Delayed diagnosis of meningitis caused by β-haemolytic group G Streptococcus in an older woman

A case of meningitis caused by group G β-hemolytic Streptococcus (dysgalactiae, subspecies equisimilis) is reported in an 83-year-old woman. Streptococci species other than Streptococcus pneumoniae are seldom found in patients with acute bacterial meningitis, therefore, our discussion is focused on this rare organism. The question of the diagnosis of meningitis in the elderly is also addressed.     

Calcium-alginate beads for the oral delivery of transforming growth factor-β1 (TGF-β1): stabilization of TGF-β1 by the addition of polyacrylic acid within acid-treated beads

The susceptibility of the gastrointestinal tract to the toxic effects of chemotherapeutic drugs remains a complication in chemotherapy. Recent studies have suggested that transforming growth factor-β₁ (TGF-β₁) can be used as a cytoprotectant against cell cycle specific drugs. This work describes the use of alginate beads as a potential oral delivery system for TGF-β₁ designed to release the drug in the lumen of the small intestine. TGF-β₁ encapsulation and extent of release from alginate beads approached 100% as determined by ¹²⁵I-labelled TGF-β₁. However, when assayed by ELISA and a growth inhibition assay, nearly all immunoreactivity and bioactivity was lost, apparently due to a very high affinity of the alginate for TGF-β₁. This limitation was overcome by two novel methods: (1) incorporation of selected polyanions within the alginate beads to ‘shield’ TGF-β₁ from interaction with alginate and (2) exposure of the alginate beads containing TGF-β₁ to 0.1 N HCl (acid treatment) to simultaneously reduce the molecular weight of the alginate and its ability to interact with TGF- β₁. If the beads were only acid treated, just 8% of the immunoreactivity ofTGF-β₁ was retained. If polyacrylic acid (90 kDa) was added to the beads, 50% of the immunoreactivity of TGF-β₁ was retained. However, when TGF-β₁ was released from acid-treated beads also containing polyacrylic acid, more than 80% of the TGF-β₁ remained immunoreactive and bioactive. The retained TGF-β₁ activity after release from the beads was found to continue to increase with increasing concentrations of polyacrylic acid, until a concentration was reached where beads would not form. The dramatic increase in retained TGF-β₁ activity is attributed to the ability of polyacrylic acid to shield TGF-β₁ from interaction with lower molecular fragments of alginate.     

Development of γG, γA, γM, β1C/β1A, C′1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, plasminogen, α1-antitrypsin, orosomucoid, β-lipoprotein, α2-macroglobulin, and prealbumin in the human conceptus

The synthesis of γG, γA, γM, β_1C/β_1A, C′1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, α₁-antitrypsin, orosomucoid, β-lipoprotein, α₂-macroglobulin, and prealbumin was studied in 15 normal human embryos and fetuses of 29 days to 18 wk gestation and in the yolk sacs of four embryos from 5.5 to 11.5 wk gestation using tissue culture in ¹⁴C-labeled amino acids followed by radioimmunoelectrophoresis. The human embryo as early as 29 day gestation synthesized β_1C/β_1A, C′1 esterase inhibitor, transferrin, hemopexin, α₁-antitrypsin, β-lipoprotein, α₂-macroglobulin, and prealbumin in culture. At 32 days gestation ceruloplasmin and orosomucoid were also synthesized, but synthesis of fibrinogen was not observed before 5.5 wk. Synthesis of γM occurred as early as 10.5 wk gestation, and γG synthesis was found in cultures as early as 12 wk gestation; γA synthesis was not detected in any of the tissue cultures. With the exception of the γ-globulins, each of the proteins studied was synthesized by the liver, but additional sites of synthesis for some of these proteins were also found. Synthesis of γG and γM occurred primarily in the spleen, but other sites of synthesis were noted as well.     

Fulminant septicemia of Bacillus cereus resistant to carbapenem in a patient with biphenotypic acute leukemia

We report a case of fulminant septicemia with Bacillus cereus resistant to carbapenem. A 33-year-old man was suffering from febrile neutropenia (FN) on day 15 after the start of remission-induction therapy for biphenotypic acute leukemia under gut decontamination with polymyxin B and nystatin. Meropenem, a carbapenem, was administered according to the guideline for FN. Two days later (on day 17), he complained of severe abdominal pain, lost consciousness, went into sudden cardiopulmonary arrest, and died. Autopsy showed multiple spots of hemorrhage and necrosis caused by bacterial plaque in the brain, lungs, and liver. B. cereus was isolated from a blood sample obtained in the morning on day 17 and it was after his death that the isolated B. cereus was revealed to be resistant to carbapenem. B. cereus obtained from blood samples has been reported to be usually sensitive to carbapenem and also to vancomycin, new quinolones, and clindamycin. If B. cereus resistant to carbapem increases, our method of gut decontamination with polymyxin B and nystatin may have to be changed to one containing a new quinolone for the prevention of septicemia. Careful watching to determine whether B. cereus resistant to carbapem increases may be also important for empiric therapy, because carbapenem is often selected as the initial therapy for FN in patients with severe neutropenia.     

Catalyst-free chemoselective α-sulfenylation/β-thiolation for α,β-unsaturated carbonyl compounds

A novel, efficient, catalyst-free and product-controllable strategy has been developed for the chemoselective α-sulfenylation/β-thiolation of α,β-unsaturated carbonyl compounds. An aromatic sulfur group could be chemoselectively introduced at α- or β-position of carbonyls with different sulfur reagents under slightly changed reaction conditions. A series of desired products were obtained in moderate to excellent yields. Mechanistic studies revealed that B₂pin₂ played the key role in activating the transformation towards the β-thiolation of α,β-unsaturated carbonyl compounds. This transition-metal-catalyst-free method provides a convenient and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.

This catalyst-free method provides a useful and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.     

Optical and dielectric properties of NaCoPO4 in the three phases α, β and γ

In this work, we are interested in the synthesis of monophosphate α-NaCoPO₄, β-NaCoPO₄ and γ-NaCoPO₄ compounds by mechanochemical method and their characterization by X-ray powder diffraction patterns. These compounds are crystallized in the orthorhombic, hexagonal and monoclinic system, in Pnma, P6₅ and P2₁/n space groups, respectively. The optical properties were measured by means of the UV-vis absorption spectrometry in order to deduce the absorption coefficient α and optical band gap E_g. The calculated values of the indirect band gaps (E_gi) for three samples were estimated at 4.71 eV, 4.63 eV and 3.8 for compounds α, β and γ, respectively. The Tauc model was used to determine the optical gap energy of the synthesized compounds. Then, the results of the dielectric proprieties measured by varying the frequency are described.

In this work, we are interested in the synthesis of monophosphate α-NaCoPO₄, β-NaCoPO₄ and γ-NaCoPO₄ compounds by mechanochemical method and their characterization by X-ray powder diffraction patterns.     

Biochemical assay for amyloid β deposits to distinguish Alzheimer's disease from other dementias

Biochemical markers for Alzheimer's disease (AD) are of great value for precise diagnosis and in studies of the pathogenetic processes of this disease. A new biochemical assay allowing to differentiate AD from other forms of dementia is described. The assay is based on the extraction of amyloid β (Aβ) from milligram amounts of brain tissue by using 20% acetonitrile in 0.1% trifluoroacetic acid and its detection by Western blotting. The presence of the 4 kDa Aβ was demonstrated in all cases of AD (n=8) that were diagnosed by the independent histopathological examination of the postmortem tissues. No Aβ was found in tissue extracts from seven out of eight cases of other forms of dementia. In contrast to other biochemical techniques of Aβ detection in brain, the developed assay is simple; it does not require any special equipment and allows detection of Aβ using milligram amounts of brain tissue.     

The β3 subunit of the Na,K-ATPase mediates variable nociceptive sensitivity in the formalin test

It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the β₃ subunit of the Na⁺,K⁺-ATPase pump (Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, β₃ protein expression, and biophysical properties of the Na⁺,K⁺ pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the β₃ subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the β₃ subunit of the Na⁺,K⁺-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.     

Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) ε4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (ε4+, age: 72 ± 10 SD years, MMSE: 20 ± 3 SD) and 14 non-carriers (ε4−, age: 69 ± 9, MMSE: 20 ± 5) of the ε4 allele and compared them to 29 age-and-sex matched controls (age: 70 ± 9, MMSE: 28 ± 1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. ε4+ and ε4− patients showed similar performance on neuropsychological tests (p > .05, t-test). Diffuse cortical atrophy was detected for both ε4+ (p = .0001, permutation test) and ε4− patients (p = .0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5–15% greater loss in non-carriers). APOE effect in AD was not significant (p > .74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p = .002, ANOVA), in both early and late-onset patients (p < .05, ANOVA). We conclude that the ε4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.     

Sheep (Ovis aries) integrins αvβ1 and αvβ6 related to foot-and-mouth disease virus infection: Molecular cloning, sequence analysis and comparison with homologues

Four members of the αv integrin family of cellular receptors, αvβ1, αvβ3, αvβ6, and αvβ8, have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro, and integrins are believed to be the receptors used to target epithelial cells in the infected animals. To analyse roles of the αv integrins from a susceptible species as viral receptors, we have cloned sheep αv, β1, and β6 integrin cDNAs and compared them to those of other species. The coding sequences for sheep integrin αv, β1, and β6 were found to be 3147, 2397, and 2364 nuclotides in length, encoding 1048, 798, and 787 amino acids, respectively. The sheep αv, β1, and β6 subunits share many structural features including ligand binding domain and cysteine-rich region with homologues of other species. Phylogenetic trees and similarity analyses showed the close relationship of integrin genes among sheep, pigs, cattle and Bactrian camels that are susceptible to FMDV infection, which were distinct from the order Rodentia, Primates, Perissodactyla, Carnivora, Galliformes. We postulate that host tropism of FMDV may be related to divergence in integrin subunits among different species.     

THE CELLULAR ORIGIN OF HUMAN IMMUNOGLOBULINS (γ2, γ1M, γ1A)

A study was made of the cellular origin of human immunoglobulins (γ₂, γ_1M, γ_1A). The results indicated that two closely related families of cells form immunoglobulins in human lymphoid tissue: germinal (reticular) centers and plasma cells. Thus their cellular origin in addition to their known antigenic relations further justifies placing the immunoglobulins in one family of proteins. Immunoglobulins were also formed to a small extent in primitive reticular cells which resembled those of germinal centers but were separated from them. Possibly such cells were undergoing transition to the much more numerous plasma cells with which they were commonly associated. The mantles of small lymphocytes which surrounded germinal centers did not contain detectable quantities of immunoglobulins. While in general only one type of immunoglobulin was present in an individual cell or germinal center, γ₂- and γ_1M-globulin were identified on occasion in the same plasma cell and germinal center. A peculiarity of the fetal thymus gland was the presence of immunoglobulin, mainly γ_1M, in a small number of cells of small and intermediate size and primitive reticular appearance and in Hassall's corpuscles.     

Thermal stability and oxidation characteristics of α-pinene, β-pinene and α-pinene/β-pinene mixture

Turpentine is a renewable resource, has good combustion performance, and is considered to be a fuel or promising additive to diesel fuel. This is very important for the investigation of thermal stability and energy oxidation characteristics, because evaluation of energy or fuel quality assurance and use safety are necessary. The main components of turpentine are α-pinene and β-pinene, which have unsaturated double bonds and high chemical activity. By investigating their thermal stability and oxidation reaction characteristics, we know the chemical thermal properties and thermal explosion hazard of turpentine. In this present study, the thermal stability and oxidation characteristics of α-pinene, β-pinene and α-pinene/β-pinene mixture were investigated using a high sensitivity accelerating rate calorimeter (ARC) and C80 calorimeter. The important parameters of oxidation reaction and thermal stability were obtained from the temperature, pressure and exothermic behavior in chemical reaction. The results show that α-pinene and β-pinene are thermally stable without chemical reaction under a nitrogen atmosphere even when the temperature reaches 473 K. The initial exothermic temperature of the two pinenes and their mixture is 333–338 K, and the heat release (−ΔH) of their oxidation is 2745–2973 J g⁻¹. The oxidation activation energy (E_a) of α-pinene, β-pinene and α-pinene/β-pinene mixture is 116.25 kJ mol⁻¹, 121.85 kJ mol⁻¹, and 115.95 kJ mol⁻¹, respectively. There are three steps in the oxidation of pinenes: the first is the induction period of the oxidation reaction; the second is the main oxidation stage, and the pressure is reduced; the third is thermal decomposition to produce gas.

Turpentine is a renewable resource, has good combustion performance, and is considered to be a fuel or promising additive to diesel fuel.     

Electrophilic halogenations of propargyl alcohols: paths to α-haloenones, β-haloenones and mixed β,β-dihaloenones

The Meyer–Schuster rearrangement of propargyl alcohols or alkynols leading to α,β-unsaturated carbonyl compounds is well known. Yet, electrophilic halogenations of the same alkynols and their alkoxy, ester and halo derivatives are inconspicuous. This review on the halogenation reactions of propargyl alcohols and derivatives intends to give a perspective from its humble direct halogenation beginning to the present involving metal catalysis. The halogenation products of propargyl alcohols include α-fluoroenones, α-chloroenones, α-bromoenones and α-iodoenones, as well as β-haloenones and symmetrical and mixed β,β-dihaloenones. They are, in essence, tri and tetrasubstituted alkenes carrying halo-functionalization at the α- or β-carbon. This is a potential stepping stone for further construction towards challenging substituted alkenones via Pd-catalysed coupling reactions.

This review highlights the development of α-haloenone, β-haloenone and mixed β,β-dihaloenone formations from propargyl alcohols via direct electrophilic halogenations and metal catalysed-halonium interception rearrangements.     

A first-principles investigation of α, β, and γ-MnO2 as potential cathode materials in Al-ion batteries

An inexpensive and eco-friendly alternative energy storage solution is becoming more in demand as the world moves towards greener technology. We used first principles calculations to investigate α, β, and γ-MnO₂ and their Al-ion intercalation mechanism in potential applications for aluminum batteries. We explored these complexes through investigating properties such as volume change, binding/diffusion energy, and band gap to gauge each material. α-MnO₂ had almost no volume change. γ-MnO₂ had the lowest binding energy and diffusion barrier. Our study gives insight into the feasibility of using MnO₂ in aluminum batteries and guides investigation of the material within its different phases.

An inexpensive and eco-friendly alternative energy storage solution is becoming more in demand as the world moves towards greener technology.     

Retracted Article: Salvianolic acid B inhibits inflammatory response and cell apoptosis via the PI3K/Akt signaling pathway in IL-1β-induced osteoarthritis chondrocytes

Osteoarthritis (OA) is the most common joint disease among late middle-aged or elderly people. The pathological process of OA mainly involves the degeneration of cartilage tissue and deficiency of joint function. Salvianolic acid B (Sal B) is the main active ingredient of Salvia miltiorrhiza Bge, which possesses anti-inflammatory, anti apoptotic and other pharmacological activities. In this study, primary chondrocytes were cultured to investigate the effects of Sal B on the inflammatory response and apoptosis of OA induced by IL-1β, and to explore the possible mechanism. First, we determined the cytotoxicity of Sal B; the results showed that the cell activity of chondrocytes was not influenced by Sal B when the concentration was below 150 μM. Moreover, Sal B (40 and 80 μM) suppressed the expression of iNOS in OA chondrocytes induced by IL-1β, and restrained the secretion of NO, IL-6, IL-17 and TNF-α in chondrocytes obviously. Sal B (40, 80 μM) significantly alleviated the inhibitory effect of cell activity stimulated by IL-1β and up-regulated the expression of Col II and reduced the expression of Col X. Besides, Sal B down-regulated the expression level of Bax and promoted the expression of Bcl-2, showed a significant effect on promoting proliferation and inhibiting cell apoptosis. In addition, we found that IL-1β significantly reduced the ratio of p-PI3K/PI3K, p-Akt/Akt induced the nuclear translocation of AKT and inhibited the activation of the PI3K/Akt signaling pathway. Finally, the PI3K inhibitor, LY-294002, was added in IL-1β-induced chondrocytes. The results suggest that Sal B ameliorates IL-1β induced inflammation and suppresses apoptosis in OA by activating the PI3K/Akt signaling pathway. Our study reveals the mechanism of Sal B acts on OA and may provide a basis for the treatment of OA with Sal B.

Osteoarthritis (OA) is the most common joint disease among late middle-aged or elderly people.     

Heterostructures of ε-Fe2O3 and α-Fe2O3: insights from density functional theory

Many materials used in energy devices or applications suffer from the problem of electron–hole pair recombination. One promising way to overcome this problem is the use of heterostructures in place of a single material. If an electric dipole forms at the interface, such a structure can lead to a more efficient electron–hole pair separation and thus prevent recombination. Here we model and study a heterostructure comprised of two polymorphs of Fe₂O₃. Each one of the two polymorphs, α-Fe₂O₃ and ε-Fe₂O₃, individually shows promise for applications in photoelectrochemical cells. The heterostructure of these two materials is modeled by means of density functional theory. We consider both ferromagnetic as well as anti-ferromagnetic couplings at the interface between the two systems. Both individual oxides are insulating in nature and have an anti-ferromagnetic spin arrangement in their ground state. The same properties are found also in their heterostructure. The highest occupied electronic orbitals of the combined system are localized at the interface between the two iron-oxides. The localization of charges at the interface is characterized by electrons residing close to the oxygen atoms of ε-Fe₂O₃ and electron–holes localized on the iron atoms of α-Fe₂O₃, just around the interface. The band alignment at the interface of the two oxides shows a type-III broken band-gap heterostructure. The band edges of α-Fe₂O₃ are higher in energy than those of ε-Fe₂O₃. This band alignment favours a spontaneous transfer of excited photo-electrons from the conduction band of α- to the conduction band of ε-Fe₂O₃. Similarly, photo-generated holes are transferred from the valence band of ε- to the valence band of α-Fe₂O₃. Thus, the interface favours a spontaneous separation of electrons and holes in space. The conduction band of ε-Fe₂O₃, lying close to the valence band of α-Fe₂O₃, can result in band-to-band tunneling of electrons which is a characteristic property of such type-III broken band-gap heterostructures and has potential applications in tunnel field-effect transistors.

Electron–hole pair recombination is reduced in heterostructures if used in devices in place of single material.     

Effects of antisera raised against native and denatured human α-glucosidase and β-hexosaminidases on native enzyme activity

Antisera were raised in rabbits against native and sodium dodecylsulfate denatured forms of human acid α-glucosidase and β-hexosaminidases A and B.

1. (1) Anti-native enzyme antisera were able to precipitate all or nearly all enzyme activity from cell extracts, and to eliminate all stainable activity on electrophoresis.

2. (2) Antisera prepared against denatured enzymes precipitated only a minor part of enzyme activity. Electrophoretic analysis showed that these antisera were able to bind to the enzyme molecule. The result was a slowing down of the anodic migration but not immobilization. The use of variants with hexosaminidase deficiencies helped to clarify the action of the antisera on the various hexosaminidase isozymes.

Cu-catalyzed cyanomethylation of imines and α,β-alkenes with acetonitrile and its derivatives

We describe copper-catalyzed cyanomethylation of imines and α,β-alkenes with a methylnitrile source and provide an efficient route to synthesize arylacrylonitriles and β,γ-unsaturated nitriles. This method tolerates aliphatic and aromatic alkenes substituted with a variety of functional groups such as F, Cl, Br, Me, OMe, tert-Bu, NO₂, NH₂ and CO₂H with good to excellent yields (69–98%). These systems consist of inexpensive, simple copper catalyst and acetonitrile with its derivatives (α-bromo/α-iodo-acetonitrile) and are highly applicable in the industrial production of acrylonitriles.

We describe copper-catalyzed cyanomethylation of imines and α,β-alkenes with a methylnitrile source and provide an efficient route to synthesize arylacrylonitriles and β,γ-unsaturated nitriles.     

Direct β-selectivity of α,β-unsaturated γ-butyrolactam for asymmetric conjugate additions in an organocatalytic manner

The β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by a bifunctional chiral tertiary amine has been developed, which provides an efficient access to optically active β-position functionalized pyrrolidin-2-one derivatives in both high yield and enantioselectivity (up to 78% yield and 95 : 5 er). This is the first catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach.

The asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by (DHQD)₂AQN has been developed, which provides an access to β-position functionalized pyrrolidin-2-one derivatives in high levels yield and enantioselectivity.

Metal-free organocatalytic asymmetric transformations have successfully captured considerable enthusiasm of chemists as powerful methods for the synthesis of various kinds of useful chiral compounds ranging from the preparation of biologically important molecules through to novel materials.¹ Chiral pyrrolidin-2-ones have been recognized as important structural motifs that are frequently encountered in a variety of biologically active natural and synthetic compounds.² In particular, the β-position functionalized pyrrolidin-2-one backbones, which can serve as key synthetic precursors for inhibitory neurotransmitters γ-aminobutyric acids (GABA),³ selective GABA_B receptor agonists⁴ as well as antidepressant rolipram analogues,⁵ have attracted a great deal of attention. Therefore, the development of highly efficient, environmentally friendly and convenient asymmetric synthetic methods to access these versatile frameworks is particularly appealing.As a direct precursor to pyrrolidin-2-one derivatives, recently, α,β-unsaturated γ-butyrolactam has emerged as the most attractive reactant in asymmetric organometallic or organocatalytic reactions for the synthesis of chiral γ-position functionalized pyrrolidin-2-ones (Scheme 1). These elegant developments have been achieved in the research area of catalytic asymmetric vinylogous aldol,⁶ Mannich,⁷ Michael⁸ and annulation reactions⁹ in the presence of either metal catalysts or organocatalysts (a, Scheme 1). These well-developed catalytic asymmetric methods have been related to the γ-functionalized α,β-unsaturated γ-butyrolactam to date. However, in sharp contrast, the approaches toward introducing C-3 chirality at the β-position of butyrolactam through a direct catalytic manner are underdeveloped (b, Scheme 1)¹⁰ in spite of the fact that β-selective chiral functionalization of butyrolactam can directly build up α,β-functionalized pyrrolidin-2-one frameworks.Open in a separate windowScheme 1Different reactive position of α,β-unsaturated γ-butyrolactam in catalytic asymmetric reactions.So far, only a few metal-catalytic enantioselective β-selective functionalized reactions have been reported. For examples, a rhodium/diene complex catalyzed efficient asymmetric β-selective arylation^10a and alkenylation^10b have been reported by Lin group (a, Scheme 2). Procter and co-workers reported an efficient Cu(i)–NHC-catalyzed asymmetric silylation of unsaturated lactams (b, Scheme 2).^10c Despite these creative works, considerable challenges still exist in the catalytic asymmetric β-selective functionalization of γ-butyrolactam. First, the scope of nucleophiles is limited to arylboronic acids, potassium alkenyltrifluoroborates and PhMe₂SiBpin reagents. Second, the catalytic system and activation mode is restricted to metal/chiral ligands. To our knowledge, an efficient catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach has not yet been established. Therefore, the development of organocatalytic asymmetric β-selective functionalization of γ-butyrolactam are highly desirable. In conjunction with our continuing efforts in building upon chiral precedents by using chiral tertiary amine catalytic system,¹¹ we rationalized that the activated α,β-unsaturated γ-butyrolactam might serve as a β-position electron-deficient electrophile. This γ-butyrolactam may react with a properly designed electron-rich nucleophile to conduct an expected β-selective functionalized reaction of γ-butyrolactam under a bifunctional organocatalytic fashion, while avoiding the direct γ-selective vinylogous addition reaction or β,γ-selective annulation as outlined in Scheme 2. Herein we report the β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters¹² catalyzed by a bifunctional chiral tertiary amine, which provides an efficient and facile access to optically active β-position functionalized pyrrolidin-2-one derivatives with both high diastereoselectivity and enantioselectivity.Open in a separate windowScheme 2β-Selective functionalization of γ-butyrolactam via metal- (previous work) or organo- (this work) catalytic approach.To begin our initial investigation, several bifunctional organocatalysts¹³ were firstly screened to evaluate their ability to promote the β-selective asymmetric addition of γ-butyrolactam 2a with cyclic imino ester 3a in the presence of 15 mol% of catalyst loading at room temperature in CH₂Cl₂ (entries 1–6,

The CD3-γδε and CD3-ζ/η Modules Are Each Essential for Allelic Exclusion at the T Cell Receptor β Locus but Are Both Dispensable for the Initiation of V to (D)J Recombination at the T Cell Receptor–β, –γ, and –δ Loci

The pre–T cell receptor (TCR) associates with CD3-transducing subunits and triggers the selective expansion and maturation of T cell precursors expressing a TCR-β chain. Recent experiments in pre-Tα chain-deficient mice have suggested that the pre-TCR may not be required for signaling allelic exclusion at the TCR-β locus. Using CD3-ε– and CD3-ζ/η–deficient mice harboring a productively rearranged TCR-β transgene, we showed that the CD3-γδε and CD3-ζ/η modules, and by inference the pre-TCR/CD3 complex, are each essential for the establishment of allelic exclusion at the endogenous TCR-β locus. Furthermore, using mutant mice lacking both the CD3-ε and CD3-ζ/η genes, we established that the CD3 gene products are dispensable for the onset of V to (D)J recombination (V, variable; D, diversity; J, joining) at the TCR-β, TCR-γ, and TCR-δ loci. Thus, the CD3 components are differentially involved in the sequential events that make the TCR-β locus first accessible to, and later insulated from, the action of the V(D)J recombinase.