Retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks

The retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks are derived and studied in replica-symmetric mean-field theory generalizing earlier works on either the fully connected or the symmetrical extremely diluted network. Capacity-gain parameter phase diagrams are obtained for the Q=3, Q=4 and $Q=\infty$ state networks with uniformly distributed patterns of low activity in order to search for the effects of a gradual dilution of the synapses. It is shown that enlarged regions of continuous changeover into a region of optimal performance are obtained for finite stochastic noise and small but finite connectivity. The de Almeida-Thouless lines of stability are obtained for arbitrary connectivity, and the resulting phase diagrams are used to draw conclusions on the behavior of symmetrically diluted networks with other pattern distributions of either high or low activity.Comment: 21 pages, revte

Parisi Phase in a Neuron

Pattern storage by a single neuron is revisited. Generalizing Parisi's framework for spin glasses we obtain a variational free energy functional for the neuron. The solution is demonstrated at high temperature and large relative number of examples, where several phases are identified by thermodynamical stability analysis, two of them exhibiting spontaneous full replica symmetry breaking. We give analytically the curved segments of the order parameter function and in representative cases compute the free energy, the storage error, and the entropy.Comment: 4 pages in prl twocolumn format + 3 Postscript figures. Submitted to Physical Review Letter

Storage capacity of a constructive learning algorithm

Upper and lower bounds for the typical storage capacity of a constructive algorithm, the Tilinglike Learning Algorithm for the Parity Machine [M. Biehl and M. Opper, Phys. Rev. A {\bf 44} 6888 (1991)], are determined in the asymptotic limit of large training set sizes. The properties of a perceptron with threshold, learning a training set of patterns having a biased distribution of targets, needed as an intermediate step in the capacity calculation, are determined analytically. The lower bound for the capacity, determined with a cavity method, is proportional to the number of hidden units. The upper bound, obtained with the hypothesis of replica symmetry, is close to the one predicted by Mitchinson and Durbin [Biol. Cyber. {\bf 60} 345 (1989)].Comment: 13 pages, 1 figur

Chaotic Interaction of Langmuir Solitons and Long Wavelength Radiation

In this work we analyze the interaction of isolated solitary structures and ion-acoustic radiation. If the radiation amplitude is small solitary structures persists, but when the amplitude grows energy transfer towards small spatial scales occurs. We show that transfer is particularly fast when a fixed point of a low dimensional model is destroyed.Comment: LaTex + 4 eps file

Impaired p53-Mediated DNA Damage Response Contributes to Microcephaly in Nijmegen Breakage Syndrome Patient-Derived Cerebral Organoids

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within nibrin (NBN), a DNA damage repair protein. Hallmarks of NBS include chromosomal instability and clinical manifestations such as growth retardation, immunodeficiency, and progressive microcephaly. We employed induced pluripotent stem cell-derived cerebral organoids from two NBS patients to study the etiology of microcephaly. We show that NBS organoids carrying the homozygous 657del5 NBN mutation are significantly smaller with disrupted cyto-architecture. The organoids exhibit premature differentiation, and Neuronatin (NNAT) over-expression. Furthermore, pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. After exposure to bleomycin, NBS organoids undergo delayed p53-mediated DNA damage response and aberrant trans-synaptic signaling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders

Localization of substance P-like and enkephalin-like immunoreactivity within preganglionic terminals of the avian ciliary ganglion: light and electron microscopy

The avian ciliary ganglion receives its only recognized input from the nucleus of Edinger-Westphal. This is known to be a cholinergic input. In the present study, using fluorescein isothiocyanate and peroxidase- antiperoxidase immunohistochemical methods, substance P-like and enkephalin-like immunoreactivity has been found within preganglionic terminals of the avian ciliary ganglion. The ciliary ganglion is known to consist of two distinct cell populations: small choroid cells that project to the smooth muscle coat of the choroid and large ciliary neurons that send axons to both the iris and the ciliary body. Preganglionic terminals on choroid cells consist of small boutonal endings, whereas ciliary neurons receive a calyx-like cap ending around the hilus of the cell. Substance P-like and enkephalin-like immunoreactivity was localized to preganglionic axons and to both boutonal and calyx-like terminations upon cells of the ciliary ganglion. Electron microscopic studies of both substance P-like and enkephalin-like immunoreactive terminals revealed small clear core vesicles (approximately 58 nm in diameter) and two sizes of dense core vesicles (approximately 85 and approximately 119 nm in diameter). Immunoreactive staining was observed only in the smaller dense core vesicles. The unlabeled clear core vesicles were clustered at synaptic release sites, while the immunoreactive and larger unlabeled dense core vesicles usually were not near these synaptic specializations. These observations strongly imply that neuropeptides co-occur with acetylcholine in preganglionic axons of the ciliary ganglion

Optimally adapted multi-state neural networks trained with noise

The principle of adaptation in a noisy retrieval environment is extended here to a diluted attractor neural network of Q-state neurons trained with noisy data. The network is adapted to an appropriate noisy training overlap and training activity which are determined self-consistently by the optimized retrieval attractor overlap and activity. The optimized storage capacity and the corresponding retriever overlap are considerably enhanced by an adequate threshold in the states. Explicit results for improved optimal performance and new retriever phase diagrams are obtained for Q=3 and Q=4, with coexisting phases over a wide range of thresholds. Most of the interesting results are stable to replica-symmetry-breaking fluctuations.Comment: 22 pages, 5 figures, accepted for publication in PR

Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial

BACKGROUND: Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m^{2} or at least 27 kg/m^{2} with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants. FINDINGS: Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%). INTERPRETATION: Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. FUNDING: Novo Nordisk A/S