TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

Correction: TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

[This corrects the article DOI: 10.1371/journal.pbio.3002028.].

TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.

Meeting Report on the 3rd Chinese American Society for Mass Spectrometry Conference-Advancing Biological and Pharmaceutical Mass Spectrometry.

Following the highly successful Chinese American Society for Mass Spectrometry (CASMS) conferences in the previous 2 years, the 3rd CASMS Conference was held virtually on August 28-31, 2023, using the Gather.Town platform to bring together scientists in the MS field. The conference offered a 4-day agenda with a scientific program consisting of two plenary lectures, and 14 parallel symposia in which a total of 70 speakers presented technological innovations and their applications in proteomics and biological MS and metabo-lipidomics and pharmaceutical MS. In addition, 16 invited speakers/panelists presented at two research-focused and three career development workshops. Moreover, 86 posters, 12 lightning talks, 3 sponsored workshops, and 11 exhibitions were presented, from which 9 poster awards and 2 lightning talk awards were selected. Furthermore, the conference featured four young investigator awardees to highlight early-career achievements in MS from our society. The conference provided a unique scientific platform for young scientists (i.e. graduate students, postdocs, and junior faculty/investigators) to present their research, meet with prominent scientists, learn about career development, and job opportunities (http://casms.org).

Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma.

Immune checkpoint inhibitors and adoptive lymphocyte transfer-based therapies have shown great therapeutic potential in cancers with high tumor mutational burden (TMB), such as melanoma, but not in cancers with low TMB, such as mutant epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma. Precision immunotherapy is an unmet need for most cancers, particularly for cancers that respond inadequately to immune checkpoint inhibitors. Here, we employed large-scale MS-based proteogenomic profiling to identify potential immunogenic human leukocyte antigen (HLA) class I-presented peptides in melanoma and EGFR-mutant lung adenocarcinoma. Similar numbers of peptides were identified from both tumor types. Cell line and patient-specific databases (DBs) were constructed using variants identified from whole-exome sequencing. A de novo search algorithm was used to interrogate the HLA class I immunopeptidome MS data. We identified 12 variant peptides and several classes of tumor-associated antigen-derived peptides. We constructed a cancer germ line (CG) antigen DB with 285 antigens. This allowed us to identify 40 class I-presented CG antigen-derived peptides. The class I immunopeptidome comprised more than 1000 post-translationally modified (PTM) peptides representing 58 different PTMs, underscoring the critical role PTMs may play in HLA binding. Finally, leveraging de novo search algorithm and an annotated long noncoding RNA (lncRNA) DB, we developed a novel lncRNA-encoded peptide discovery pipeline to identify 44 lncRNA-derived peptides that are presented by class I. We validated tandem MS spectra of select variant, CG antigen, and lncRNA-derived peptides using synthetic peptides and performed HLA class I-binding assays to demonstrate binding to class I proteins. In summary, we provide direct evidence of HLA class I presentation of a large number of variant and tumor-associated peptides in both low and high TMB cancer. These results can potentially be useful for precision immunotherapies, such as vaccine or adoptive cell therapies in melanoma and EGFR-mutant lung cancers.

Anaemia prevalence and risk factors among children aged 6 to 23 months in rural China.

INTRODUCTION: Anaemia is a global public health problem among children. However, few studies have examined anaemia prevalence and risk factors among Chinese children of different ages, particularly in poor rural areas. This study investigated these two aspects among children aged 6 to 23 months in poor rural areas of China. METHODS: This cross-sectional study included 1132 children aged 6 to 23 months in three prefectures of the Qinba Mountains area. A finger prick blood test for haemoglobin and anaemia was conducted, along with household surveys of socio-demographic characteristics, illness characteristics, and feeding practices. Multiple linear and logistic regression analyses were used to determine predictors of anaemia. RESULTS: Overall, 42.6% of children in the study displayed anaemia. Children aged 6 to 11 months had the highest anaemia prevalence (53.6%). Anaemia risk factors differed among age-groups and throughout the overall sample. Bivariate and multivariable regression results showed that continued breastfeeding, any history of formula feeding, and consumption of iron-rich or iron-fortified foods were prominent risk factors for anaemia. However, continued breastfeeding and any history of formula feeding had the greatest impact across age-groups (both P<0.05). CONCLUSION: Anaemia remains a severe public health problem among children aged 6 to 23 months in rural China. Healthy feeding practices, nutritional health knowledge, and nutrition improvement projects are needed to reduce the burden of anaemia among children in rural areas of China.

Unnecessary caesarean section delivery in rural China: exploration of relationships with full-term gestational age and early childhood development.

INTRODUCTION: Gestational age at delivery is reportedly associated with cognitive and non-cognitive development in early childhood. Delivery at an earlier full-term gestational age has been associated with an increased rate of caesarean section (C-section) delivery; the high rate of C-section delivery in China implies that the rate of medically unnecessary C-section delivery is also high. This study investigated the relationships of medically unnecessary C-section delivery with full-term gestational age and early childhood development in rural China. METHODS: We conducted a survey of 2765 children (aged 5-24 months) who resided in 22 national designated poverty counties. Primary caregivers were interviewed to collect information regarding child and household characteristics (including the child's gestational age), each child's delivery method, and reasons for C-section delivery (if applicable). The children were assessed using the Bayley Scales of Infant Development. Developmental outcomes were compared among gestational age-groups; regression analyses were used to assess relationships among medically unnecessary C-section delivery, gestational age, and developmental outcomes. RESULTS: Overall, 56.2% of children were born at ≤39 weeks of gestation. Among C-section deliveries, 13.1% were medically necessary and >40% could clearly be classified as medically unnecessary. Repeat C-section was the most common reason given for medically unnecessary C-section delivery. For each 1-week increase in full-term gestational age, cognition scale scores increased by 0.62 points (P<0.01), language scale scores increased by 0.84 points (P<0.01), and motor scale scores increased by 0.55 points (P<0.05). Medically unnecessary Csection delivery was significantly associated with lower full-term gestational age. CONCLUSION: Higher full-term gestational age was significantly associated with better childhood developmental outcomes, indicating that medically unnecessary C-section delivery may negatively influence early childhood development.

[Application of liver venous deprivation in secondary hepatic resection of primary liver cancer].

Objective: To investigate the efficacy and safety of liver venous deprivation (LVD) before secondary resection of primary liver cancer. Methods: 56 patients with advanced primary liver cancer who were not suitable for primary resection in Liver Surgery Department of Xinxiang Central Hospital from January 2018 to January 2019 were analyzed retrospectively. They were divided into liver vein deprivation group (LVD group: LVD+ PVE, n=26) and portal vein embolization group (PVE group, n=30). The dynamic changes of liver reserve function and future liver remnant volume (FLR-V), R0 resection rate, surgical complications, postoperative recurrence rate and overall survival rate of two groups before and after LVD/PVE were compared. Results: The success rate of puncture and embolization in LVD group and PVE group was 100%. There were no grade Ⅳ complications, and there was no significant difference of grades Ⅰ, Ⅱ and Ⅲ complications between the groups (P=0.808). The FLR-V of LVD group before embolization, 7, 14 and 21 days after embolization was (493.1±25.8), (673.2±56.1), (779.5±81.6) and (853.3±85.2) cm(3), respectively. The FLR-V of PVE group before embolization, 7, 14 and 21 days after embolization were (502.4±20.1), (688.6±43.9), (656.8±73.7) and (563.5±69.1) cm(3), respectively. There was no significant difference in FLR-V between the two groups before and 7 days after embolization (P>0.05). The FLR-V of LVD group was higher than that of PVE group at 14 and 21 days after embolization (P<0.01). The preparation time of LVD group was (20.4±6.3) days, which was shorter than that of PVE group [(31.5±8.8) days, P=0.045]. The rate of secondary hepatectomy was 92.3% (24/26), which was higher than that of PVE group [70.0% (21/30), P=0.036]. The R0 resection rate was 87.5% (21/24), which was higher than that of the PVE group [57.1% (12/21), P=0.022]. However, there were no significant differences in surgical methods, operation time, intraoperative blood loss, Clavien-Dindo complication grade and length of hospital stay between the two groups (P>0.05). After hepatectomy, the median recurrence time and median survival time of LVD group were 12.6 months and 21.3 months, respectively, which were longer than those of PVE group (9.4 months and 13.5 months, respectively, P<0.01). Conclusions: For patients with advanced liver cancer who are not suitable for primary hepatectomy, preoperative LVD can significantly increase FLR-V, improve the resection rate of secondary surgery, shorten the preparation time of two operations, and do not increase surgical complications. Moreover, patients with LVD can improve the R0 resection rate of secondary surgery. The postoperative recurrence time and overall survival rate of patients with LVD are better than those of patients with PVE, and LVD has a good long-term effect.

[Overexpression of NAT10 induced platinum drugs resistance in breast cancer cell].

Objective: To observe the platinum drugs resistance effect of N-acetyltransferase 10 (NAT10) overexpression in breast cancer cell line and elucidate the underlining mechanisms. Methods: The experiment was divided into wild-type (MCF-7 wild-type cells without any treatment) group, NAT10 overexpression group (H-NAT10 plasmid transfected into MCF-7 cells) and NAT10 knockdown group (SH-NAT10 plasmid transfected into MCF-7 cells). The invasion was detected by Transwell array, the interaction between NAT10 and PARP1 was detected by co-immunoprecipitation. The impact of NAT10 overexpression or knockdown on the acetylation level of PARP1 and its half-life was also determined. Immunostaining and IP array were used to detect the recruitment of DNA damage repair protein by acetylated PARP1. Flow cytometry was used to detect the cell apoptosis. Results: Transwell invasion assay showed that the number of cell invasion was 483.00±46.90 in the NAT10 overexpression group, 469.00±40.50 in the NAT10 knockdown group, and 445.00±35.50 in the MCF-7 wild-type cells, and the differences were not statistically significant (P>0.05). In the presence of 10 µmol/L oxaliplatin, the number of cell invasion was 502.00±45.60 in the NAT10 overexpression group and 105.00±20.50 in the NAT10 knockdown group, both statistically significant (P<0.05) compared with 219.00±31.50 in wild-type cells. In the presence of 10 µmol/L oxaliplatin, NAT10 overexpression enhanced the binding of PARP1 to NAT10 compared with wild-type cells, whereas the use of the NAT10 inhibitor Remodelin inhibited the mutual binding of the two. Overexpression of NAT10 induced PARP1 acetylation followed by increased PARP1 binding to XRCC1, and knockdown of NAT10 expression reduced PARP1 binding to XRCC1. Overexpression of NAT10 enhanced PARP1 binding to LIG3, while knockdown of NAT10 expression decreased PARP1 binding to LIG3. In 10 µmol/L oxaliplatin-treated cells, the γH2AX expression level was 0.38±0.02 in NAT10 overexpressing cells and 1.36±0.15 in NAT10 knockdown cells, both statistically significant (P<0.05) compared with 1.00±0.00 in wild-type cells. In 10 µmol/L oxaliplatin treated cells, the apoptosis rate was (6.54±0.68)% in the NAT10 overexpression group and (12.98±2.54)% in the NAT10 knockdown group, both of which were statistically significant (P<0.05) compared with (9.67±0.37)% in wild-type cells. Conclusion: NAT10 overexpression enhances the binding of NAT10 to PARP1 and promotes the acetylation of PARP1, which in turn prolongs the half-life of PARP1, thus enhancing PARP1 recruitment of DNA damage repair related proteins to the damage sites, promoting DNA damage repair and ultimately the survival of breast cancer cells.

Molecular mechanisms underlying catalytic activity of delta 6 desaturase from Glossomastix chrysoplasta and Thalassiosira pseudonana.

Delta 6 desaturase (FADS2) is a critical bifunctional enzyme required for PUFA biosynthesis. In some organisms, FADS2s have high substrate specificity, whereas in others, they have high catalytic activity. Previously, we analyzed the molecular mechanisms underlying high FADS2 substrate specificity; in this study, we assessed those underlying the high catalytic activity of FADS2s from Glossomastix chrysoplasta and Thalassiosira pseudonana To understand the structural basis of this catalytic activity, GcFADS2 and TpFADS2 sequences were divided into nine sections, and a domain-swapping approach was applied to examine the role of each section in facilitating the catalytic activity of the overall protein. The results revealed two regions essential to this process: one that extends from the end of the fourth to the beginning of the fifth cytoplasmic transmembrane domain, and another that includes the C-terminal region that occurs after the sixth cytoplasmic transmembrane domain. Based on the domain-swapping analyses, the amino acid residues at ten sites were identified to differ between the GcFADS2 and TpFADS2 sequences, and therefore further analyzed by site-directed mutagenesis. T302V, S322A, Y375F, and M384S/M385 substitutions in TpFADS2 significantly affected FADS2 catalytic efficiency. This study offers a solid basis for in-depth understanding of catalytic efficiency of FADS2.

Precision determination of absolute neutron flux.

A technique for establishing the total neutron rate of a highly-collimated monochromatic cold neutron beam was demonstrated using an alpha-gamma counter. The method involves only the counting of measured rates and is independent of neutron cross sections, decay chain branching ratios, and neutron beam energy. For the measurement, a target of 10B-enriched boron carbide totally absorbed the neutrons in a monochromatic beam, and the rate of absorbed neutrons was determined by counting 478 keV gamma rays from neutron capture on 10B with calibrated high-purity germanium detectors. A second measurement based on Bragg diffraction from a perfect silicon crystal was performed to determine the mean de Broglie wavelength of the beam to a precision of 0.024%. With these measurements, the detection efficiency of a neutron monitor based on neutron absorption on 6Li was determined to an overall uncertainty of 0.058%. We discuss the principle of the alpha-gamma method and present details of how the measurement was performed including the systematic effects. We also describe how this method may be used for applications in neutron dosimetry and metrology, fundamental neutron physics, and neutron cross section measurements.

A randomized controlled trial of self-regulated modified constraint-induced movement therapy in sub-acute stroke patients.

BACKGROUND AND PURPOSE: Emerging research suggests the use of self-regulation (SR) for improving functional regain in patients post stroke. SR is proposed to produce an added effect to effective modified constraint-induced movement therapy (mCIMT). This study aimed to examine the effect of a self-regulated mCIMT programme (SR-mCIMT) for functional regain in patients with sub-acute stroke. METHODS: Eighty-six patients completed the trial: SR-mCIMT, n = 29; mCIMT, n = 31; or conventional functional rehabilitation, n = 26. All interventions were 2-week therapist-guided training. Outcome measurements, taken by a blinded assessor, examined arm function [Action Research Arm Test (ARAT), Fugl-Meyer Assessment (FMA)], daily task performance [Lawton Instrumental Activities of Daily Living Scale (Lawton IADL)] and self-perceived arm use in functional tasks [Motor Activity Log (MAL)]. RESULTS: Significant differences were found with the SR-mCIMT outperforming the other groups after the intervention (ARAT, P = 0.006; FMA, Lawton IADL and MAL, all Ps < 0.001). In terms of the carry-over effect, the SR-mCIMT group outperformed in the hand and coordination subscales of ARAT and FMA (P = 0.012-0.013) and the self-perceived quality of arm use (P = 0.002). CONCLUSION: A combination of SR and mCIMT could produce an added effect in functional regain in patients post stroke.

Safety and efficacy of multipolar pulmonary vein ablation catheter vs. irrigated radiofrequency ablation for paroxysmal atrial fibrillation: a randomized multicentre trial.

AIMS: The current challenge in atrial fibrillation (AF) treatment is to develop effective, efficient, and safe ablation strategies. This randomized controlled trial assesses the medium-term efficacy of duty-cycled radiofrequency ablation via the circular pulmonary vein ablation catheter (PVAC) vs. conventional electro-anatomically guided wide-area circumferential ablation (WACA). METHODS AND RESULTS: One hundred and eighty-eight patients (mean age 62 ± 12 years, 116 M : 72 F) with paroxysmal AF were prospectively randomized to PVAC or WACA strategies and sequentially followed for 12 months. The primary endpoint was freedom from symptomatic or documented >30 s AF off medications for 7 days at 12 months post-procedure. One hundred and eighty-three patients completed 12 m follow-up. Ninety-four patients underwent PVAC PV isolation with 372 of 376 pulmonary veins (PVs) successfully isolated and all PVs isolated in 92 WACA patients. Three WACA and no PVAC patients developed tamponade. Fifty-six percent of WACA and 60% of PVAC patients were free of AF at 12 months post-procedure (P = ns) with a significant attrition rate from 77 to 78%, respectively, at 6 months. The mean procedure (140 ± 43 vs. 167 ± 42 min, P<0.0001), fluoroscopy (35 ± 16 vs. 42 ± 20 min, P<0.05) times were significantly shorter for PVAC than for WACA. Two patients developed strokes within 72 h of the procedure in the PVAC group, one possibly related directly to PVAC ablation in a high-risk patient and none in the WACA group (P = ns). Two of the 47 patients in the PVAC group who underwent repeat ablation had sub-clinical mild PV stenoses of 25-50% and 1 WACA patient developed delayed severe PV stenosis requiring venoplasty. CONCLUSION: The pulmonary vein ablation catheter is equivalent in efficacy to WACA with reduced procedural and fluoroscopy times. However, there is a risk of thrombo-embolic and pulmonary stenosis complications which needs to be addressed and prospectively monitored. CLINICALTRIALSGOV IDENTIFIER: NCT00678340.

TDP-43 loss induces extensive cryptic polyadenylation in ALS/FTD.

Nuclear depletion and cytoplasmic aggregation of the RNA-binding protein TDP-43 is the hallmark of ALS, occurring in over 97% of cases. A key consequence of TDP-43 nuclear loss is the de-repression of cryptic exons. Whilst TDP-43 regulated cryptic splicing is increasingly well catalogued, cryptic alternative polyadenylation (APA) events, which define the 3' end of last exons, have been largely overlooked, especially when not associated with novel upstream splice junctions. We developed a novel bioinformatic approach to reliably identify distinct APA event types: alternative last exons (ALE), 3'UTR extensions (3'Ext) and intronic polyadenylation (IPA) events. We identified novel neuronal cryptic APA sites induced by TDP-43 loss of function by systematically applying our pipeline to a compendium of publicly available and in house datasets. We find that TDP-43 binding sites and target motifs are enriched at these cryptic events and that TDP-43 can have both repressive and enhancing action on APA. Importantly, all categories of cryptic APA can also be identified in ALS and FTD post mortem brain regions with TDP-43 proteinopathy underlining their potential disease relevance. RNA-seq and Ribo-seq analyses indicate that distinct cryptic APA categories have different downstream effects on transcript and translation. Intriguingly, cryptic 3'Exts occur in multiple transcription factors, such as ELK1, SIX3, and TLX1, and lead to an increase in wild-type protein levels and function. Finally, we show that an increase in RNA stability leading to a higher cytoplasmic localisation underlies these observations. In summary, we demonstrate that TDP-43 nuclear depletion induces a novel category of cryptic RNA processing events and we expand the palette of TDP-43 loss consequences by showing this can also lead to an increase in normal protein translation.

TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia.

Genetic variation at the transmembrane protein 106B gene (TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Improved determination of the neutron lifetime.

The most precise determination of the neutron lifetime using the beam method was completed in 2005 and reported a result of τ(n)=(886.3±1.2[stat]±3.2[syst]) s. The dominant uncertainties were attributed to the absolute determination of the fluence of the neutron beam (2.7 s). The fluence was measured with a neutron monitor that counted the neutron-induced charged particles from absorption in a thin, well-characterized 6Li deposit. The detection efficiency of the monitor was calculated from the areal density of the deposit, the detector solid angle, and the evaluated nuclear data file, ENDF/B-VI 6Li(n,t)4He thermal neutron cross section. In the current work, we measure the detection efficiency of the same monitor used in the neutron lifetime measurement with a second, totally absorbing neutron detector. This direct approach does not rely on the 6Li(n,t)4He cross section or any other nuclear data. The detection efficiency is consistent with the value used in 2005 but is measured with a precision of 0.057%, which represents a fivefold improvement in the uncertainty. We verify the temporal stability of the neutron monitor through ancillary measurements, allowing us to apply the measured neutron monitor efficiency to the lifetime result from the 2005 experiment. The updated lifetime is τ(n)=(887.7±1.2[stat]±1.9[syst]) s.

The short-chain fatty acid acetate coordinates with CD30 to modulate T-cell survival.

As an important substrate for cell metabolism, the short-chain fatty acid acetate emerges as a regulator of cell fate and function. However, its role in T-cell survival and its underlying mechanisms remain largely unknown. Here, we demonstrate that acetate modulates T-cell apoptosis via potentiation of α-tubulin acetylation. We further show that acetate treatment effectively increases the expression of the tumor necrosis factor receptor (TNFR) family member CD30 by enhancing its gene transcription. Moreover, CD30 physically associates with and stabilizes the deacetylase HDAC6, which deacetylates α-tubulin to decrease microtubule stability. Proteomic profiling of CD30 knockout (Cd30-/-) T-cells reveals elevated expression of anti-apoptotic BCL2 family proteins and thus promotes T-cell survival via a microtubule-Bcl-2 axis. Taken together, our results demonstrate that acetate is a regulator of T-cell survival by controlling levels of acetylated α-tubulin. This suggests that therapeutic manipulation of acetate metabolism may facilitate optimal T-cell responses in pathological conditions.

Variant biomarker discovery using mass spectrometry-based proteogenomics.

Genomic diversity plays critical roles in risk of disease pathogenesis and diagnosis. While genomic variants-including single nucleotide variants, frameshift variants, and mis-splicing isoforms-are commonly detected at the DNA or RNA level, their translated variant protein or polypeptide products are ultimately the functional units of the associated disease. These products are often released in biofluids and could be leveraged for clinical diagnosis and patient stratification. Recent emergence of integrated analysis of genomics with mass spectrometry-based proteomics for biomarker discovery, also known as proteogenomics, have significantly advanced the understanding disease risk variants, precise medicine, and biomarker discovery. In this review, we discuss variant proteins in the context of cancers and neurodegenerative diseases, outline current and emerging proteogenomic approaches for biomarker discovery, and provide a comprehensive proteogenomic strategy for detection of putative biomarker candidates in human biospecimens. This strategy can be implemented for proteogenomic studies in any field of enquiry. Our review timely addresses the need of biomarkers for aging related diseases.