Silver 2,4'-Bipyridine Coordination Polymer for the High-Capacity Trapping of Perrhenate, A Pertechnetate Surrogate.

Pertechnetate, the most stable form of the radionuclide 99Tc in aerobic aqueous systems, is a hazardous anion present in nuclear waste. Its high mobility in water makes the remediation of the anion challenging. In the past decade, significant effort has been placed into finding materials capable of adsorbing this species. Here, we present the synthesis and high-resolution crystal structure of the coordination polymer [Ag(2,4'-bipyridine)]NO3, which is capable of sequestering perrhenate─a pertechnetate surrogate─through anion exchange to form another new coordination polymer, [Ag(2,4'-bipyridine)]ReO4. Both the beginning and end structures were solved by single-crystal X-ray diffraction and the adsorption reaction was monitored through inductively coupled plasma-optical emission spectroscopy and UV-vis spectroscopy. The exchange reaction follows a pseudo-second-order mechanism and the maximum adsorption capacity is 764 mg ReO4/g [Ag(2,4'-bipyridine)]NO3, one of the highest recorded for a coordination polymer or metal-organic framework. A solvent-mediated recrystallization mechanism was determined by monitoring the ion-exchange reaction by scanning electron microscopy-energy-dispersive spectroscopy and powder X-ray diffraction.

Evaluation of epigenetic methylation biomarkers for the detection of colorectal cancer using droplet digital PCR.

Colorectal cancer (CRC) is the third most common cancer worldwide. Screening programs allow early diagnosis and have improved the clinical management of this disease. Aberrant DNA methylation is increasingly being explored as potential biomarkers for many types of cancers. In this study we investigate the methylation of ten target genes in 105 CRC and paired normal adjacent colonic tissue samples using a MethylLight droplet digital PCR (ML-ddPCR) assay. Receiver operator characteristic (ROC) curves were used to determine the diagnostic performance of all target genes individually and in combination. All 515 different combinations of genes showed significantly higher levels of methylation in CRC tissue. The combination of multiple target genes into a single test generally resulted in greater diagnostic accuracy when compared to single target genes. Our data confirms that ML-ddPCR is able to reliably detect significant differences in DNA methylation between CRC tissue and normal adjacent colonic tissue in a specific selection of target genes.

Selective Chromium(VI) Trapping by an Acetate-Releasing Coordination Polymer.

We report the high-capacity and selective uptake of Cr(VI) from water using the coordination polymer silver bipyridine acetate (SBA, [Ag(4,4'-bipy)][CH3CO2]·3H2O). Cr capture involves the release of acetate, and we have structurally characterized two of the product phases that form: silver bipyridine chromate (SBC, SLUG-56, [Ag(4,4'-bipy)][CrO4]0.5·3.5H2O) and silver bipyridine dichromate (SBDC, SLUG-57, [Ag(4,4'-bipy)][Cr2O7]0.5·H2O). SBA maintains a high Cr uptake capacity over a wide range of pH values (2-10), reaching a maximum of 143 mg Cr/g at pH 4. This Cr uptake capacity is one of the highest among coordination polymers. SBA offers the additional benefits of a one-step, room temperature, aqueous synthesis and its release of a non-toxic anion following Cr(VI) capture, acetate. Furthermore, SBA capture of Cr(VI) remains >97% in the presence of a 50-fold molar excess of sulfate, nitrate, or carbonate. We also investigated the Cr(VI) sequestration abilities of silver 1,2-bis(4-pyridyl)ethane nitrate (SEN, [Ag(4,4'-bpe)][NO3]) and structurally characterized the silver 1,2-bis(4-pyridyl)ethane chromate (SEC, SLUG-58, [Ag(4,4'-bpe)][CrO4]0.5) product. SEN was, however, a less effective Cr(VI) sequestering material than SBA.

A crystal-structural study of Pauling-Corey rippled sheets.

Following the seminal theoretical work on the pleated ß-sheet published by Pauling and Corey in 1951, the rippled ß-sheet was hypothesized by the same authors in 1953. In the pleated ß-sheet the interacting ß-strands have the same chirality, whereas in the rippled ß-sheet the interacting ß-strands are mirror-images. Unlike with the pleated ß-sheet that is now common textbook knowledge, the rippled ß-sheet has been much slower to evolve. Much of the experimental work on rippled sheets came from groups that study aggregating racemic peptide systems over the course of the past decade. This includes MAX1/DMAX hydrogels (Schneider), L/D-KFE8 aggregating systems (Nilsson), and racemic Amyloid ß mixtures (Raskatov). Whether a racemic peptide mixture is "ripple-genic" (i.e., whether it forms a rippled sheet) or "pleat-genic" (i.e., whether it forms a pleated sheet) is likely governed by a complex interplay of thermodynamic and kinetic effects. Structural insights into rippled sheets remain limited to only a very few studies that combined sparse experimental structural constraints with molecular modeling. Crystal structures of rippled sheets are needed so we can rationally design rippled sheet architectures. Here we report a high-resolution crystal structure, in which (l,l,l)-triphenylalanine and (d,d,d)-triphenylalanine form dimeric antiparallel rippled sheets, which pack into herringbone layer structures. The arrangements of the tripeptides and their mirror-images in the individual dimers were in excellent agreement with the theoretical predictions by Pauling and Corey. A subsequent mining of the PDB identified three orphaned rippled sheets among racemic protein crystal structures.

Utility of incorporating a gene-based lung cancer risk test on uptake and adherence in a community-based lung cancer screening pilot study.

Based on the results of randomized control trials, screening for lung cancer using computed tomography (CT) is now widely recommended. However, adherence to screening remains an issue outside the clinical trial setting. This study examines the utility of biomarker-based risk assessment on uptake and subsequent adherence in a community screening study. In a single arm pilot study, current or former smokers > 50 years old with 20 + pack year history were recruited following local advertising. One hundred and fifty seven participants volunteered to participate in the study that offered an optional gene-based lung cancer risk assessment followed by low-dose CT according to a standardised screening protocol. All 157 volunteers who attended visit 1 underwent the gene-based risk assessment comprising of a clinical questionnaire and buccal swab. Of this group, 154 subsequently attended for CT screening (98%) and were followed prospectively for a median of 2.7 years. A participant's adherence to screening was influenced by their baseline lung cancer risk category, with overall adherence in those with a positive scan being significantly greater in the "very high" risk group compared to "moderate" and "high" risk categories (71% vs 52%, Odds ratio = 2.27, 95% confidence interval of 1.02-5.05, P = 0.047). Those in the "moderate" risk group were not different to those in the "high" risk group (52% and 52%, P > 0.05). In this proof-of-concept study, personalised gene-based lung cancer risk assessment was well accepted, associated with a 98% uptake for screening and increased adherence for those in the highest risk group.

CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5' and 3' ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. METHODS: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. RESULTS: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. CONCLUSIONS: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

Paternal impacts on development: identification of genomic regions vulnerable to oxidative DNA damage in human spermatozoa.

STUDY QUESTION: Do all regions of the paternal genome within the gamete display equivalent vulnerability to oxidative DNA damage? SUMMARY ANSWER: Oxidative DNA damage is not randomly distributed in mature human spermatozoa but is instead targeted, with particular chromosomes being especially vulnerable to oxidative stress. WHAT IS KNOWN ALREADY: Oxidative DNA damage is frequently encountered in the spermatozoa of male infertility patients. Such lesions can influence the incidence of de novo mutations in children, yet it remains to be established whether all regions of the sperm genome display equivalent susceptibility to attack by reactive oxygen species. STUDY DESIGN, SIZE, DURATION: Human spermatozoa obtained from normozoospermic males (n = 8) were split into equivalent samples and subjected to either hydrogen peroxide (H2O2) treatment or vehicle controls before extraction of oxidized DNA using a modified DNA immunoprecipitation (MoDIP) protocol. Specific regions of the genome susceptible to oxidative damage were identified by next-generation sequencing and validated in the spermatozoa of normozoospermic males (n = 18) and in patients undergoing infertility evaluation (n = 14). PARTICIPANTS/MATERIALS, SETTING, METHODS: Human spermatozoa were obtained from normozoospermic males and divided into two identical samples prior to being incubated with either H2O2 (5 mm, 1 h) to elicit oxidative stress or an equal volume of vehicle (untreated controls). Alternatively, spermatozoa were obtained from fertility patients assessed as having high basal levels of oxidative stress within their spermatozoa. All semen samples were subjected to MoDIP to selectively isolate oxidized DNA, prior to sequencing of the resultant DNA fragments using a next-generation whole-genomic sequencing platform. Bioinformatic analysis was then employed to identify genomic regions vulnerable to oxidative damage, several of which were selected for real-time quantitative PCR (qPCR) validation. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately 9000 genomic regions, 150-1000 bp in size, were identified as highly vulnerable to oxidative damage in human spermatozoa. Specific chromosomes showed differential susceptibility to damage, with chromosome 15 being particularly sensitive to oxidative attack while the sex chromosomes were protected. Susceptible regions generally lay outside protamine- and histone-packaged domains. Furthermore, we confirmed that these susceptible genomic sites experienced a dramatic (2-15-fold) increase in their burden of oxidative DNA damage in patients undergoing infertility evaluation compared to normal healthy donors. LIMITATIONS, REASONS FOR CAUTION: The limited number of samples analysed in this study warrants external validation, as do the implications of our findings. Selection of male fertility patients was based on high basal levels of oxidative stress within their spermatozoa as opposed to specific sub-classes of male factor infertility. WIDER IMPLICATIONS OF THE FINDINGS: The identification of genomic regions susceptible to oxidation in the male germ line will be of value in focusing future analyses into the mutational load carried by children in response to paternal factors such as age, the treatment of male infertility using ART and paternal exposure to environmental toxicants. STUDY FUNDING/COMPETING INTEREST(S): Project support was provided by the University of Newcastle's (UoN) Priority Research Centre for Reproductive Science. M.J.X. was a recipient of a UoN International Postgraduate Research Scholarship. B.N. is the recipient of a National Health and Medical Research Council of Australia Senior Research Fellowship. Authors declare no conflict of interest.

A Cationic Silver Pyrazine Coordination Polymer with High Capacity Anion Uptake from Water.

We report the first example of linker modification for an N-donor Ag-based cationic material while maintaining and in some cases increasing the anion exchange capacity. Cationic silver(I) pyrazine nitrate selectively traps harmful oxo-anions from water such as permanganate, perrhenate and a variety of α,ω-alkanedicarboxylates. We chose these anions as initial examples of exchange for potential water purification. The host-guest interaction between the cationic layers of π-stacked silver pyrazine polymers and the incoming/outgoing interlamellar anions allows for the exchange. The exchange capacity over 24 h reached 435 and 818 mg/g for permanganate and perrhenate, respectively, a record for a crystalline metal-organic material and over five times the exchange capacity compared to commercial resin. The material also undergoes organic exchange as an analog for pharmaceutical waste, some of which have a carboxylate functionality at the neutral pH range typical of natural water sources. Both the as-synthesized and exchanged materials are characterized by a variety of analytical techniques.

Exchange Capability of Cationic Silver 4,4'-Bipyrdine Materials for Potential Water Remediation: Structure, Stability, and Anion Exchange Properties.

An in-depth study of the class of cationic materials [Ag(4,4'-bipy)+][X-] (where X- = CH3CO2-, NO3-, BF4-, ClO4-, and MnO4-) has led to key insights on the relationship between anion hydration energy, material structure, solubility, and stability. Since these materials show promise for their potential as water remediation tools, understanding their properties in detail is of significant importance. The structure of the starting and ending materials is the main driving force behind the resultant stability and solubility and can be successfully used to predict the ion exchange capabilities. The solubility trend was determined to be, from most soluble to least soluble, X- = CH3CO2- > NO3- ∼ BF4- > ClO4- > MnO4-. Kinetics and thermal stability also follow predictable trends but involve additional factors. For instance, the kinetics of NO3- to MnO4- exchange was much slower than expected based on that seen for NO3- to ClO4-. Powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the materials. Solubility was determined by inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis. Ion exchange was analyzed with ion chromatography (IC) and ultraviolet-visible spectroscopy (UV-vis), and thermal stability was determined with thermogravimetric analysis (TGA).

Low-level parental mosaicism in an apparent de novo case of Peutz-Jeghers syndrome.

We report the case of a female found to have mosaicism for mutation in the STK11 gene, with the mutant allele expressed in her gametes, evident by her affected offspring, and in her gastrointestinal tract demonstrated on an excised polyp analysed for diagnosis. Mosaicism for Peutz-Jeghers syndrome (PJS) has been reported in a small number of cases previously but a clinical presentation such as this has not previously been described. This finding of mosaicism was several years after initial investigations failed to identify the same STK11 mutation in this woman whose son was diagnosed with PJS at a young age. This case highlights the importance of considering mosaicism as an explanation for apparent de novo cases of PJS syndrome. It also has implications for genetic counselling, predictive testing and cancer screening.

Desulfurization of JP-8 jet fuel: challenges and adsorptive materials.

The desulfurization of JP-8 (Jet Propellant 8) fuel is of interest to the U.S. military because of its potential use as a fuel source for solid oxide fuel cells (SOFCs). SOFCs can be used to supply a steady stream of power during military silent watch missions. Adsorptive desulfurization is a promising alternative to hydrodesulfurization, which is unable to remove refractory sulfur compounds and achieve the ultra-low sulfur levels necessary to prevent poisoning of SOFCs. Adsorptive desulfurization could be a portable, on-site process performed on JP-8 stocks already in the field. Within the vast field of fuel processing/reformation, herein we focus on the current status of adsorptive desulfurization performed on JP-8 jet fuel. Currently, the best performing sorbents are those utilizing high surface area porous frameworks with pore sizes large enough to accommodate sulfur contaminants. Additionally, a variety of metals in ionic, metallic, and oxide form serve as promising active sites within these sorbents. Most reports focus on reformation technologies and sorbent materials for gas-phase desulfurization and hydrogen purification of low-sulfur content diesel or light fraction jet fuel. JP-8 is unique to the Army in terms of supply. This review will thus focus on ongoing efforts in the room temperature liquid desulfurization of JP-8 and its higher levels of impurities that are more complex and difficult to remove.

Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort.

OBJECTIVE: Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene-environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene-environment interactions that may explain additional risk variation. STUDY DESIGN: This was a case-control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. METHODS: The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. RESULTS: The models including environmental risk factors only had pseudo R2 values of 16.5-28.3% and AUC of 0.75-0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10-4-4.83 × 10-12) and increased the pseudo R2 by about 1-2% and AUC by 1-3%. None of the gene-environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. CONCLUSION: This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene-environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection.

New EPCAM founder deletion in Polish population.

It is well known that founder mutations associated with cancer risk have useful implications for molecular diagnostics. We report the presence of a founder mutation in EPCAM involved in the etiology of Lynch syndrome (LS). The mutation extends nearly 8.7 kb (c.858 + 2478_*4507del) and is shared by 8 Polish families. Family members suffered almost exclusively from colorectal cancer; however, pancreatic and gastric cancers were also apparent. Next to mutations c. 2041G>A in MLH1 gene and c.942+3A>T in MSH2, the deletion mutation encompassing EPCAM is one of the most common causative changes responsible for LS in Poland.

Anion exchange dynamics in the capture of perchlorate by a cationic Ag-based MOF.

We report a detailed study of the host-guest interaction for a cationic metal-organic framework that can reversibly capture perchlorate. The structural transformation and flexibility of silver 4,4'-bipyridine nitrate (SBN) upon formation of silver 4,4'-bipyridine perchlorate (SBP) was evaluated by monitoring the anion exchange dynamics using a combination of powder X-ray diffraction (PXRD) with multinuclear 13C, 15N and 109Ag solid-state NMR spectra at different time intervals of the anion exchange. The structural transformation from SBN to SBP is complete within 70 minutes and was determined to take place by a solvent-mediated process. This pathway is confirmed by the morphological changes of the two crystalline materials observed by SEM. This key understanding may lead to application of this material towards perchlorate capture.

Reversible, Selective Trapping of Perchlorate from Water in Record Capacity by a Cationic Metal-Organic Framework.

We report the capture of ppm-level aqueous perchlorate in record capacity and kinetics via the complete anion exchange of a cationic metal-organic framework. Ambient conditions were used for both the synthesis of silver 4,4'-bipyridine nitrate (SBN) and the exchange, forming silver 4,4'-bipyridine perchlorate (SBP). The exchange was complete within 90 min, and the capacity was 354 mg/g, representing 99% removal. These values are greater than current anion exchangers such as the resins Amberlite IRA-400 (249 mg/g), Purolite A530E (104 mg/g), and layered double hydroxides (28 mg/g). Moreover, unlike resins and layered double hydroxides, SBN is fully reusable and displays 96% regeneration to SBN in nitrate solution, with new crystal formation allowing the indefinite cycling for perchlorate. We show seven cycles as proof of concept. Perchlorate contamination of water represents a serious health threat because it is a thyroid endocrine disruptor. This noncomplexing anionic pollutant is significantly mobile and environmentally persistent. Removal of other anionic pollutants from water such as chromate, pertechnetate, or arsenate may be possible by this methodology.

Erbium hydroxide ethanedisulfonate: a cationic layered material with organic anion exchange capability.

We describe a cationic erbium-based material [Er12(OH)29(H2O)5][O3SCH2CH2SO3]3.5·5H2O. As synthesized, the material is water stable and capable of complete organic anion exchange for a variety of α,ω-alkanedicarboxylates. We chose these anions as initial examples of exchange and as an analog for pharmaceutical waste, some of which have a carboxylate functionality at neutral pH range. Free-floating and partially anchored organosulfonate anions reside between the cationic corrugated layers and allow for exchange. The structure also displays a reversible hydration event above 100 °C. Both the as-synthesized and the exchanged materials are characterized by a variety of analytical techniques.

Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort.

AIMS: To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. METHODS: We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. RESULTS: After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. CONCLUSION: This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations.

Cumulative effects of genetic markers and the detection of advanced colorectal neoplasias by population screening.

Genetic markers associated with colorectal cancer may be used in population screening for the early identification of patients at elevated risk of disease. We genotyped 3059 individuals with no cancer family history for eight markers previously associated with colorectal cancer. After colonoscopy, the genetic profile of cases with advanced colorectal neoplasia (213) was compared with the rest (2846). rs2066847 and rs6983267 were significantly associated with the risk of advanced colorectal neoplasia but with limited effect on their own [odds ratio (OR) 1.59; 95% confidence interval (CI) 1.02-2.41; p = 0.033 and OR 1.45; 95% CI 1.02-2.12; p = 0.044, respectively]. Cumulative effects, in contrast, were associated with high risk: the combination of rs2066847, rs6983267, rs4779584, rs3802842 and rs4939827 minimized the number of markers considered, while maximizing the relative size of the carrier group and the risk associated to it, for example, for at least two cumulated risk markers, OR is 2.57 (95% CI 1.50-4.71; corrected p-value 0.0079) and for three or more, OR is 3.57 (95% CI 1.91-6.96; corrected p-value 0.00074). The identification of cumulative models of - otherwise - low-risk markers could be valuable in defining risk groups, within an otherwise low-risk population (no cancer family history).