AAV-Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness.

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness.

Improved Glycaemic and Weight Management Are Associated with Better Quality of Life in People with Type 2 Diabetes Treated with Tirzepatide.

INTRODUCTION: Limited data are available on the relationship between quality of life (QoL) change and significant degrees of reduction in glycated haemoglobin (HbA1c) and/or weight loss in people with type 2 diabetes (T2D). We explored the associations between HbA1c targets and/or weight loss achieved and patient-reported outcomes (PROs) in adults with T2D treated with tirzepatide, a first-in-class once weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, using pooled data from SURPASS-1 to -5 Phase 3 clinical trials. METHODS: PROs were assessed using five instruments at baseline and endpoint (Week 40 in SURPASS-1, -2 and -5; Week 52 in SURPASS-3 and -4): Impact of Weight on Quality of Life-Lite Clinical Trials Version; Impact of Weight on Self-Perception (IW-SP) questionnaire; Ability to Perform Physical Activities of Daily Living (APPADL); Diabetes Treatment Satisfaction Questionnaire change; and EQ-5D-5L. All PROs were assessed in participants receiving pooled doses of tirzepatide (5, 10 or 15 mg) and achieving HbA1c targets of < 5.7%, ≥ 5.7-≤ 6.5% and > 6.5% or achieving ≥ 0-< 5%, ≥ 5-< 10%, ≥ 10-< 15% and ≥ 15% weight loss from baseline at endpoint. The APPADL, IW-SP and EQ visual analogue scores were evaluated in participants achieving each combination of HbA1c target and weight loss. RESULTS: Achievement of lower HbA1c targets or higher body weight percentage losses were each associated with greater improvements in QoL than achievement of higher HbA1c targets or lower body weight percentage losses, respectively. Achievement of lower HbA1c targets in combination with greater weight loss was generally associated with the best QoL ratings. CONCLUSIONS: Our findings demonstrate that HbA1c targets and significant percentage body weight reduction thresholds need to be achieved for people with T2D to help substantially increase their overall health-related QoL. Tirzepatide treatment may allow a high proportion of people with T2D to achieve these targets, enabling improved QoL. CLINICAL TRIAL REGISTRATION: SURPASS-1: NCT03954834; SURPASS-2: NCT03987919; SURPASS-3: NCT03882970; SURPASS-4: NCT03730662; SURPASS-5: NCT04039503.

Limited data exist about the relationship between quality of life (QoL) and changes in clinical measures, for example management of blood sugar levels and weight, in people with type 2 diabetes. We explored the associations between glucose and weight loss targets achieved and QoL outcomes reported by adults treated with tirzepatide, the first glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for the treatment of people with type 2 diabetes, using data from SURPASS-1 to -5 Phase 3 clinical trials.Five questionnaires, developed to evaluate patients' health-related QoL, were completed by patients at the beginning and end of the clinical trials, which was after 40 weeks for SURPASS-1, -2 and -5 and after 52 weeks for SURPASS-3 and -4, or when the person left the trial if this was before the official end. These questionnaires were: EQ-5D-5L (SURPASS-1 to -5); Impact of Weight on Self-Perception questionnaire (SURPASS-1 to -5); Ability to Perform Physical Activities of Daily Living (SURPASS-1 to -5); Diabetes Treatment Satisfaction Questionnaire change (SURPASS-2 to -5); and Impact of Weight on Quality of Life­Lite Clinical Trials Version (SURPASS-2 only).Overall, achievement of lower glucose targets or higher percentage of body weight losses were each associated with greater improvements in QoL. Achievement of lower glucose targets in combination with greater weight loss was generally associated with the highest health-related QoL ratings.Tirzepatide treatment may allow a high proportion of people with type 2 diabetes to achieve lower glucose levels and higher weight loss, enabling improved health-related QoL.

Atomically precise Ni6(SC2H4Ph)12 nanoclusters on graphitic carbon nitride nanosheets for boosting photocatalytic hydrogen evolution.

Much effort has been devoted to improving the photocatalytic capacity of graphitic carbon nitride (g-C3N4). In this paper, we reported the successful synthesis of a hybrid photocatalyst with superb photocatalytic hydrogen production activity through decorating atomically precise Ni6(SC2H4Ph)12 nanoclusters on g-C3N4 nanosheets (labeled as Ni6/g-C3N4) at room temperature. Zeta potential experiments demonstrated that the electrostatic interaction between Ni6 and g-C3N4 led to the formation of Ni6/g-C3N4. The photocatalytic measurements revealed that the 5 %-Ni6/g-C3N4 prepared with the original mass ratio of m(Ni6)/m(g-C3N4) = 1/20 exhibited the strongest hydrogen production activity. In the system with triethanolamine (TEOA) as the sacrifice agent, the visible-light hydrogen production rate reached up to 5.87 mmol h-1 g-1, approximately 290 times higher than that of pure g-C3N4 (0.02 mmol h-1 g-1). Density functional theory (DFT) calculations testified that the above significant enhancement of photocatalytic hydrogen evolution of the hybrid photocatalyst arose from the photogenerated electrons transfer from Ni6 to g-C3N4.

Detecting spatial chirp signals by Luneburg lens based transformation medium.

Gradient refractive index (GRIN) lens-based chirp signal chirpiness detection usually relies on the fractional Fourier transform (FRFT) functionality of a quadratic GRIN lens and is limited by paraxial conditions. In this paper, a non-FRFT mechanism-based chirpiness detection GRIN lens is proposed that converts the Luneburg lens' focus capacity of input plane waves to the designed lens' focusing of input chirp waves using transformation optics, and the source chirpiness can be obtained by sweeping the illumination wavelength rather than locating the focusing pulse, consequently greatly increasing the upper limit of the chirpiness detection range. The feasibility and robustness of the method are verified through numerical simulations.

Characterization of exploratory patterns and hippocampal-prefrontal network oscillations during the emergence of free exploration.

During free exploration, the emergence of patterned and sequential behavioral responses to an unknown environment reflects exploration traits and adaptation. However, the behavioral dynamics and neural substrates underlying the exploratory behavior remain poorly understood. We developed computational tools to quantify the exploratory behavior and performed in vivo electrophysiological recordings in a large arena in which mice made sequential excursions into unknown territory. Occupancy entropy was calculated to characterize the cumulative and moment-to-moment behavioral dynamics in explored and unexplored territories. Local field potential analysis revealed that the theta activity in the dorsal hippocampus (dHPC) was highly correlated with the occupancy entropy. Individual dHPC and prefrontal cortex (PFC) oscillatory activities could classify various aspects of free exploration. Initiation of exploration was accompanied by a coordinated decrease and increase in theta activity in PFC and dHPC, respectively. Our results indicate that dHPC and PFC work synergistically in shaping free exploration by modulating exploratory traits during emergence and visits to an unknown environment.

Relationship of adiponectin and leptin with autoimmunity in children with new-onset type 1 diabetes: a pilot study.

AIM: To explore racial differences in adiponectin, and leptin and their relationship with islet autoimmunity in children with new-onset type 1 diabetes (T1D). METHODS: Medical records were reviewed from a cohort of new-onset clinically diagnosed T1D subjects matched by race, age, gender, and year of diagnosis. Sera were available for 156 subjects (77 African American (AA), 79 Caucasian (C), 48% male, age of 11.1 ± 3.8 yr) and assayed for adiponectin and leptin prior to (D0), 3, 5 d, and 2-4 months (M3) after insulin therapy and islet autoantibodies to GAD, IA2, insulin, and ICA were measured at onset. RESULTS: Adiponectin levels increased significantly following insulin therapy by day 5 (D5) (D0: 13.7 ± 7.2 vs. D5: 21.3 ± 9.9 µg/mL, p < 0.0001), but no further significant increase from D5 to M3. At DO, AA had lower adiponectin levels (10.5 vs. 15.7 µg/mL, p = 0.01), were more often overweight than C (55 vs. 18%, BMI ≥ 85th‰) and fewer had positive autoantibodies (72 vs. 87%, p = 0.05). Racial differences in adipocytokines disappeared after adjustment for BMI. At M3, subjects with more number of positive autoantibodies had higher adiponectin levels (p = 0.043) and adiponectin/leptin ratio (ALR) (p = 0.01), and lower leptin levels (p = 0.016). CONCLUSION: Adiponectin levels increased acutely with insulin therapy. Significantly lower adiponectin levels in AA were related to greater adiposity and not race. These pilot data showing those with the fewest autoantibodies had the lowest adiponectin levels, supporting the concept that insulin-resistant subjects may present with clinical T1D at earlier stages of ß-cell damage.

A study of the genus Limnophora Robineau-Desvoidy (Diptera: Muscidae), with descriptions of six new species from China.

This paper provides the characters of genus Limnophora (Diptera: Muscidae) and a key to the Chinese species of Limnophora, six new species collected from Hainan Island of China, namely, L. brevispatula, n. sp., L. cothurnosurstyla, n. sp., L. dyadocerca, n. sp., L. longitarsis, n. sp., L. nuditibia, n. sp. and L. ypocerca, n. sp. are diagnosed, described and illustrated, a new record species in China, namely, L. argentifrons ( Shinonaga et Kano, 1977 ), is also included.

Production and properties of an inhibitor of the Pseudomonas autoinducer by Pseudomonas aeruginosa.

An inhibitor was found in the culture fluid of Pseudomonas aeruginosa PAO1, which could inhibit the activity of the Pseudomonas autoinducer (PAI). The maximal inhibitory activity occurred in stationary phase culture sup ernatant. The PAI inhibitor did not influence the cell growth and the PAI production by P. aeruginosa PAO1 when the PAI inhibitor was added into culture medium. The induced expression of lacZ in the reporter strain Agrobacterium tumefaciens NT1 was suppressed by this PAI inhibitor, whereas inhibition could be relieved by increasing the auto inducer concentration. The quorum sensing of P. aeruginosa was inhibited presumably by inhibiting the inducing activity of Pseudomonas autoinducer but not by inhibiting the production of Pseudomonas autoinducer. It was demonstrated that the structure of the PAI inhibitor was different from that of acyl-homoserine lactones.