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The X-ray structure of the title compound has been determined for the first time. Data on its 1H–13C-NMR coupling constants and 15N-NMR spectrum are also given.

The title compound was obtained in low yield in the condensation of ethyl pyruvate and lactic acid. Its structure is determined by NMR methods and x-ray diffraction and the mechanism for formation of this 1:2 adduct from the initial 1:1 adduct is considered. Publisher PDF

Assessments of sperm DNA damage are controversial because of perceived uncertainties over the relationship with pregnancy and the limited range of therapies available should positive results be returned. In this article, we highlight recent data supporting a chain of associations between oxidative stress in the male germ line, DNA damage in spermatozoa, defective DNA repair in the oocyte, the mutational load carried by the resulting embryo and the long-term health trajectory of the offspring. Any condition capable of generating oxidative damage in spermatozoa (age, obesity, smoking, prolonged abstinence, varicocele, chemical exposures, radiation etc.) is capable of influencing offspring health in this manner, creating a range of pathologies in the progeny including neuropsychiatric disorders and cancer. If sperm DNA damage is detected, there are several therapeutic interventions that can be introduced to improve DNA quality prior to the use of these cells in ART. We therefore argue that infertility specialists should be engaged in the diagnosis and remediation of sperm DNA damage as a matter of best practice, in order to minimize the risk of adverse health outcomes in children conceived using ART.

The teaching of the chemistry of the elements at the University of St Andrews by Professor Thomas Purdie FRS is examined with reference to selections from a collection of recently discovered historic wallcharts and extracts from his detailed hand-written lecture notes. Together these reveal a comprehensive and exciting programme of lectures incorporating numerous practical demonstrations which were continually updated to reflect the latest state of knowledge in what was a rapidly changing field. This article is part of the theme issue ‘Mendeleev and the periodic table’.

The vacuum ultraviolet (VUV) spectrum for cyclohepta-1,3,5-triene up to 10.8 eV shows several broad bands, which are compared with electron impact spectra. Local curve fitting exposed groups of sharp vibrational peaks, which are assigned to Rydberg states. The vertical excitation profile of the VUV spectrum, reproduced by time dependent density functional theory (TDDFT), gives a good interpretation of the principal regions of absorption. Fourth order Möller–Plessett perturbation theory, including single, double, and quadruple excitations, showed that the lowest singlet and triplet states retain CS symmetry. This contrasts with TDDFT where several low-lying excited states are planar. Detailed vibrational analysis of the first UV band was performed by Franck–Condon, Herzberg–Teller, and their combined methods. These show the dominance of mid-range frequencies, while the lowest frequency (75 cm−1) has negligible importance. In contrast, the second excited (Rydberg) state shows a major progression with separations of 115 (6) cm−1. This is interpreted by re-analysis of the X2A′ ionic state at the anharmonic level. Extremely low exponent Gaussian functions enabled several low-lying Rydberg state energies to be determined theoretically; extrapolation of the 3s-, 4s-, and 5s-Rydberg state calculated energies gives the adiabatic ionization energy as 7.837 eV (4) with δ 0.964 (2). Similarly, extrapolation of the centroids of the observed Rydberg states gave the vertical ionization energy (VIE) as VIE1 = 8.675 ± 0.077, close to the photoelectron spectroscopy VIE value [8.55 (1) eV]. Postprint

The strong inter-relationship between cyclohepta-1,3,5-triene (CHT) and norcaradiene (NCD) systems observed in some reactions has been extended to include the energy surfaces for some low-lying ionic states. Equilibrium structures for ionic states of CHT with

The X-ray structure of the title compound has been determined and the structure shows an exo-configured planar dithiolanone ring. This is in contrast to the few previous dithiolanones to be characterised crystallographically, which are all twisted.

Synchrotron-based photoelectron spectra (PES) of norbornadiene (NBD) and quadricyclane (QC) differ significantly from those in previous studies. The adiabatic ionization energy (AIE1) for NBD, assigned to the 2B1 state at 8.279 eV, shows a progression of 18 members with decreasing vibration frequency from 390 cm−1 to 340 cm−1; our calculated frequency is 381 cm−1. Similarly, the AIE1 for QC at 7.671 eV, assigned to the 2B2 state, discloses a vibrational progression of nine or more members with vibration frequency decreasing from 703 cm−1 to 660 cm−1; our calculated vibration frequency is 663 cm−1. These AIEs, determined by coupled cluster and fourth order Møller–Plesset perturbation theory, were very similar to the corresponding second order perturbation theory results. The calculated AIE symmetry sequences are 2B1 < 2A1 < 2A2 < 2B2 for NBD and 2B2 < 2A2 < 2B1 < 2A1 for QC. The overall PES vertical ionization energy profiles for both compounds were closely reproduced by Tamm–Dancoff approximation energies and intensities. The vibrational structure of the ionic states, determined using Franck–Condon methods, gave a good account of the observed spectra, but the observed envelopes for both IE1 are complex sets of vibrations, rather than single progressions. The NMR spectra for QC showed residual second order properties at 300 MHz; both QC and NBD have been theoretically analyzed in greater detail using AA/BB/CC/XX/ spectra, where all H are coupled; the magnetic shielding and spin–spin coupling constants obtained are similar to experimental values. Postprint Postprint

A series of amino acid-derived chiral benzylthio alcohols have been prepared and characterized. A chiral mercapto alcohol derived from S-leucine has been used to form three chiral 2,4-disubstituted 1,3-oxathiolanes. One of these has been oxidized to the S-oxide and another to the S,S-dioxide. The cis and trans isomers have been characterized by 1H NMR in each case and it appears that thermal epimerisation at C-2 is possible at the sulfoxide oxidation state. The X-ray structure of major trans diastereomer of 2-phenyl-4-isobutyl-1,3-oxathiolane S,S-dioxide shows an envelope conformation with oxygen at the flap and an internal angle at sulfur of just 93.8°. This compound fragments upon flash vacuum pyrolysis at 700°C to give SO2, benzaldehyde and 4-methylpent-1-ene.

A second polymorph of 4-aminobenzyl alcohol [orthorhombic, a = 8.95051(15), b = 5.8248(1), c = 12.1645(2) Å, space group Pna21] shows a "herringbone" structure with stacks of hydrogen-bonded molecules when viewed down the b-axis. Publisher PDF

We thank EPSRC (UK) for a studentship to ANG. Ten new oxo-stabilised phosphonium ylides containing substituted thiophene groups, as well as two deuterium-labelled analogues, are prepared and fully characterised. Upon flash vacuum pyrolysis at 800 °C, the simpler examples undergo extrusion of Ph3PO coupled with domino cyclisation to give thieno[3,2-b]furan and thieno[3,4-b]furan products but the corresponding approach to a thieno[2,3-b]furan fails. One ylide designed to give a thieno[3,4-b]furan instead gives phenylbutadiyne and 2-phenyl-3-vinylthiophene at 725 °C and the mechanism of this unusual process is elucidated by deuterium labelling. Attempts to access more complex heterocyclic products from extended methoxythienyl ylides failed. Two ylides bearing a 3-methyl-2-thienylacryloyl group gave 5-benzylbenzothiophene, 5-(α-methylbenzyl)benzothiophene and fluoreno[3,4-b]thiophene upon FVP at 800 °C and the mechanism was again elucidated by deuterium labelling. Postprint

The Big Blue λSelect-cII selection system has been employed along with whole-exome sequencing to examine the susceptibility of the male germ line to mutation in two challenging situations (i) exposure to a chemotherapeutic regime including bleomycin, etoposide and cis-platinum (BEP) and (ii) the ageing process. A 3-week exposure to BEP induced complete azoospermia associated with a loss of developing germ cells and extensive vacuolization of Sertoli cell cytoplasm. Following cessation of treatment, spermatozoa first appeared in the caput epididymis after 6 weeks and by 12 weeks motile spermatozoa could be recovered from the cauda, although the count (P P P P

BACKGROUND International studies reporting outcomes following emergency laparotomies have consistently demonstrated wide inter-hospital variation and a 30-day mortality in excess of 10%. The UK then prioritized the funding of the National Emergency Laparotomy Audit. In a prospective Western Australian audit there was minimal inter-hospital variation and a 6.6% 30-day mortality. In the absence of any multi-hospital Australian data the aim of the present study was to compare national administrative data with that previously reported. METHODS Data on emergency laparotomies performed in Australian public hospitals during 2013/2014 and 2014/2015 were extracted from admitted patient activity and costing data sets collated by the Independent Hospital Pricing Authority. The data sets, containing episode-level data relating to admitted acute and sub-acute care patients, included administrative, demographic and clinical information such as patient age, cost, length of stay, in-hospital mortality, diagnosis and surgical procedure details. RESULTS Ninety-nine public hospitals undertaking at least 50 emergency laparotomies performed 20 388 procedures over the 2 years. The overall in-hospital mortality was 5.2%. There was a wide interstate and inter-hospital variation in risk-adjusted in-hospital mortality (4.8-6.6% and 0-9.3%, respectively), length of stay (12.5-16.8 days and 5.8-18.9 days, respectively) and intensive care unit admissions (24.5-40.2% and 0-75.7%, respectively). CONCLUSION This data suggest the wide variation in outcomes and care process observed overseas exist in Australia. However, administrative data has considerable limitations and is not a substitute for high quality prospective data. Minimizing variations through prospective quality improvement processes will improve patient outcomes.

The reproductive consequences of global warming are not currently understood. In order to address this issue, we have examined the reproductive consequences of exposing male mice to a mild heat stress. For this purpose, adult male mice were exposed to an elevated ambient temperature of 35°C under two exposure models. The first involved acute exposure for 24 h, followed by recovery periods between 1 day and 6 weeks. The alternative heating regimen involved a daily exposure of 8 h for periods of 1 or 2 weeks. In our acute model, we identified elevated sperm mitochondrial ROS generation (P 0.05), increased sperm membrane fluidity (P 0.05), DNA damage in the form of single-strand breaks (P 0.001), and oxidative DNA damage (P 0.05), characteristic of an oxidative stress cascade. This DNA damage was detected in pachytene spermatocytes (P 0.001) and round spermatids (P 0.001) isolated from testes after 1 day heat recovery. Despite these lesions, the spermatozoa of heat-treated mice exhibited no differences in their ability to achieve hallmarks of capacitation or to fertilize the oocyte and support development of embryos to the blastocyst stage (all P 0.05). Collectively, our acute heat stress model supports the existence of heat susceptible stages of germ cell development, with the round spermatids being most perturbed and spermatogonial stem cells exhibiting resistance to this insult. Such findings were complemented by our chronic heat stress model, which further supported the vulnerability of the round spermatid population.

A synchrotron-based vacuum ultraviolet (VUV) absorption spectrum of norbornadiene (NBD) is reported, and the extensive vibrational structure obtained has been analyzed. The previously known 5b 13s-Rydberg state has been reinterpreted by comparison with our recent high-resolution photoelectron spectral analysis of the X 2B 1 ionic state. Additional vibrational details in the region of this Rydberg state are observed in its VUV spectrum when compared with the photoelectron 2B 1 ionic state; this is attributed to the underlying valence state structure in the VUV. Valence and Rydberg state energies have been obtained by configuration interaction and time-dependent density functional theoretical methods. Several low-lying singlet valence states, especially those that arise from ππ* excitations, conventionally termed NV 1 to NV 4, have been examined in detail. Their Franck-Condon (FC) and Herzberg-Teller (HT) profiles have been investigated and fitted to the VUV spectrum. Estimates of the experimental 0 0 band positions have been made from these fits. The anomaly of the observed UV absorption by the 1A 2 state of NBD is attributed to HT effects. Generally, the HT components are less than 10% of the FC terms. The calculated 5b 13s lowest Rydberg state also shows a low level of HT components. The observed electron impact spectra of NBD have been analyzed in detail in terms of triplet states.

The authors thank EPSRC (UK) for a DTA studentship (Grant No. EP/P501768/1). Six stabilised phosphonium ylides bearing ortho-benzylaminophenyl and cinnamoyl (or a heterocyclic analogue) groups have been prepared and upon flash vacuum pyrolysis at 800 °C were found to undergo cascade cyclization processes to give mainly 3-styrylquinolines but also in some cases ring-fused carbazoles and other fused-ring heterocyclic products. By starting with an appropriate ring-methylated precursor the natural product Eustifoline D was obtained in 19% yield in the pyrolysis in addition to the 3-(2-furylethenyl)quinoline (46%). Postprint

The authors thank EPSRC (UK) for a studentship to ANG. Thirty-six new stabilised phosphonium ylides designed to undergo thermal loss of Ph3PO and radical domino cyclisation have been prepared and are generally found to undergo the desired reaction under flash vacuum pyrolysis conditions at 850 °C. A wide range of tetra- and penta-cyclic fused ring heterocycles, many previously unknown, are thus formed in moderate to high yield in a single step. By using suitably substituted starting materials, substituents such as CH3 and Cl can be installed at various positions in the products. The method has also been demonstrated in a combinatorial mode to generate a small library of twelve fused ring heterocycles in a single pyrolysis. Postprint

Oesophagectomy (OG) and pancreaticoduodenectomy (PD) remain associated with significant perioperative mortality rates (POMR). Improved outcomes in high-volume centres have led to these procedures being centralised in some countries. This retrospective, population-based cohort study was conducted to determine the Australian national, and state and territory based POMR associated with OG and PD, and assess trends over time. Logistic regression analysis was performed using de-identified procedural data between 1 July 2005 and 30 June 2013 from the Australian Institute of Health and Welfare. Codes relating to OG and PD contained in the Australian Classification of Health Interventions were used to extract patient data. Mortality rates were risk adjusted for age, gender and urgency of admission. Temporal trends and differences between states/territories were investigated. The average Australian POMR throughout the study period was 3.5 and 3.0% for OG and PD, respectively. OG POMR showed no significant change over time (P = 0.30) or variation between states (P = 0.079). The annual POMR associated with PD, however, showed a significant decrease during the study period (P = 0.01) with variation in PD POMR outcomes evident amongst different regions (P = 0.0004). This study demonstrates a comparable Australian PD and OG POMR when correlated with international studies. National PD POMR improved throughout the study with consistent improvement across the states and territories. This study does, however, show variation in PD POMR between states and territories. Potential intra-state variation merits further investigation.

Background The Western Australian Audit of Surgical Mortality was established in 2002. A 10-year analysis suggested it was the primary driver in the subsequent fall in surgeon-related mortality. Between 2004 and 2010 the Royal Australasian College of Surgeons established mortality audits in other states. The aim of this study was to examine national data from the Australian Institute of Health and Welfare (AIHW) to determine if a similar fall in mortality was observed across Australia. Method The AIHW collects procedure and outcome data for all surgical admissions. AIHW data from 2005/2006 to 2012/2013 was used to assess changes in surgical mortality. Results Over the 8 years surgical admissions increased by 23%, while mortality fell by 18% and the mortality per admission fell by 33% (P < 0.0001). A similar decrease was seen in all regions. The mortality reduction was overwhelmingly observed in elderly patients admitted as an emergency. Conclusion The commencement of this nation-wide mortality audit was associated with a sharp decline in perioperative mortality. In the absence of any influences from other changes in clinical governance or new quality programmes it is probable it had a causal effect. The reduced mortality was most evident in high-risk patients. This study adds to the evidence that national audits are associated with improved outcomes.

The authors are grateful to EPSRC and Glaxo-Wellcome (now GSK) for their support of this work through a CASE Studentship to TM. Pyrolysis, either neat or in diphenyl ether solution, results in the conversion of both 4-triphenylphosphoranylidenetetrahydrofuran-2,3,5-trione and 4-triphenylphosphoranylidenetetrahydrothio-phene-2,3,5-trione into 3,5-bis(triphenylphosphoranylidene)cyclopentane-1,2,4-trione. These reactions involve extrusion of CO2 or COS to give 3-triphenylphosphoranylidenecyclopropane-1,2-dione which further loses CO to give triphenylphosphoranylideneketene. The precise way in which these two reactive phosphorus compounds combine to give the observed product has been examined by chemical and isotopic labelling studies. Cyclotrimerization of triphenylphosphoranylideneketene upon thermolysis in diphenyl ether has also been observed for the first time. The erroneous literature interpretation of the 13C NMR spectrum for triphenylphosphoranylideneketene is corrected. Publisher PDF

This work was supported by B.P. Flash vacuum pyrolysis at 600 °C through glass wool coated with freshly sublimed magnesium is examined as a preparative method for dehalogenative coupling in organic synthesis. Substituted benzylidene chlorides give predominantly the corresponding stilbenes and in some cases these are readily isolated in pure form. With an ortho-halogen substituent, additional cyclisation gives phenanthrenes but the method is not compatible with the presence of several reactive groups. An ortho-methoxy substituent leads to unexpected formation of mono- and dimethyl products. With 1,4-bis(dihalomethyl)benzenes, halogenated polymers are deposited directly from the gas phase via generation of halogenated p-xylylenes. The 1,2- and 1,3-isomers lead respectively to benzocyclobutadiene, isolated as a dimer, and to pyrene. The 1,4-bis(trihalomethyl)benzenes give more highly halogenated polymers directly from the gas phase via halogenated p-xylylenes. While halobenzenes generally give the corresponding benzenes and biphenyls, 1,2-dihalobenzenes additionally produce triphenylene in preparatively useful yield by a process not involving intermediacy of free benzyne. Postprint

Lipid peroxidation products, such as 4-hydroxynonenal (4HNE), are causative agents responsible for extensive protein damage within the male and female germlines. Recently, we have demonstrated that 4HNE production can initiate the proteolytic degradation of the molecular chaperone Heat Shock Protein A2 (HSPA2) in male germ cells. These events may be partially responsible for HSPA2 deficiency in the spermatozoa of patients that repeatedly fail in vitro fertilization. Given this, mechanisms that limit the production of 4HNE will be highly advantageous for the preservation of male fertility. The propagation of 4HNE in somatic cells has been linked to the enzymatic actions of arachidonate 15-lipoxygenase (ALOX15), a member of the lipoxygenase family of proteins. In view of this association, this study sought to explore ALOX15 as a physiological target to manipulate the levels of 4HNE produced in the male germline. Herein, we have demonstrated that ALOX15 is markedly upregulated in response to oxidative stress in round spermatids and the GC-2 cell line. Pharmacological inhibition of ALOX15 in GC-2 cells resulted in a significant reduction in both mitochondrial and cytoplasmic reactive oxygen species, as well as a dramatic reduction in 4HNE. Importantly, the reduced bioavailability of this aldehyde appears to confer positive downstream effects to its target proteins such that HSPA2 could be protected from damage by 4HNE. Taken together, these results suggest that the actions of ALOX15 are intimately tied to the production of 4HNE. Thus, the ALOX15 protein may be a promising new target for the mitigation of germline oxidative stress.

Artificially generated radiofrequency-electromagnetic energy (RF-EME) is now ubiquitous in our environment owing to the utilization of mobile phone and Wi-Fi based communication devices. While several studies have revealed that RF-EME is capable of eliciting biological stress, particularly in the context of the male reproductive system, the mechanistic basis of this biophysical interaction remains largely unresolved. To extend these studies, here we exposed unrestrained male mice to RF-EME generated via a dedicated waveguide (905 MHz, 2.2 W/kg) for 12 h per day for a period of 1, 3 or 5 weeks. The testes of exposed mice exhibited no evidence of gross histological change or elevated stress, irrespective of the RF-EME exposure regimen. By contrast, 5 weeks of RF-EME exposure adversely impacted the vitality and motility profiles of mature epididymal spermatozoa. These spermatozoa also experienced increased mitochondrial generation of reactive oxygen species after 1 week of exposure, with elevated DNA oxidation and fragmentation across all exposure periods. Notwithstanding these lesions, RF-EME exposure did not impair the fertilization competence of spermatozoa nor their ability to support early embryonic development. This study supports the utility of male germ cells as sensitive tools with which to assess the biological impacts of whole-body RF-EME exposure.

Background The sperm protein IZUMO1 (Izumo sperm-egg fusion 1) and its recently identified binding partner on the oolemma, IZUMO1R, are among the first ligand-receptor pairs shown to be essential for gamete recognition and adhesion. However, the IZUMO1-IZUMO1R interaction does not appear to be directly responsible for promoting the fusion of the gamete membranes, suggesting that this critical phase of the fertilization cascade requires the concerted action of alternative fusogenic machinery. It has therefore been proposed that IZUMO1 may play a secondary role in the organization and/or stabilization of higher-order heteromeric complexes in spermatozoa that are required for membrane fusion. Results Here, we show that fertilization-competent (acrosome reacted) mouse spermatozoa harbor several high molecular weight protein complexes, a subset of which are readily able to adhere to solubilized oolemmal proteins. At least two of these complexes contain IZUMO1 in partnership with GLI pathogenesis-related 1 like 1 (GLIPR1L1). This interaction is associated with lipid rafts and is dynamically remodeled upon the induction of acrosomal exocytosis in preparation for sperm adhesion to the oolemma. Accordingly, the selective ablation of GLIPR1L1 leads to compromised sperm function characterized by a reduced ability to undergo the acrosome reaction and a failure of IZUMO1 redistribution. Conclusions Collectively, this study characterizes multimeric protein complexes on the sperm surface and identifies GLIPRL1L1 as a physiologically relevant regulator of IZUMO1 function and the fertilization process.

Due to its particular "silent" metabolic state, without transcription or translation, and a low level of cytosolic protective activities, mature sperm is a cellular type of aerobic organisms particularly at risk of oxidative damage. Despite the efforts of the male genital tract to treat this problem, a subcellular compartment of the sperm, the nucleus, and consequently, the paternal DNA cannot be effectively protected. There is an accumulation of evidence that oxidative damage to sperm DNA is quite common in male infertilities/subfertilities with potential harmful impacts on reproductive success, including the transgenerational inheritance of a paternal chromosomal lot carrying mutations.

More than 1000 genes are predicted to be predominantly expressed in mouse testis, yet many of them remain unstudied in terms of their roles in spermatogenesis and sperm function and their essentiality in male reproduction. Since individually indispensable factors can provide important implications for the diagnosis of genetically related idiopathic male infertility and may serve as candidate targets for the development of nonhormonal male contraceptives, our laboratories continuously analyze the functions of testis-enriched genes in vivo by generating knockout mouse lines using the CRISPR/Cas9 system. The dispensability of genes in male reproduction is easily determined by examining the fecundity of knockout males. During our large-scale screening of essential factors, we knocked out 30 genes that have a strong bias of expression in the testis and are mostly conserved in mammalian species including human. Fertility tests reveal that the mutant males exhibited normal fecundity, suggesting these genes are individually dispensable for male reproduction. Since such functionally redundant genes are of diminished biological and clinical significance, we believe that it is crucial to disseminate this list of genes, along with their phenotypic information, to the scientific community to avoid unnecessary expenditure of time and research funds and duplication of efforts by other laboratories., Thirty testis-enriched genes are dispensable for male fertility based on phenotypic analyses of knockout mice produced by the CRISPR/Cas9 system.

Authors thank the Engineering and Physical Sciences Research Council and CRITICAT Centre for Doctoral Training for financial support [Grant code: EP/L016419/1]. Gas-phase reaction of 1,3-dithiolane-2-thione over molybdenum trioxide supported on pumice stone results in efficient conversion into 1,3-dithiolan-2-one. The solid reagent is regenerated on exposure to air and thus acts as a catalyst for the overall conversion of the thione and oxygen from the air into the ketone and sulfur dioxide. The process can be carried out under either dynamic vacuum or atmospheric pressure flow conditions and using a solid reagent prepared either by physical mixing of MoO3 with the support or by solution impregnation, with an isolated yield of up to 67% obtained. Publisher PDF

The chemistry of the known thieno[b]pyrrolones and dihydrothieno[b]pyrrolones, as well as ring-fused analogs, is reviewed up to the end of 2018 with 200 literature references. For each system, the properties, reactivity, synthesis, and applications are systematically covered.

The recent developments in the synthesis of cyclic imides since 2000 are reviewed with an emphasis on high-yielding general methods. The synthetic approaches are divided into fragment-based methods, oxidation of pyrrolidines and lactams, ring expansion and ring contraction, and N- and C-functionalization of imides. Each section is further subdivided according to the details of the methods used and detailed conditions and yields are given for each with a total of 106 literature references.