Interplay of lattice-spin-orbital coupling and Jahn-Teller effect in noncollinear spinel TixMn1-x(FeyCo1-y)2O4: a neutron diffraction study.

Local magnetostructural changes and dynamical spin fluctuations in doubly diluted spinel TixMn1‒x(FeyCo1‒y)2O4has been reported by means of neutron diffraction and magnetization studies. Two distinct sets of compositions (i)x(Ti) = 0.20 andy(Fe) = 0.18; (ii)x(Ti) = 0.40 andy(Fe) = 0.435 have been considered for this study. The first compound of equivalent stoichiometry Ti0.20Mn0.80Fe0.36Co1.64O4exhibits enhanced tetragonal distortion across the ferrimagnetic transition temperatureTC= 258 K in comparison to the end compound MnCo2O4(TC∼ 180 K) with a characteristic ratioct/√2atof 0.99795(8) demonstrating robust lattice-spin-orbital coupling. However, in the second case Ti0.40Mn0.60Fe0.87Co1.13O4with higherB-site compositions, the presence of Jahn-Teller ions with distinct behavior appears to counterbalance the strong tetragonal distortion thereby ceasing the lattice-spin-orbital coupling. Both the investigated systems show the coexistence of noncollinear antiferromagnetic and ferrimagnetic components in cubic and tetragonal settings. On the other hand, the dynamical ac-susceptibility,χac(T) reveals a cluster spin-glass state with Gabay-Toulouse (GT) like mixed phases behaviour belowTC. Such dispersive behaviour appears to be sensitive to the level of octahedral substitution. Further, the field dependence ofχac(T) follows the weak anisotropic GT-line behaviour with crossover exponent Φ lies in the range 1.38-1.52 on theH-Tplane which is in contrast to theB-site Ti substituted MnCo2O4spinel that appears to follow irreversible non-mean-field AT-line behaviour (Φ âˆ¼ 3 +δ). Finally, the Arrott plots analysis indicates the presence of a pseudo first-order like transition (T< 20 K) which is in consonance with and zero crossover of the magnetic entropy change within the frozen spin-glass regime.

Charge-ordering breakdown dynamics and ferromagnetic resonance studies ofB-site Cu diluted Pr1‒xSrxMnO3.

Here, we report the influence of Jahn-Teller active Cu substitution on the charge-ordering (CO) characteristics of one of the well-known manganite Pr0.45Sr0.55MnO3(S55) with a distorted tetragonal structure. Magnetization studies unveil a complex magnetic phase diagram for S55, showing distinct temperature ranges corresponding to various magnetic phases: a ferromagnetic phase dominated by the Double Exchange interaction withTC∼ 220.5 K, an antiferromagnetic phase belowTN∼ 207.6 K induced by CO with a transition temperature ofTCO∼ 210 K consistent with the specific heatCP(T) data, and a mixed phase in the rangeTNTN(T

Magnetic exchange interactions and non-Debye relaxation in spin-3/2 frustrated Kagomé magnet Co3V2O8.

We report the experimental determination of the magnetic exchange parameter (J/kB= 2.88 ± 0.02 K) for the Spin-3/2 ferromagnetic (FM) Kagomé lattice system: Co3V2O8using the temperature dependence of dc-magnetic susceptibilityχ(T) data by employing the fundamental Heisenberg linear chain model. Our results are quite consistent with the theoretically reported nearest neighbor dominant FM exchange coupling strengthJex-NN∼2.45 K. Five different magnetic phase transitions (6.2-11.2 K) and spin-flip transitions (9.6-7.7 kOe) have been probed using the∂(χT)/∂Tvs.T, heat capacity (CP-T) and differential isothermal magnetization curves. Among such sequence of transitions, the prominent ones being incommensurate antiferromagnetic (AFM) state at 11.2 K, commensurate AFM state at 8.8 K, and commensurate FM state across 6.2 K. All the successive magnetic phase transitions have been mapped onto a single H-T plane through which one can easily distinguish the above-mentioned different phases. The magnetic contribution of theCP-TnearTN(11.2 K) has been analyzed using the power-law expressionCM=A|T-TN|-αresulting in the critical exponentα= 0.18 ± 0.01 (0.15 ± 0.003) forTTN), respectively for the Co3V2O8. It is interesting to note that non-Debye type dipole relaxation is quite prominent in Co3V2O8and was evident from the Kohlrausch-Williams-Watts analysis of complex modulus and impedance spectra (0⩽ß⩽1). Mott's variable-range hopping of charge carriers process is evident through the resistivity analysis (ρac-T-1/4) in the temperature range 275 ∘C-350 ∘C. Moreover, the frequency-dependent analysis ofσac(ω) follows Jonscher's power law yielding two distinct activation energies (Ea∼0.37 and 2.29 eV) between the temperature range 39 ∘C-99 ∘C and 240 ∘C-321 ∘C.

Reentrant canonical spin-glass dynamics and tunable field-induced transitions in (GeMn)Co2O4Kagomé lattice.

We report on the reentrant canonical semi spin-glass characteristics and controllable field-induced transitions in distorted Kagomé symmetry of (GeMn)Co2O4. ThisB-site spinel exhibits complicated, yet interesting magnetic behaviour in which the longitudinal ferrimagnetic (FiM) order sets in below the Néel temperatureTFN∼ 77 K due to uneven moments of divalent Co (↑ 5.33µB) and tetravalent Mn (↓ 3.87µB) which coexists with transverse spin-glass state below 72.85 K. Such complicated magnetic behaviour is suggested to result from the competing anisotropic superexchange interactions (JAB/kB∼ 4.3 K,JAA/kB∼ -6.2 K andJBB/kB∼ -3.3 K) between the cations, which is extracted following the Néel's expression for the two-sublattice model of FiM. Dynamical susceptibility (χac(f, T)) and relaxation of thermoremanent magnetization,MTRM(t) data have been analysed by means of the empirical scaling-laws such as Vogel-Fulcher law and Power law of critical slowing down. Both of which reveal the reentrant spin-glass like character which evolves through a number of intermediate metastable states. The magnitude of Mydosh parameter (Ω âˆ¼ 0.002), critical exponentzυ= (6.7 ± 0.07), spin relaxation timeτ0= (2.33 ± 0.1) × 10-18s, activation energyEa/kB= (69.8 ± 0.95) K and interparticle interaction strength (T0= 71.6 K) provide the experimental evidences for canonical spin-glass state below the spin freezing temperatureTF= 72.85 K. The field dependence ofTFobtained fromχac(T) follows the irreversibility in terms of de Almeida-Thouless mean-field instability in which the magnitude of crossover scaling exponent Φ turns out to be ∼2.9 for the (Ge0.8Mn0.2)Co2O4. Isothermal magnetization plots reveal two field-induced transitions across 9.52 kOe (HSF1) and 45.6 kOe (HSF2) associated with the FiM domains and spin-flip transition, respectively. Analysis of the inverse paramagnetic susceptibilityχp-1χp=χ-χ0after subtracting the temperature independent diamagnetic termχ0(=-3 × 10-3emu mol-1Oe-1) results in the effective magnetic momentµeff= 7.654µB/f.u. This agrees well with the theoretically obtainedµeff= 7.58µB/f.u. resulting the cation distributionMn0.24+↓A[Co22+↑]BO4in support of the Hund's ground state spin configurationS=3/2andS= 1/2of Mn4+and Co2+, respectively. TheH-Tphase diagram has been established by analysing all the parameters (TF(H),TFN(H),HSF1(T) andHSF2(T)) extracted from various magnetization measurements. This diagram enables clear differentiation among the different phases of the (GeMn)Co2O4and also illustrates the demarcation between short-range and long-range ordered regions.

Probing the incoherent admixture of low and high-spin states of Co in (LaPr)CoO3perovskite: focus on structural phase transitions.

We report the mixed valence and intermediate spin-state (IS) transitions in Pr substituted LaCoO3perovskites in the form of bulk and nanostructures. Various compositions (x) of La1-xPrxCoO3(0 ⩽x⩽ 0.9) were synthesized using the sol-gel process under moderate heat treatment conditions (600 °C). The structural analysis of these compounds reveals a phase crossover from the monoclinic phase (space group, s.g.:I2/a) to an orthorhombic one (s.g.:Pbnm), and a rhombohedral phase (s.g.:R-3c) to an orthorhombic one (s.g.:Pnma) in the bulk and nanostructures, respectively, for the composition range 0 ⩽x⩽ 0.6. Such a structural transformation remarkably reduces the Jahn-Teller distortion factor ΔJT: 0.374 → 0.0016 signifying the dominant role of the IS state (SAvg= 1) of trivalent Co ions in the investigated system. Magnetization measurements reveal the ferromagnetic (FM) nature of bulk LaCoO3along with a weak antiferromagnetic (AFM) component coexisting with an FM component. This coexistence results in a weak loop-asymmetry (zero-field exchange-bias effect ∼134 Oe) at low temperatures. Here the FM ordering occurs due to the double-exchange interaction (JEX/kB∼ 11.25 K) between the tetravalent and trivalent Co ions. Significant decrease in the ordering temperatures was noticed in the nanostructures (TC∼ 50 K) as compared to the bulk counterpart (∼90 K) due to the finite size/surface effects in the pristine compound. However, the incorporation of Pr leads to the development of a strong AFM component (JEX/kB∼ 18.2 K) and enhances the ordering temperatures (∼145 K forx= 0.9) with negligible FM correlations in both bulk and nanostructures of LaPrCoO3due to the dominant super-exchange interaction: Co3+/4+‒O‒Co3+/4+. Further evidence of the incoherent mixture of low-spin (LS) and high-spin (HS) states comes from theM-Hmeasurements which yields a saturation magnetization ofMS∼ 275 emu mol-1(under the limit of 1/H→ 0) consistent with the theoretical value of 279 emu mol-1corresponding to the spin admixture: 65% LS + 10% IS of trivalent Co along with 25% of LS Co4+in the bulk pristine compound. A similar analysis yields: Co3+[30% LS + 20% IS] + Co4+[50% of LS] for the nanostructures of LaCoO3,yet the Pr substitution decreases the spin admixture configuration. The Kubelka-Munk analysis of the optical absorbance results in a significant decrease in the optical energy band gap (Eg:1.86 → 1.80 eV) with the incorporation of Pr in LaCoO3which corroborates the above results.

Spin-liquid state with precursor ferromagnetic clusters interacting antiferromagnetically in frustrated glassy tetragonal spinel Zn0.8Cu0.2FeMnO4.

Spinels (AB2O4) with magnetic ions occupying only the octahedralBsites have inherent magnetic frustration which inhibits magnetic long-range order (LRO) but may lead to exotic states. Here we report on the magnetic properties of the tetragonal spinel Zn0.8Cu0.2FeMnO4, the tetragonality resulting from the Jahn-Teller active Mn3+ions. X-ray diffraction and x-ray photoelectron spectroscopy of the sample yielded the composition (Zn0.82+Cu0.22+)A[Fe0.42+Fe0.63+Mn3+]BO4‒δ. Analysis of the temperature dependence of magnetization (M), ac magnetic susceptibilities (χ'andχ''), dc susceptibility (χ), heat capacityCp, and neutron diffraction (ND) measurements show complex temperature-dependent short-range order (SRO) but without LRO. The data ofχ vs. Tfits the Curie-Weiss law:χ = C/(T ‒ θ) fromT= 250 K to 400 K withθ≃ 185 K signifying dominant ferromagnetic (FM) coupling with the FM exchange constantJ/kB= 17 K, andC= 3.29 emu K mol‒1Oe‒1yielding an effective magnetic momentµeff= 5.13µBresulting from the high-spin states of Cu2+(Asite) and Fe2+(Bsite), while theBsite trivalent ions Mn3+and Fe3+are in their low-spin states. The extrapolated saturation magnetization obtained from theM vs. Hdata atT= 2 K is explained using the spin arrangement (Cu2+↓)A[Fe2+↑, Fe3+↓, Mn3+↑]Bleading to FM clusters interact antiferromagnetically at low temperatures. Temperature dependence of d(χT)/dTshows the onset of ferrimagnetism below ∼100 K and peaks near 47 K and 24 K. The relaxation timeτobtained from temperature and frequency dependence ofχ″when fit to the power law and Vogel-Fulcher laws confirm the cluster spin-glass (SG) state. The magnetic field dependence of the SG temperatureTSGHfollows the equation:TSGH=TSG01-AH2/ϕwithTSG(0) = 46.6 K,A= 8.6 × 10‒3Oe‒0.593andϕ= 3.37. The temperature dependence of hysteresis loops yields coercivityHC∼ 3.8 kOe at 2 K without exchange-bias, butHCdecreases with increase inTbecoming zero above 24 K, theTSG(H) forH= 800 Oe. Variations ofCpvs. Tfrom 2 K to 200 K inH=0 andH=90 kOe do not show any peak characteristic of LRO. However, after correcting for the lattice contribution, a broad weak peak typically of SRO becomes evident centered around 40 K. ForT< 9 K,Cpvaries asT2; a typical signature of spin-liquids (SLs). Comparison of the ND measurements at 1.7 K and 79.4 K shows absence of LRO. Time dependence of thermo-remanent magnetizationMTRM(t) studies below 9 K reveal weakening of the inter-cluster interaction with increase in temperature. A summary of these results is that in Zn0.8Cu0.2FeMnO4, ferromagnetic clusters interact antiferromagnetically without LRO but producing a cluster SG state atTSG(0) = 46.6 K, followed by SL behavior below 9 K.

Interplay between proteasome function and inflammatory responses in e-cig vapor condensate-challenged lung epithelial cells.

Exposure to cigarettes and other nicotine-based products results in persistent inflammation in the lung. In recent years, electronic cigarettes (e-cigs) have become extremely popular among adults and youth alike. E-cigarette vapor-induced oxidative stress promotes protein breakdown, DNA damage and cell death, culminating in a variety of respiratory diseases. The proteasome, a multi-catalytic protease, superintends protein degradation within the cell. When cells are stimulated with inflammatory cytokines such as IFN-γ and TNF-α, the constitutive catalytic proteasome subunits are replaced by the inducible subunits-low-molecular mass polypeptide (LMP)2 (ß1i), multi-catalytic endopeptidase complex-like (MECL)1 (ß2i), and LMP7 (ß5i), which are required for the production of certain MHC class I-restricted T-cell epitopes. In this study, we used human alveolar epithelial cells (A549) and exposed them to filtered air or (1%) tobacco-flavored (TF) electronic cigarette vapor condensate (ECVC) ± nicotine (6 mg/ml) (TF-ECVC ± N) for 24 h. We observed an increase in the levels of IFN-γ, TNF-α, and inducible proteasome subunits (LMP7/PSMB8, LMP2/PSMB9, MECL1/PSMB10), and a reduced expression of constitutive proteasome subunits (ß1/PSMB6 and ß2/PSMB7) in challenged A549 cells. Interestingly, knockdown of the inducible proteasome subunit LMP7 reversed ECVC-induced expression of NADPH oxidase and immunoproteasome subunits in A549 cells. In addition, pre-exposure to an LMP7 inhibitor (ONX-0914) abrogated the mRNA expression of several NOX subunits and rescued the excessive production/release of inflammatory cytokines/chemokines (IL-6, IL-8, CCL2, and CCL5) in ECVC-challenged cells. Our findings suggest an important role of LMP7 in regulating the expression of inflammatory mediators during ECVC exposure. Overall, our results provide evidence for proteasome-dependent ROS-mediated inflammation in ECVC-challenged cells.

Effect of Ce substitution on the local magnetic ordering and phonon instabilities in antiferromagnetic DyCrO3perovskites.

A detailed crystal structure analysis, temperature and field dependence of magnetic characteristics and phonon instabilities for different compositions (0.1 ⩽x⩽ 0.5) of Dy1-xCexCrO3solid-solutions have been reported. All the investigated compounds exhibit distorted orthorhombic crystal structure with a distortion factor ofdOct/dCell∼ 6 × 10-3/3.5 ppm (forx∼ 0.2) forPbnmspace group that follows Vegard's law. The bonds between apical oxygen atoms (OA1) and Cr atoms stand more rigidly in comparison with the basal oxygen atoms (OB1/OB2) resulting the octahedral distortion and thereby causing the changes in phonon modes. The CrO6octahedral tilt angleθrotates with respect to the Miller pseudocubic axis [101] which varies from 10.36° (x= 0.1) to 12.25° (x= 0.5) and significantly influences the Ag(5) phonon stability by 3% for a change in A-site mean radius from 1.095 Å to 1.141 Å forx= 0.1 and 0.5, respectively. From the magnetization measurements we find that these series of compositions exhibit canted antiferromagnetic (AFM) ordering with Néel temperature,TN1that increases from 151.8 K (x= 0.1) to 162 K (x= 0.5) which also manifests as a significant reduction in the magneto-crystalline anisotropy (HK∼ 2.58 kOe → 2.07 kOe,K1∼ 36.47 J m-3→ 18.97 J m-3) while maintaining the stable Γ4(Gx,Ay,Fz) AFM configuration. Both Dzyaloshinskii-Moriya interaction method and modified Curie-Weiss law are employed to analyse the inverse paramagnetic susceptibility,χ-1(T>TN1). Further, we have evaluated the symmetric (JS) and antisymmetric exchange (DAS) constants, which show progressively increasing trend (JS→ 10.08 K to 11.18 K andDAS→ 1.24 K to 1.73 K) with the incorporation of Ce inside the perovskite lattice. Furthermore, the role of Ce substitution on the low-temperature spin reorientation transition (TSR∼ 3.5 K → 16.8 K pertaining to the Γ25phase configuration) and emergence ofΓ2(Fx,Cy,Gz;FxR,CyR)weak-FM phase between 31 K and 45.5 K are discussed in consonance with the phonon spectra.

Magnetization reversal, field-induced transitions andH-Tphase diagram of Y1-xCexCrO3.

We report a systematic study of the magnetic phase diagram in theH-Tplane, negative magnetization (NM), exchange interactions and field-induced spin-flop transitions in the distorted perovskite Y1-xCexCrO3. Locked AFM and weak-FM configurations in Γ4(Gz,Fy,Ax) phase of YCrO3(S= 3/2 ground state) unlocks into the Γ2(Fz,Gy,Cx;FzR,CxR) phase of the canted AFM and FM structures with the dilute substitution of Ce (x⩾ 0.05). The asymmetric and symmetric exchange interaction (JAS∼ 0.11 meV andJS∼ 0.85 meV) between the trivalent Ce and Cr enable the positive quartic-anisotropy field (HK4∼ 2.85 × 102Oe) along with the second order anisotropy field (HK2∼ 5.93 × 102Oe). Unlike the pristine YCrO3compound, the Ce incorporated system exhibits a giant fourth-order anisotropy constant (K4= 1.35 × 105erg/c.c.) due to the asymmetric exchange interaction between the trivalent Ce-Cr which further lifts the free energy of the system and causes lag in the onset of AFM ordering showing the significant thermal hysteresis (ΔT∼ 10 K) in the field-cooled (FC)-warming measurement protocol as compared to the FC-cooling mode. The H-T phase diagram, mapped from the isothermal magnetization data and differential magnetic susceptibility data with different measurement protocols clearly distinguishes three prominent regions below theTN(∼150 K), viz (i) long-range canted AFM + weak FM phase (Γ4(Gz,Fy,Ax)), (ii) Γ24mixed phase and (iii) robust Γ2(Fz,Gy,Cx;FzR,CxR) AFM + FM phases. Tunable spin-flopped transition (∼ 30 kOe), significant negative exchange-bias field (HEB∼ 2.5 kOe), huge coercive field (HC∼ 22 kOe) and large NM (ΔM∼ 280 emu/mole) are the unique characteristic features of the current investigated system.

Neutron diffraction evidence for local spin canting, weak Jahn-Teller distortion, and magnetic compensation in Ti1-x Mn x Co2O4 spinel.

A systematic study using neutron diffraction and magnetic susceptibility is reported on Mn substituted ferrimagnetic inverse spinel Ti1-x Mn x Co2O4 in the temperature interval 1.6 K [Formula: see text] T [Formula: see text] 300 K. Our neutron diffraction study reveals cooperative distortions of the TO6 octahedra in the Ti1-x Mn x Co2O4 system for all the Jahn-Teller active ions T = Mn3+ , Ti3+ and Co3+ , having the electronic configurations 3d 1, 3d 4 and 3d 6, respectively which are confirmed by the x-ray photoelectron spectroscopy. Two specific compositions (x = 0.2 and 0.4) have been chosen in this study because these two systems show unique features such as; (i) noncollinear Yafet-Kittel type magnetic ordering, and (ii) weak tetragonal distortion with c/a < 1, in which the apical bond length d c (T B -O) is longer than the equatorial bond length d ab (T B -O) due to the splitting of the e g level of Mn3+ ions into [Formula: see text] and [Formula: see text]. For the composition x = 0.4, the distortion in the T B O6 octahedra is stronger as compared to x = 0.2 because of the higher content of trivalent Mn. Ferrimagnetic ordering in Ti0.6Mn0.4Co2O4 and Ti0.8Mn0.2Co2O4 sets in at 110.3 and 78.2 K, respectively due to the presence of unequal magnetic moments of cations, where Ti3+ , Mn3+ , and Co3+ occupy the octahedral, whereas, Co2+ sits in the tetrahedral site. For both compounds an additional weak antiferromagnetic component could be observed lying perpendicular to the ferrimagnetic component. The analysis of static and dynamic magnetic susceptibilities combined with the heat-capacity data reveals a magnetic compensation phenomenon (MCP) at T COMP = 25.4 K in Ti0.8Mn0.2Co2O4 and a reentrant spin-glass behaviour in Ti0.6Mn0.4Co2O4 with a freezing temperature of ∼110.1 K. The MCP in this compound is characterized by sign reversal of magnetization and bipolar exchange bias effect below T COMP with its magnitude depending on the direction of external magnetic field and the cooling protocol.

Association between obesity and sperm quality.

There is awareness of likelihood of abnormal spermatozoa in obese men; however, results from previous studies are inconclusive. Advances in computer-aided sperm analysis (CASA) enable precise evaluation of sperm quality and include assessment of several parameters. We studied a retrospective cohort of 1285 men with CASA data from our infertility clinic during 2016. Obesity (BMI ≥30) was associated with lower (mean ± SE) volume (-0.28 ± 0.12, p-value = .04), sperm count (48.36 ± 16.51, p-value = .002), concentration (-15.83 ± 5.40, p-value = .01), progressive motility (-4.45 ± 1.92, p-value = .001), total motility (-5.50 ± 2.12, p-value = .002), average curve velocity (µm/s) (-2.09 ± 0.85, p-value = .001), average path velocity (µm/s) (-1.59 ± 0.75, p-value = .006), and higher per cent head defects (0.92 ± 0.81, p-value = .02), thin heads (1.12 ± 0.39, p-value = .007) and pyriform heads (1.36 ± 0.65, p-value = .02). Obese men were also more likely to have (odds ratio, 95% CI) oligospermia (1.67, 1.15-2.41, p-value = .007) and asthenospermia (1.82, 1.20-2.77, p-value = .005). This is the first report of abnormal sperm parameters in obese men based on CASA. Clinicians may need to factor in paternal obesity prior to assisted reproduction.

Genomic determinants of chronic myelomonocytic leukemia.

The biology, clinical phenotype and progression rate of chronic myelomonocytic leukemia (CMML) are highly variable due to diverse initiating and secondary clonal genetic events. To determine the effects of molecular features including clonal hierarchy in CMML, we studied whole-exome and targeted next-generation sequencing data from 150 patients with robust clinical and molecular annotation assessed cross-sectionally and at serial time points of disease evolution. To identify molecular lesions unique to CMML, we compared it to the related myeloid neoplasms (N=586), including juvenile myelomonocytic leukemia, myelodysplastic syndromes (MDS) and primary monocytic acute myeloid leukemia and discerned distinct molecular profiles despite similar pathomorphological features. Within CMML, mutations in certain pathways correlated with clinical classification, for example, proliferative vs dysplastic features. While most CMML patients (59%) had ancestral (dominant/co-dominant) mutations involving TET2, SRSF2 or ASXL1 genes, secondary subclonal hierarchy correlated with clinical phenotypes or outcomes. For example, progression was associated with acquisition of new expanding clones carrying biallelic TET2 mutations or RAS family, or spliceosomal gene mutations. In contrast, dysplastic features correlated with mutations usually encountered in MDS (for example, SF3B1 and U2AF1). Classification of CMML based on hierarchies of ancestral and subclonal mutational events may correlate strongly with clinical features and prognosis.

Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms.

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1(MT) and IDH2(MT) are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients.

On the nature of magnetic state in the spinel Co2SnO4.

In the spinel Co2SnO4, coexistence of ferrimagnetic ordering below T(N) ≃ 41 K followed by a spin glass state below T(SG) ≃ 39 K was proposed recently based on the temperature dependence of magnetization M(T) data. Here new measurements of the temperature dependence of the specific heat C(P)(T), ac-susceptibilities χ'(T) and χ″(T) measured at frequencies between 0.51 and 1.2 kHz, and the hysteresis loop parameters (coercivity H(C)(T) and remanence M(R)(T)) in two differently prepared samples of Co2SnO4 are reported. The presence of the Co(2+) and Sn(4+) states is confirmed by x-ray photoelectron spectroscopy (XPS) yielding the structure: Co2SnO4 = [Co(2+)][Co(2+)Sn(4+)]O4. The data of C(P) versus T shows only an inflection near 39 K characteristic of spin-glass ordering. The analysis of the frequency dependence of ac-magnetic susceptibility data near 39 K using the Vogel-Fulcher law and the power-law of the critical slowing-down suggests the presence of spin clusters in the system which is close to a spin-glass state. With a decrease in temperature below 39 K, the temperature dependence of the coercivity H(C) and remanence M(R) for the zero-field cooled samples show both H(C) and M(R) reaching their peak magnitudes near 25 K, then decreasing with decreasing T and becoming negligible below 15 K. The plot of C(P)/T versus T also yields a weak inflection near 15 K. This temperature dependence of H(C) and remanence M(R) is likely associated with the different magnitudes of the magnetic moments of Co(2+) ions on the 'A' and 'B' sites and their different temperature dependence.

Bioequivalence of two lansoprazole delayed release capsules 30 mg in healthy male volunteers under fasting, fed and fasting-applesauce conditions: a partial replicate crossover study design to estimate the pharmacokinetics of highly variable drugs.

An open-label, 2-treatment, 3-sequence, 3-period, single-dose, partial replicate crossover studies under fasting (n=48), fed (n=60) and fasting-applesauce (n=48) (sprinkled on one table spoonful of applesauce) modalities were conducted in healthy adult male volunteers to evaluate bioequivalence between 2 formulations of lansoprazole delayed release capsules 30 mg. In all the 3 studies, as per randomization, either test or reference formulations were administered in a crossover manner with a required washout period of at least 7 days. Blood samples were collected adequately (0-24 h) to determine lansoprazole plasma concentrations using a validated LC-MS/MS analytical method. To characterize the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞, Tmax, Kel and T1/2) of lansoprazole, non-compartmental analysis and ANOVA was applied on ln-transformed values. The bioequivalence was tested based on within-subject variability of the reference formulation. In fasting and fed studies (within-subject variability>30%) bioequivalence was evaluated with scaled average bioequivalence, hence for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞, the 95% upper confidence bound for (µT-µR)2-θσ2 WR was ≤0, and the point estimates (test-to-reference ratio) were within the regulatory acceptance limit 80.00-125.00%. In fasting-applesauce study (within-subject variability<30%) bioequivalence was evaluated with average bioequivalence, the 90% CI of ln-transformed data of Cmax, AUC0-t and AUC0-∞ were within the regulatory acceptance limit 80.00-125.00%. Based on these aforesaid statistical inferences, it was concluded that the test formulation is bioequivalent to reference formulation.

Bioequivalence of fixed dose combination of atorvastatin 10 mg and aspirin 150 mg capsules: a randomized, open-label, single-dose, two-way crossover study in healthy human subjects.

The present study evaluated the bioavailability and bioequivalence of fixed dose combination test formulation (atorvastatin 10 mg and aspirin 150 mg capsule) against marketed reference formulations (Lipitor® tablets 10 mg and Nu-Seals tablets 75 mg). This study was an open label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover trial in 80 healthy adult human volunteers under fasting conditions. Plasma concentrations of atorvastatin, aspirin and salicylic acid were quantified using LC-MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental model and mean pharmacokinetic parameters were comparable between test and reference formulations. The mean pharmacokinetic parameters (AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞) for atorvastatin test and reference formulations were (52.69 ng.h/mL, 55.64 ng.h/mL, 9.45 ng/mL, 0.18 1/h and 0.17 1/h) and (52.20 ng.h/mL, 55.38 ng.h/mL, 10.25 ng/mL, 0.20 1/h and 0.19 1/h) respectively; and for aspirin were (1 378.62 ng.h/mL, 1 383.90 ng.h/mL, 1 022.18 ng/mL, 0.75 1/h and 0.75 1/h) and (1 314.17 ng.h/mL, 1 314.50 ng.h/mL, 985.90 ng/mL, 0.75 1/h and 0.75 1/h) respectively. Where as for salicylic acid, above parameters were (42 357.57 ng.h/mL, 44 139.47 ng.h/mL, 9 820.15 ng/mL, 0.24 1/h and 0.23 1/h) and (40 217.08 ng.h/mL, 42 032.44 ng.h/mL, 9 569.18 ng/mL, 0.24 1/h and 0.24 1/h) respectively for test and reference formulations. The 90% confidence intervals of atorvastatin and salicylic acid for AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞ parameters were found to be within the acceptable regulatory bioequivalence limits. In conclusion, the new fixed dose combination test formulation was bioequivalent to the reference formulations under fasting conditions.

Bioequivalence study of two subcutaneous formulations of dalteparin: randomized, single-dose, two-sequence, two-period, cross-over study in healthy volunteers.

OBJECTIVE: This study assessed relative bioavailability of a new subcutaneous formulation, test (T) (dalteparin sodium 95000 IU/3.8 mL) with the branded product (R) in healthy subjects to meet the regulatory requirements of bioequivalence in the US. METHODS: This was an open label, randomized, single dose, two-sequence, two-period cross-over study under fasting conditions. A total of 88 healthy adult volunteers were randomized to either of the treatment arms (T or R) separated by a washout period of 7 days. Pharmacodynamic surrogates, namely anti-Xa and anti-IIa activity, heparin clotting assay (heptest), and activated partial thromboplastin time (aPTT) were used as a tool to establish bioequivalence between these two formulations. Blood samples were collected up to 36 h post-dose to characterize the primary pharmacokinetic parameters A max, AUC0- t , and AUC0-∞ for anti-Xa and anti-IIa and heptest; parameters (Δt )max and AU(Δt ) for aPTT. RESULTS: For anti-Xa activity, the means (SD) of A max (IU/mL) were 1.34 (0.25) [range = 0.59-2.03] and 1.39 (0.35) [range = 0.65-2.69]; AUC0- t (IU•h/mL) values were 11.4 (2.76) [range = 2.89-19.5] and 12.1 (2.87) [range = 2.52-21.30]; AUC0 - ∞ (IU•h/mL) values were 13.1 (3.59) [range = 3.15-28.2] and 14.5 (4.97) [range = 2.79-36.1] for test and branded formulations, respectively. For anti-IIa activity, the means (SD) of A max (IU/mL) were 0.34 (0.12) [range = 0.14-0.72] and 0.34 (0.13) [range = 0.11-0.84]; AUC0- t (IU•h/mL) values were 2.05 (0.72) [range = 0.61-4.69] and 2.11 (0.76) [range = 0.84-4.80]; AUC0 - ∞ (IU•h/mL) values were 2.47 (0.80) [range = 0.76-6.29] and 2.61 (0.86) [range = 1.31-5.36], for test and branded formulations, respectively. The 90% CI for all the primary pharmacokinetic parameters of all the pharmacodynamic surrogates tested met the regulatory bioequivalence criterion of 80.00-125.00%. CONCLUSION: The test product met the US regulatory criteria of bioequivalence relative to the branded product in this single dose bioequivalence study. Study limitations include open-label single dose design.

Magnetocaloric effect and improved relative cooling power in (La(0.7)Sr(0.3)MnO(3)/SrRuO(3)) superlattices.

Magnetic properties of a series of (La(0.7)Sr(0.3)MnO(3)/SrRuO(3)) superlattices, where the SrRuO(3) layer thickness is varying, are examined. A room-temperature magnetocaloric effect is obtained owing to the finite size effect which reduces the T(C) of La(0.7)Sr(0.3)MnO(3) layers. While the working temperature ranges are enlarged, - ΔS(M)(max) values remain similar to the values in polycrystalline La(0.7)Sr(0.3)MnO(3). Consequently, the relative cooling powers are significantly improved, the microscopic mechanism of which is related to the effect of the interfaces at La(0.7)Sr(0.3)MnO(3)/SrRuO(3) and higher nanostructural disorder. This study indicates that artificial oxide superlattices/multilayers might provide an alternative pathway in searching for efficient room-temperature magnetic refrigerator for (nano) micro-scale systems.