157 research outputs found
Ecological risk assessment of heavy metals in sediment and implications for sustainable management of Baiyangdian watershed in China
Stilling and its Aerodynamic Effects on Pan Evaporation
Declines in wind speed (u) (termed as âstillingâ) has been reported in many regions of the world. To explore the temporal trends of u and its aerodynamic effects is vital to understand the changes in water resources. This study analyzed the changes of temporal trends for u and its aerodynamic effects using the data during 1959-2000 at 266 stations across China. The improved PenPan model was used to estimate pan evaporation (Epan) and quantify the contribution of radiative and aerodynamic components (aerodynamic component separated into wind speed u, vapour pressure deficit D, and air temperature Ta). Climate factors include Epan measured with the standard Chinese 20 cm diameter pan, u, Ta, relative humidity (rh) and sunshine hours (sh). The results showed: stilling occurred in most of stations (206 among 266) and 105 stations presented significant decreasing trends at 99% confidence level; stilling was the main cause for controlling the trends in Epan in most part of China, especially in the west and north of China. The results indicated that decreasing trends in Epan due to stilling would inevitably alter water resources, and should be put further investigation incorporation other factors
Monensin causes dose dependent inhibition of Mycobacterium avium subspecies paratuberculosis in radiometric culture
<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium avium </it>subspecies <it>paratuberculosis </it>(MAP) causes a chronic wasting diarrheal disease in ruminants called Johne's disease, that is evocative of human inflammatory bowel disease (IBD). Agents used to treat IBD, called "anti-inflammatories", immuno-modulators" and "immuno-suppressants" inhibit MAP growth in culture. We concluded that, unknowingly, the medical profession has been treating MAP since sulfasalazine's introduction in 1942. Monensin, called a "Growth Enhancer" in cattle, ameliorates Johne's disease without a documented mechanism of action. We hypothesized that Monensin would inhibit MAP in culture.</p> <p>Methods</p> <p>Using the radiometric <sup>14</sup>CO<sub>2 </sub>Bactec<sup>Âź </sup>system, that expresses mycobacterial growth in arbitrary growth index (GI) units, we studied the effect of Monensin on the growth kinetic of MAP isolated from humans with IBD ("Dominic", "Ben" & UCF-4) and cattle with Johne's disease (303 & ATCC 19698.) Results are expressed as percent inhibition of cumulative GI (%âÎcGI).</p> <p>Results</p> <p>The positive control Clofazimine inhibits every strain tested. The negative controls Cycloheximide & Phthalimide, have no inhibition on any MAP strain. Monensin has dose dependent inhibition on every MAP strain tested. The most susceptible human isolate was UCF-4 (73% â ÎcGI at 1 ÎŒg/ml) and bovine isolate was 303 (73% â ÎcGI at 4 ÎŒg/ml.) Monensin additionally inhibits <it>M. avium </it>ATCC 25291 (87% â ÎcGI at 64 ÎŒg/ml) & BCG (92% â ÎcGI at 16 ÎŒg/ml).</p> <p>Discussion</p> <p>We show that in radiometric culture the "Growth Enhancer" Monensin causes dose dependent inhibition of mycobacteria including MAP. We posit that the "Growth Enhancer" effect of Monensin may, at least in part, be due to inhibition of MAP in clinical or sub-clinical Johne's disease.</p
PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.
p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes
The Janus Interface: How Fine-Tuning in Large Language Models Amplifies the Privacy Risks
The era post-2018 marked the advent of Large Language Models (LLMs), with
innovations such as OpenAI's ChatGPT showcasing prodigious linguistic prowess.
As the industry galloped toward augmenting model parameters and capitalizing on
vast swaths of human language data, security and privacy challenges also
emerged. Foremost among these is the potential inadvertent accrual of Personal
Identifiable Information (PII) during web-based data acquisition, posing risks
of unintended PII disclosure. While strategies like RLHF during training and
Catastrophic Forgetting have been marshaled to control the risk of privacy
infringements, recent advancements in LLMs, epitomized by OpenAI's fine-tuning
interface for GPT-3.5, have reignited concerns. One may ask: can the
fine-tuning of LLMs precipitate the leakage of personal information embedded
within training datasets? This paper reports the first endeavor to seek the
answer to the question, particularly our discovery of a new LLM exploitation
avenue, called the Janus attack. In the attack, one can construct a PII
association task, whereby an LLM is fine-tuned using a minuscule PII dataset,
to potentially reinstate and reveal concealed PIIs. Our findings indicate that,
with a trivial fine-tuning outlay, LLMs such as GPT-3.5 can transition from
being impermeable to PII extraction to a state where they divulge a substantial
proportion of concealed PII. This research, through its deep dive into the
Janus attack vector, underscores the imperative of navigating the intricate
interplay between LLM utility and privacy preservation
Novel Y-chromosomal microdeletions associated with non-obstructive azoospermia uncovered by high throughput sequencing of sequence-tagged sites (STSs)
Y-chromosomal microdeletion (YCM) serves as an important genetic factor in non-obstructive azoospermia (NOA). Multiplex polymerase chain reaction (PCR) is routinely used to detect YCMs by tracing sequence-tagged sites (STSs) in the Y chromosome. Here we introduce a novel methodology in which we sequence 1,787 (post-filtering) STSs distributed across the entire male-specific Y chromosome (MSY) in parallel to uncover known and novel YCMs. We validated this approach with 766 Chinese men with NOA and 683 ethnically matched healthy individuals and detected 481 and 98 STSs that were deleted in the NOA and control group, representing a substantial portion of novel YCMs which significantly influenced the functions of spermatogenic genes. The NOA patients tended to carry more and rarer deletions that were enriched in nearby intragenic regions. Haplogroup O2* was revealed to be a protective lineage for NOA, in which the enrichment of b1/b3 deletion in haplogroup C was also observed. In summary, our work provides a new high-resolution portrait of deletions in the Y chromosome.National Key Scientific Program of China [2011CB944303]; National Nature Science Foundation of China [31271244, 31471344]; Promotion Program for Shenzhen Key Laboratory [CXB201104220045A]; Shenzhen Project of Science and Technology [JCYJ20130402113131202, JCYJ20140415162543017]SCI(E)[email protected]; [email protected]; [email protected]
SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis
Smoking cessation prolongs survival and decreases mortality of patients with nonâsmallâcell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenomeâwide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a twoâstage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for earlyâstage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histologyâstratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rateâq †0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histologyâspecific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 Ă 10-7]. Further, the effect of smoking cessation on earlyâstage LUAD survival varied across patients with different methylation levels of cg02268510SIPA1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 Ă 10-3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 2.1835; 95% CI: 1.27-3.74; P = 4.46 Ă 10â3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylationâspecific drug targeting
On the Action of Methotrexate and 6-Mercaptopurine on M. avium Subspecies paratuberculosis
BACKGROUND: Clinical improvement in inflammatory bowel disease (IBD) treated with methotrexate and 6-mercaptopurine (6-MP) is associated with a decrease in pro-inflammatory cytokines. This has been presumed to indicate the mechanism of action of methotrexate and 6-MP. Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We hypothesized that the clinical efficacy of methotrexate and 6-MP in IBD may be to simply inhibit the growth of MAP. METHODOLOGY: The effect on MAP growth kinetics by methotrexate and 6-MP were evaluated in cell culture of two strains each of MAP and M. avium using a radiometric ((14)CO(2) BACTECÂź) detection system that quantifies mycobacterial growth as arbitrary âgrowth index unitsâ (GI). Efficacy data are presented as âpercent decrease in cumulative GIâ (% âÎcGI). PRINCIPAL FINDINGS: The positive control antibiotic (clarithromycin) has â„85% âÎcGI at a concentration of 0.5 ”g/ml. The negative control (ampicillin) has minimal inhibition at 64 ”g/ml. MAP ATCC 19698 shows â„80% âÎcGI for both agents by 4 ”g/ml. With the other three isolates, although more effective than ampicillin, 6-MP is consistently less effective than methotrexate. CONCLUSIONS: We show that methotrexate and 6-MP inhibit MAP growth in vitro. Each of the four isolates manifests different % âÎcGI. These data are compatible with the hypothesis that the clinical improvement in patients with IBD treated with methotrexate and 6-MP could be due to treating a MAP infection. The decrease in pro-inflammatory cytokines, thought to be the primary mechanism of action, may simply be a normal, secondary, physiological response. We conclude that henceforth, in clinical studies that evaluate the effect of anti-MAP agents in IBD, the use of methotrexate and 6-MP should be excluded from any control groups
On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat "inflammatory" bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC(R)) detection system that quantifies mycobacterial growth as arbitrary "growth index units" (GI). Efficacy data are presented as "percent decrease in cumulative GI" (%-DeltacGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%-DeltacGI at 64 microg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%-DeltacGI at 4 microg/ml) is as effective as methotrexate, our positive control (88%-DeltacGI at 4 microg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups
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