Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions.

SynTEF1, a prototype synthetic genome reader/regulator (SynGR), was designed to target GAA triplet repeats and restore the expression of frataxin (FXN) in Friedreich's ataxia patients. It achieves this complex task by recruiting BRD4, via a pan-BET ligand (JQ1), to the GAA repeats by using a sequence-selective DNA-binding polyamide. When bound to specific genomic loci in this way, JQ1 functions as a chemical prosthetic for acetyl-lysine residues that are natural targets of the two tandem bromodomains (BD1 and BD2) in bromo- and extra-terminal domain (BET) proteins. As next-generation BET ligands were disclosed, we tested a select set with improved physicochemical, pharmacological, and bromodomain-selective properties as substitutes for JQ1 in the SynGR design. Here, we report two unexpected findings: (1) SynGRs bearing pan-BET or BD2-selective ligands license transcription at the FXN locus, whereas those bearing BD1-selective ligands do not, and (2) rather than being neutral or inhibitory, an untethered BD1-selective ligand (GSK778) substantively enhances the activity of all active SynGRs. The failure of BD1-selective SynGRs to recruit BRD4/BET proteins suggests that rather than functioning as "epigenetic/chromatin mimics," active SynGRs mimic the functions of natural transcription factors in engaging BET proteins through BD2 binding. Moreover, the enhanced activity of SynGRs upon cotreatment with the BD1-selective ligand suggests that natural transcription factors compete for a limited pool of nonchromatin-bound BET proteins, and blocking BD1 directs pan-BET ligands to more effectively engage BD2. Taken together, SynGRs as chemical probes provide unique insights into the molecular recognition principles utilized by natural factors to precisely regulate gene expression, and they guide the design of more sophisticated synthetic gene regulators with greater therapeutic potential.

Ex vivo testing of air-cooled CW/modulated 30 W thulium fiber laser for lithotripsy.

A diode-pumped, air-cooled, all-fiber, quasi-continuous-wave thulium laser at an operating wavelength of 1.94 µm has been designed to study the performance of the laser parameter on the rate of fragmentation and its dependence on stone composition, fragmented particle size, as well as the retropulsion effect. The optimized laser cavity with an active fiber core/cladding diameter of 10/130 µm under a counter-propagating pump provides a stable laser power of 30 W at a slope efficiency of 50% and wall plug efficiency of 17%. The rate of fragmentation along with the retropulsion effect has been studied with human calcium oxalate monohydrate (COM) urinary stones (N=36) of different composition by using the designed laser and 200-µm-core low OH silica delivery fiber. The thulium fiber laser setting of 2.7 J pulse energy at the pulse rate of 10 Hz, pulse width of 90 ms, and peak power of 30 W is successful in breaking human COM stones in a controlled manner at a fragmentation rate of 0.8±0.4 mg/s, with almost uniform fragments of particle size less than 1.6 mm. During the stone fragmentation, the stone displacement (retropulsion effect) is less than 15 mm, even for the fragmented stone mass of 15±5 mg.

Rogue waves in a linear cavity Yb-fiber laser through spectral filtering induced pulse instability.

In this Letter, experimental observation of dissipative rogue waves (DRWs) due to spectral filtering induced pulse instabilities in a mode-locked ytterbium (Yb) fiber laser has been presented. A semiconductor saturable absorber mirror was used to mode-lock the linear cavity laser and a chirped fiber Bragg grating (CFBG) was used for dispersion management, which also acted as a spectral filter and output coupler. Under stable conditions, the cavity delivered dispersion managed dissipative solitons of 447 fs duration and 0.69 nJ pulse energy at 10.19 MHz repetition rate with uniform intensity distribution over a long time span. As the spectral width increased with pump power, random intensity fluctuations were observed in the pulse train due to the filtering effect of the CFBG. Employing a dispersive Fourier transform by stretching the output pulse train in time allowed the existence of DRWs more than 4 times stronger than the significant wave height to be observed. Further increments of pump power led to a stable multi-pulsing state.

Hybrid pumped gain-switched thulium fiber laser at a high repetition rate.

A gain-switched all-fiber thulium laser at 2 µm with high repetition rate has been demonstrated under a hybrid pumping scheme combined of a pulsed pump at 1.56 µm and CW pump at 793 nm. The in-band pulsed pump at 1.56 µm triggers the gain-switching pulses while the CW pump at 793 nm facilitates the energy storage. Therefore, the seed cavity delivers high energy pulses allowing the elimination of multistage amplification. Such hybrid pump configuration is effective for generating gain-switched pulses of high average power with better slope efficiency and pulse width of a few hundreds of a nanosecond. The optimized cavity under such hybrid pump configuration provides output power of 5.92 W from the gain-switched oscillator with slope efficiency of 60% and pulse width of 300 ns at a repetition rate of 344 kHz. Maximum pulse energy of 17.2 µJ and peak power of 53.9 W has been achieved at this repetition rate. Stable gain-switched pulses at reduced pump pulse energy have been achieved by the use of a CW pump at 793 nm. This novel pump configuration facilitates gain switch at higher repetition rates where enough pump pulse energy may not be available. The gain-switched laser also operates at 520 kHz and 1.3 MHz repetition rate by changing the 1.56 µm pulsed pump and cavity length.

Diverse mode of operation of an all-normal-dispersion mode-locked fiber laser employing two nonlinear loop mirrors.

In this paper, we propose an all-normal-dispersion ytterbium-fiber laser with a novel ring cavity architecture having two nonlinear amplifying loop mirrors (NALM) as saturable absorbers, capable of delivering distinctly different pulses with adjustable features. By optimizing the loop lengths of the individual NALMs, the cavity can be operated to deliver Q-switched mode-locked (Q-ML) pulse bunches with adjustable repetition rates, mode-locked pulses in dissipative soliton resonance (DSR) regime or noise-like pulse (NLP) regime with tunable pulse width. The DSR pulses exhibit characteristic narrowband spectrum, while the NLPs exhibit large broadband spectrum. The operation regime of the laser can be controlled by adjusting the amplifier pump powers and the polarization controllers. To the best of the authors' knowledge, this is the first demonstration of a single mode-locked cavity where narrowband DSR pulses and broadband NLPs alongside Q-ML pulse bunches can be selectively generated by employing two NALMs.

High repetition rate gain-switched 1.94 µm fiber laser pumped by 1.56 µm dissipative soliton resonance fiber laser.

A dissipative soliton resonance (DSR) mode-locked Er:Yb fiber laser has been used to pump a thulium fiber laser to generate gain-switched pulses at high repetition rates. Here 412 ns long DSR pulses with a center wavelength of around 1.56 µm at a repetition rate of 410 kHz have been fed to a thulium fiber laser, resulting in generation of gain-switched pulses at 1.94 µm. The minimum pulse width achieved was 256 ns with an average power of 4.6 W at 66% slope efficiency. Gain-switched pulses at 520 kHz and 750 kHz were generated through changing the pump pulse repetition rate by modifying the DSR cavity. To the best of our knowledge, this is the first demonstration of a high repetition rate gain-switched thulium fiber laser pumped by a DSR mode-locked fiber laser. As DSR pulses can be generated with high seed average power and energy independent of the operating wavelength regime as well as mode-locking technique, the proposed method can be applied to generate gain-switched pulses at high repetition rates and various wavelengths without the need of any optical or electrical modulators.

Critically Ill Obstetric Patients in a General Critical Care Unit: A 5 Years' Retrospective Study in a Public Teaching Hospital of Eastern India.

BACKGROUND: Critical care services are essential for the subset of obstetric patients suffering from severe maternal morbidity. Studies on obstetric critical care are important for benchmarking the issues which need to be addressed while managing critically ill obstetric patients. Although there are several published studies on obstetric critical care from India and abroad, studies from Eastern India are limited. The present study was conducted to fill in this lacuna and to audit the obstetric critical care admissions over a 5 years' period. SETTINGS AND DESIGN: Retrospective cohort study conducted in the general critical care unit (CCU) of a government teaching hospital. MATERIALS AND METHODS: The records of all obstetric patients managed in the CCU over a span of 5 years (January 2011-December 2015) were analyzed. RESULTS: During the study, 205 obstetric patients were admitted with a CCU admission rate of 2.1 per 1000 deliveries. Obstetric hemorrhage (34.64%) was the most common primary diagnosis among them followed by pregnancy-induced hypertension (26.83%). Severe hemorrhage leading to organ failure (40.48%) was the main direct indication of admission. Invasive ventilation was needed in 75.61% patients, and overall obstetric mortality rate was 33.66%. The median duration (in days) of invasive ventilation was 2 (interquartile range [IQR] 1-7), and the median length of CCU stay (in days) was 5 (IQR 3-9). CONCLUSIONS: Adequate number of critical care beds, a dedicated obstetric high dependency unit, and effective coordination between critical care and maternity services may prove helpful in high volume obstetric centers.

Mirtazapine Is Effective in Steroid Withdrawal Syndrome Related Depression: A Case Report

Steroid withdrawal syndrome (SWS) following steroid dependence is becoming a common clinical condition. It may be associated with body image disorder. Though selective serotonin reuptake inhibitors (SSRIs) are found to be effective SWS associated depression, data for this clinical condition is limited. We present a case of SWS associated with body image disorder which improved with mirtazapine. Mirtazapine might be better option than SSRIs in this subgroup of patients for its noradrenergic property and better gastrointestinal profile. More research should explore its efficacy in this clinical condition.

Airway accidents in critical care unit: A 3-year retrospective study in a Public Teaching Hospital of Eastern India.

BACKGROUND: Although tracheal tubes are essential devices to control and protect airway in a critical care unit (CCU), they are not free from complications. AIMS: To document the incidence and nature of airway accidents in the CCU of a government teaching hospital in Eastern India. METHODS: Retrospective analysis of all airway accidents in a 5-bedded (medical and surgical) CCU. The number, types, timing, and severity of airway accidents were analyzed. RESULTS: The total accident rate was 19 in 233 intubated and/or tracheostomized patients over 1657 tube days (TDs) during 3 years. Fourteen occurred in 232 endotracheally intubated patients over 1075 endotracheal tube (ETT) days, and five occurred in 44 tracheostomized patients over 580 tracheostomy TDs. Fifteen accidents were due to blocked tubes. Rest four were unplanned extubations (UEs), all being accidental extubations. All blockages occurred during night shifts and all UEs during day shifts. Five accidents were mild, the rest moderate. No major accident led to cardiorespiratory arrest or death. All blockages occurred after 7(th) day of intubation. The outcome of accidents were more favorable in tracheostomy group compared to ETT group (P = 0.001). CONCLUSIONS: The prevalence of airway accidents was 8.2 accidents per 100 patients. Blockages were the most common accidents followed by UEs. Ten out of the 15 blockages and all 4 UEs were in endotracheally intubated patients. Tracheostomized patients had 5 blockages and no UEs.