Cyclin F Is Degraded during G2-M by Mechanisms Fundamentally Different from Other Cyclins

Cyclin F, a cyclin that can form SCF complexes and bind to cyclin B, oscillates in the cell cycle with a pattern similar to cyclin A and cyclin B. Ectopic expression of cyclin F arrests the cell cycle in G2/M. How the level of cyclin F is regulated during the cell cycle is completely obscure. Here we show that, similar to cyclin A, cyclin F is degraded when the spindle assembly checkpoint is activated and accumulates when the DNA damage checkpoint is activated. Cyclin F is a very unstable protein throughout much of the cell cycle. Unlike other cyclins, degradation of cyclin F is independent of ubiquitination and proteasome-mediated pathways. Interestingly, proteolysis of cyclin F is likely to involve metalloproteases. Rapid destruction of cyclin F does not require the N-terminal F-box motif but requires the COOH-terminal PEST sequences. The PEST region alone is sufficient to interfere with the degradation of cyclin F and confer instability when fused to cyclin A. These data show that although cyclin F is degraded at similar time as the mitotic cyclins, the underlying mechanisms are entirely distinct

Similarities and Differences in the Fermiology of Kagome Metals AV3_{3}Sb5_{5} (A=K, Rb, Cs) Revealed by Shubnikov-de Haas Oscillations

Materials with AV$_3$Sb$_5$ (A=K, Rb, Cs) stoichiometry are recently discovered kagome superconductors with the electronic structure featuring a Dirac band, van Hove singularities and flat bands. These systems undergo anomalous charge-density-wave (CDW) transitions at $T_{\rm CDW}$~80-100 K, resulting in the reconstruction of the Fermi surface from the pristine phase. Although comprehensive investigations of the electronic structure via quantum oscillations (QOs) have been performed on the sister compounds CsV$_3$Sb$_5$ and RbV$_3$Sb$_5$, a detailed QO study of KV$_3$Sb$_5$ is so far absent. Here, we report the Shubnikov-de Haas QO study in KV$_3$Sb$_5$. We resolve a large number of new frequencies with the highest frequency of 2202 T (occupying ~54% of the Brillouin zone area in the $k_x$-$k_y$ plane). The Lifshitz-Kosevich analysis further gives relatively small cyclotron effective masses, and the angular dependence study reveals the two-dimensional nature of the frequencies with a sufficient signal-to-noise ratio. Finally, we compare the QO spectra for all three AV$_3$Sb$_5$ compounds collected under the same conditions, enabling us to point out the similarities and differences across these systems. Our results fill in the gap of the QO study in KV$_3$Sb$_5$ and provide valuable data to understand the band structure of all three members of AV$_3$Sb$_5$.Comment: 8 pages, 4 figure

Efficacy, safety and immunogenicity of a human rotavirus vaccine (RIX4414) in Hong Kong children up to three years of age: A randomized, controlled trial

AbstractBackgroundA phase III, double-blind, randomized, controlled trial was conducted in Hong Kong to evaluate the efficacy, safety and immunogenicity of a human rotavirus vaccine, RIX4414 (Rotarix™) against severe rotavirus gastroenteritis in children up to three years of age.MethodsHealthy infants aged 6–12 weeks were enrolled between 08-December-2003 and 31-August-2005 and received two oral doses of either RIX4414 vaccine (N=1513) or placebo (N=1512) given 2 months apart. Vaccine efficacy was assessed from two weeks post-Dose 2 until the children were two and three years of age. Anti-rotavirus IgA seroconversion rate was calculated pre-vaccination and 1–2 months post-Dose 2 using ELISA (cut-off=20U/mL) for 100 infants. Safety was assessed until the children were two years of age; serious adverse events (SAEs) were recorded throughout the study period.ResultsIn children aged two and three years of life, vaccine efficacy against severe rotavirus gastroenteritis was 95.6% (95% CI: 73.1%–99.9%) and 96.1% (95% CI: 76.5%–99.9%), respectively. The seroconversion rate 1–2 months after the second dose of RIX4414 was 97.5% (95% CI: 86.8%–99.9%). At least one SAE was recorded in 439 and 477 infants who were administered RIX4414 and placebo, respectively (p-value=0.130). Six intussusception cases were reported (RIX4414=4; placebo=2) and none was assessed to be vaccine-related.ConclusionRIX4414 was efficacious, immunogenic and safe in the prevention of rotavirus gastroenteritis for at least two years post-vaccination in Hong Kong children

Specialized Roles of the Two Mitotic Cyclins in Somatic Cells: Cyclin A as an Activator of M Phase–promoting Factor

The role of cyclin B-CDC2 as M phase-promoting factor (MPF) is well established, but the precise functions of cyclin A remain a crucial outstanding issue. Here we show that down-regulation of cyclin A induces a G2 phase arrest through a checkpoint-independent inactivation of cyclin B-CDC2 by inhibitory phosphorylation. The phenotype is rescued by expressing cyclin A resistant to the RNA interference. In contrast, down-regulation of cyclin B disrupts mitosis without inactivating cyclin A-CDK, indicating that cyclin A-CDK acts upstream of cyclin B-CDC2. Even when ectopically expressed, cyclin A cannot replace cyclin B in driving mitosis, indicating the specific role of cyclin B as a component of MPF. Deregulation of WEE1, but not the PLK1-CDC25 axis, can override the arrest caused by cyclin A knockdown, suggesting that cyclin A-CDK may tip the balance of the cyclin B-CDC2 bistable system by initiating the inactivation of WEE1. These observations show that cyclin A cannot form MPF independent of cyclin B and underscore a critical role of cyclin A as a trigger for MPF activation

DNA Damage during the Spindle-Assembly Checkpoint Degrades CDC25A, Inhibits Cyclin–CDC2 Complexes, and Reverses Cells to Interphase

Cell cycle checkpoints that monitor DNA damage and spindle assembly are essential for the maintenance of genetic integrity, and drugs that target these checkpoints are important chemotherapeutic agents. We have examined how cells respond to DNA damage while the spindle-assembly checkpoint is activated. Single cell electrophoresis and phosphorylation of histone H2AX indicated that several chemotherapeutic agents could induce DNA damage during mitotic block. DNA damage during mitotic block triggered CDC2 inactivation, histone H3 dephosphorylation, and chromosome decondensation. Cells did not progress into G(1) but seemed to retract to a G(2)-like state containing 4N DNA content, with stabilized cyclin A and cyclin B1 binding to Thr14/Tyr15-phosphorylated CDC2. The loss of mitotic cells was not due to cell death because there was no discernible effect on caspase-3 activation, DNA fragmentation, or viability. Extensive DNA damage during mitotic block inactivated cyclin B1-CDC2 and prevented G(1) entry when the block was removed. The mitotic DNA damage responses were independent of p53 and pRb, but they were dependent on ATM. CDC25A that accumulated during mitosis was rapidly destroyed after DNA damage in an ATM-dependent manner. Ectopic expression of CDC25A or nonphosphorylatable CDC2 effectively inhibited the dephosphorylation of histone H3 after DNA damage. Hence, although spindle disruption and DNA damage provide conflicting signals to regulate CDC2, the negative regulation by the DNA damage checkpoint could overcome the positive regulation by the spindle-assembly checkpoint

Shubnikov–de Haas oscillations of biaxial-strain-tuned superconductors in pulsed magnetic field up to 60 T

Two-dimensional (2D) materials have gained increasing prominence not only in fundamental research but also in daily applications. However, to fully harness their potential, it is crucial to optimize their properties with an external parameter and track the electronic structure simultaneously. Magnetotransport over a wide magnetic field range is a powerful method to probe the electronic structure and, for metallic 2D materials, quantum oscillations superimposed on the transport signals encode Fermi surface parameters. In this manuscript, we utilize biaxial strain as an external tuning parameter and investigate the effects of strain on the electronic properties of two quasi-2D superconductors, MoTe2 and RbV3Sb5, by measuring their magnetoresistance in pulsed magnetic fields up to 60 T. With a careful selection of insulating substrates, we demonstrate the possibility of both the compressive and tensile biaxial strains imposed on MoTe2 and RbV3Sb5, respectively. For both systems, the applied strain has led to superconducting critical temperature enhancement compared to their free-standing counterparts, proving the effectiveness of this biaxial strain method at cryogenic temperatures. Clear quantum oscillations in the magnetoresistance—the Shubnikov–de Haas (SdH) effect—are obtained in both samples. In strained MoTe2, the magnetoresistance exhibits a nearly quadratic dependence on the magnetic field and remains non-saturating even at the highest field, whereas in strained RbV3Sb5, two SdH frequencies showed a substantial enhancement in effective mass values, hinting at a possible enhancement of charge fluctuations. Our results demonstrate that combining biaxial strain and pulsed magnetic field paves the way for studying 2D materials under unprecedented conditions

Anomalous Hall effect and two-dimensional Fermi surfaces in the charge-density-wave state of kagome metal RbV3Sb5

AV _3 Sb _5 (A = Cs, K, Rb) is a recently discovered superconducting system ( $T_\mathrm{c}\sim0.9$ –2.5 K) in which the vanadium atoms adopt the kagome structure. Intriguingly, these systems enter a charge-density-wave (CDW) phase ( $T_\mathrm{CDW}\sim80$ –100 K), and further evidence shows that the time-reversal symmetry is broken in the CDW phase. Concurrently, the anomalous Hall effect (AHE) has been observed in KV _3 Sb _5 and CsV _3 Sb _5 inside the novel CDW phase. Here, we report a comprehensive study of a high-quality RbV _3 Sb _5 single crystal with magnetotransport measurements. Our data demonstrate the emergence of the AHE in RbV _3 Sb _5 when the CDW state develops. The magnitude of the anomalous Hall resistivity in the low temperature limit is comparable to the reported values in KV _3 Sb _5 and CsV _3 Sb _5 . The magnetoresistance channel further reveals a rich spectrum of quantum oscillation frequencies, many of which have not been reported before. In particular, a large quantum oscillation frequency (2235 T), which occupies ∼56% of the Brillouin zone area, was recorded. For the quantum oscillation frequencies with sufficient signal-to-noise ratio, we further perform field angle-dependent measurements, and our data indicate two-dimensional Fermi surfaces in RbV _3 Sb _5 . Our results provide indispensable information for understanding the AHE and band structure in kagome metal AV _3 Sb _5