System modelling is important for studying the motion laws of dynamical systems. Parameters of the system models can be estimated through identification methods from measurement data. This paper develops a gradient-based and a least-squares-based iterative estimation algorithms to estimate the parameters for a multi-input multi-output (MIMO) system with coloured auto-regressive moving average (ARMA) noise from input-output data, based on the gradient search and least-squares principles, respectively. The key is to replace the unknown noise terms and residuals contained in the information vector with their corresponding estimates at the previous iteration. The simulation test results indicate that the proposed algorithms are effective.

Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping.

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The circadian-related hormones, melatonin and cortisol, have oncostatic and immunosuppressive properties. This study examined the relationship between these two biomarkers and the presence of prostate cancer. We measured their major metabolites in urine collected from 120 newly diagnosed prostate cancer patients and 240 age-matched controls from January 2011 to April 2014. Compared with patients with lower urinary melatonin-sulfate or melatonin-sulfate/cortisol (MT/C) ratio levels, those with above-median levels were significantly less likely to have prostate cancer (adjusted OR (aOR) = 0.59, 95% CI = 0.35–0.99; aOR = 0.46, 95% CI: 0.27–0.77) or advanced stage prostate cancer (aOR = 0.49, 95% CI = 0.26–0.89; aOR = 0.33, 95% CI = 0.17–0.62). The combined effect of both low MT/C ratios and PSA levels exceeding 10 ng/ml was an 8.82-fold greater likelihood of prostate cancer and a 32.06-fold greater likelihood of advanced stage prostate cancer, compared to those with both high MT/C ratios and PSA levels less than 10 ng/ml. In conclusion, patients with high melatonin-sulfate levels or a high MT/C ratio were less likely to have prostate cancer or advanced stage prostate. Besides, a finding of a low MT/C ratio combined with a PSA level exceeding 10 ng/ml showed the greatest potential in detecting prostate cancer and advanced stage prostate cancer.

Mutations in the dystrophin (DMD) gene and consequent loss of dystrophin cause Duchenne muscular dystrophy (DMD). A promising therapy for DMD, single-exon skipping using antisense phosphorodiamidate morpholino oligomers (PMOs), currently confronts major issues that an antisense drug induces the production of functionally undefined dystrophin and may not be similarly efficacious among patients with different mutations. Accordingly, the applicability of this approach is limited to out-of-frame mutations. Here, using an exon-skipping efficiency predictive tool, we designed three different PMO-cocktail sets for exons 45-55 skipping aiming to produce a dystrophin form with preserved functionality as seen in milder/asymptomatic individuals with an in-frame exons 45-55 deletion. Of them, the most effective set was composed of select PMOs of which each efficiently skips an assigned exon in cell-based screening. Its combinational PMOs fitted to different deletions of immortalized DMD patient-muscle cells significantly induced exons 45-55-skipped transcripts with removing three, eight or ten exons and dystrophin restoration as represented by Western blotting. In vivo skipping of the maximum eleven human DMD exons was confirmed in humanized mice. The finding indicates that our PMO set can be used as mutation-tailored cocktails for exons 45-55 skipping and treat over 65% DMD patients carrying out-of-or in-frame deletions.

In addition to testosterone (T), the emerging role of sex hormone-binding globulin (SHBG) in pathogenesis of metabolic syndrome (MetS) has been noted recently. However, reports of associations with serum adipocytokine levels are still limited. Therefore, we conducted this study to evaluate whether serum T and SHBG levels are independent predictors for the risk of MetS that are associated with adiponectin and leptin levels in 614 Taiwanese men over 40 years old collected from a free health screening. Subjects in the lowest quartile of TT and SHBG levels are exposed to a 1.58 and 3.22 times risk of developing MetS, as compared to those in the highest quartile of TT and SHBG levels. However, SHBG retains its significance independent of TT as a MetS risk predictor, but not vice versa. In addition, SHBG was significantly correlated with both adiponectin and leptin levels even after adjusting for TT levels. In conclusion, SHBG served as a major predictor for the risk of MetS and was correlated with serum adiponectin and leptin levels that are independent of T. Further studies are needed to elucidate the true role of SHBG in the pathogenesis of MetS and possible mechanisms associated with serum adiponectin and leptin levels.

Occupational noise exposure is associated with cardiovascular disease, but little is known about the contributions of noise frequency components. This retrospective study investigated the relationship between exposure to different noise frequencies and the incidence of hypertension. A cohort of 1,002 volunteers from 4 machinery and equipment manufacturing companies in Taichung, Taiwan, was followed from 1973 to 2012. Personal noise measurements and environmental octave-band analyses were performed to divide subjects into different exposure groups. Cox regression models were used to estimate the relative risk of hypertension. Participants exposed to ≥80 A-weighted decibels (dBA) over 8 years had a higher relative risk of hypertension (relative risk = 1.38, 95% confidence interval: 1.02, 1.85) compared with those exposed to <75 dBA. Significant exposure-response patterns were observed between incident hypertension and stratum of noise exposure at frequencies of 250 Hz, 1 kHz, 2 kHz, 4 kHz, and 8 kHz. The strongest effect was found at 4 kHz; a 20-dBA increase in noise exposure at 4 kHz was associated with a 34% higher risk of hypertension (relative risk = 1.34, 95% confidence interval: 1.01, 1.77). Occupational noise exposure may be associated with an increased risk of hypertension, and the 4 kHz component of occupational noise exposure may have the strongest relationship with hypertension.

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