in mice result in clinical features resembling disorders found in human aging. Although the importance of transmembrane-type alphaKl has been demonstrated, less is known regarding the physiological importance of soluble-type alphaKl (salphaKl) in circulation.

Relevant use of Klotho in FGF19 subfamily signaling system in vivo.

Alpha-Klotho (alpha-Kl) and its homolog, beta-Klotho (beta-Kl) are key regulators of mineral homeostasis and bile acid/cholesterol metabolism, respectively. FGF15/ humanFGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Analyses of functional interactions between alpha- and beta-Kl and FGF19 factors in wild-type, alpha-kl(-/-), and beta-kl(-/-) mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, and 1,25(OH)(2)D and an analogous regulatory network composed of beta-Kl, FGF15/humanFGF19, and bile acids that regulate bile acid/cholesterol metabolism.